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Miklos DB, Riedell PA, Bokun A, Chavez JC, Schuster SJ. Leveraging the Immunomodulatory Potential of Ibrutinib for Improved Outcomes of T Cell-Mediated Therapies of B Cell Malignancies: A Narrative Review. Target Oncol 2025; 20:217-234. [PMID: 40035913 PMCID: PMC11933223 DOI: 10.1007/s11523-025-01133-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/10/2025] [Indexed: 03/06/2025]
Abstract
Standard treatment options for B cell malignancies include immunochemotherapies and/or targeted therapies, which often provide temporary disease remission. However, many patients do not achieve complete remission with these treatments, develop resistance, and eventually experience disease relapse. New immunomodulatory treatments, such as T cell-based therapies, show promise in treating various types of blood cancers, including B cell malignancies. However, their effectiveness is often limited by the immunosuppressive tumor microenvironment and altered function of patient-derived T cells. Ibrutinib, a Bruton tyrosine kinase inhibitor, has been shown to restore immune balance and function in patients with chronic lymphocytic leukemia. Ibrutinib is being studied as adjuvant or combinatorial therapy with chimeric antigen receptor (CAR) T cells or T cell-engaging bispecific antibodies for the treatment of B cell malignancies. Current evidence suggests that ibrutinib could be beneficial when used before, during, or after CAR T cell administration, potentially providing higher complete response rates and reduced toxicity. In conclusion, existing evidence strongly supports the combined use of ibrutinib and T cell therapies. However, additional clinical trials are needed to further validate the effectiveness of this treatment strategy in patients with various B cell malignancies.
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Affiliation(s)
- David B Miklos
- Stanford University School of Medicine, Stanford, CA, USA
| | - Peter A Riedell
- David and Etta Jonas Center for Cellular Therapy, The University of Chicago, Chicago, IL, USA
| | - Alex Bokun
- Janssen Biotech, Inc., a Johnson & Johnson company, Horsham, PA, USA.
| | - Julio C Chavez
- Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL, USA
| | - Stephen J Schuster
- Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
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2
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Liu J, Zhao Y, Zhao H. Chimeric antigen receptor T-cell therapy in autoimmune diseases. Front Immunol 2024; 15:1492552. [PMID: 39628482 PMCID: PMC11611814 DOI: 10.3389/fimmu.2024.1492552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Accepted: 10/28/2024] [Indexed: 12/06/2024] Open
Abstract
The administration of T cells that have been modified to carry chimeric antigen receptors (CARs) aimed at B cells has been an effective strategy in treating B cell malignancies. This breakthrough has spurred the creation of CAR T cells intended to specifically reduce or alter the faulty immune responses associated with autoimmune disorders. Early positive outcomes from clinical trials involving CAR T cells that target the B cell protein CD19 in patients suffering from autoimmune diseases driven by B cells have been reported. Additional strategies are being developed to broaden the use of CAR T cell therapy and enhance its safety in autoimmune conditions. These include employing chimeric autoantireceptors (CAAR) to specifically eliminate B cells that are reactive to autoantigens, and using regulatory T cells (Tregs) engineered to carry antigen-specific CARs for precise immune modulation. This discussion emphasizes key factors such as choosing the right target cell groups, designing CAR constructs, defining tolerable side effects, and achieving a lasting immune modification, all of which are critical for safely integrating CAR T cell therapy in treating autoimmune diseases.
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MESH Headings
- Humans
- Autoimmune Diseases/therapy
- Autoimmune Diseases/immunology
- Receptors, Chimeric Antigen/immunology
- Receptors, Chimeric Antigen/genetics
- Immunotherapy, Adoptive/methods
- Immunotherapy, Adoptive/adverse effects
- Animals
- T-Lymphocytes/immunology
- T-Lymphocytes/transplantation
- T-Lymphocytes, Regulatory/immunology
- B-Lymphocytes/immunology
- Receptors, Antigen, T-Cell/immunology
- Receptors, Antigen, T-Cell/genetics
- Autoantigens/immunology
- Antigens, CD19/immunology
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Affiliation(s)
- Jie Liu
- Department of Neurosurgery, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Yan Zhao
- Department of Respiratory, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Hai Zhao
- Department of Neurosurgery, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
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3
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Chung JB, Brudno JN, Borie D, Kochenderfer JN. Chimeric antigen receptor T cell therapy for autoimmune disease. Nat Rev Immunol 2024; 24:830-845. [PMID: 38831163 DOI: 10.1038/s41577-024-01035-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/17/2024] [Indexed: 06/05/2024]
Abstract
Infusion of T cells engineered to express chimeric antigen receptors (CARs) that target B cells has proven to be a successful treatment for B cell malignancies. This success inspired the development of CAR T cells to selectively deplete or modulate the aberrant immune responses that underlie autoimmune disease. Promising results are emerging from clinical trials of CAR T cells targeting the B cell protein CD19 in patients with B cell-driven autoimmune diseases. Further approaches are being designed to extend the application and improve safety of CAR T cell therapy in the setting of autoimmunity, including the use of chimeric autoantibody receptors to selectively deplete autoantigen-specific B cells and the use of regulatory T cells engineered to express antigen-specific CARs for targeted immune modulation. Here, we highlight important considerations, such as optimal target cell populations, CAR construct design, acceptable toxicities and potential for lasting immune reset, that will inform the eventual safe adoption of CAR T cell therapy for the treatment of autoimmune diseases.
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Affiliation(s)
| | - Jennifer N Brudno
- Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | | | - James N Kochenderfer
- Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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4
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Gamal W, Mediavilla-Varela M, Uriepero-Palma A, Pinilla-Ibarz J, Sahakian E. Optimization of In Vitro Th17 Polarization for Adoptive Cell Therapy in Chronic Lymphocytic Leukemia. Int J Mol Sci 2024; 25:6324. [PMID: 38928031 PMCID: PMC11203624 DOI: 10.3390/ijms25126324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 05/22/2024] [Accepted: 06/02/2024] [Indexed: 06/28/2024] Open
Abstract
Although preclinical investigations have shown notable efficacy in solid tumor models utilizing in vitro-differentiated Th17 cells for adoptive cell therapy (ACT), the potential benefits of this strategy in enhancing ACT efficacy in hematological malignancies, such as chronic lymphocytic leukemia (CLL), remain unexplored. CLL is a B-cell malignancy with a clinical challenge of increased resistance to targeted therapies. T-cell therapies, including chimeric antigen receptor (CAR) T cells, have demonstrated limited success in CLL, which is attributed to CLL-mediated T-cell dysfunction and skewing toward immunosuppressive phenotypes. Herein, we illustrate the feasibility of polarizing CD4+ T cells from the Eμ-TCL1 murine model, the most representative model for human CLL, into Th17 phenotype, employing a protocol of T-cell activation through the inducible co-stimulator (ICOS) alongside a polarizing cytokine mixture. We demonstrate augmented memory properties of in vitro-polarized IL-17-producing T cells, and preliminary in vivo persistence in leukemia-bearing mice. Our findings gain translational relevance through successful viral transduction of Eμ-TCL1 CD4+ T cells with a CD19-targeted CAR construct during in vitro Th17 polarization. Th17 CAR T cells exhibited remarkable persistence upon encountering antigen-expressing target cells. This study represents the first demonstration of the potential of in vitro-differentiated Th17 cells to enhance ACT efficacy in CLL.
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MESH Headings
- Leukemia, Lymphocytic, Chronic, B-Cell/therapy
- Leukemia, Lymphocytic, Chronic, B-Cell/immunology
- Animals
- Th17 Cells/immunology
- Mice
- Immunotherapy, Adoptive/methods
- Humans
- Lymphocyte Activation/immunology
- Receptors, Chimeric Antigen/immunology
- Receptors, Chimeric Antigen/metabolism
- Cell Differentiation
- Disease Models, Animal
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Affiliation(s)
- Wael Gamal
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
| | | | - Angimar Uriepero-Palma
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
| | - Javier Pinilla-Ibarz
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
- Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
| | - Eva Sahakian
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
- Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
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Yıldırım C. Galectin-9, a pro-survival factor inducing immunosuppression, leukemic cell transformation and expansion. Mol Biol Rep 2024; 51:571. [PMID: 38662155 DOI: 10.1007/s11033-024-09563-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Accepted: 04/17/2024] [Indexed: 04/26/2024]
Abstract
Leukemia is a malignancy of the bone marrow and blood originating from self-renewing cancerous immature blast cells or transformed leukocytes. Despite improvements in treatments, leukemia remains still a serious disease with poor prognosis because of disease heterogeneity, drug resistance and relapse. There is emerging evidence that differentially expression of co-signaling molecules play a critical role in tumor immune evasion. Galectin-9 (Gal-9) is one of the key proteins that leukemic cells express, secrete, and use to proliferate, self-renew, and survive. It also suppresses host immune responses controlled by T and NK cells, enabling leukemic cells to evade immune surveillance. The present review provides the molecular mechanisms of Gal-9-induced immune evasion in leukemia. Understanding the complex immune evasion machinery driven by Gal-9 expressing leukemic cells will enable the identification of novel therapeutic strategies for efficient immunotherapy in leukemic patients. Combined treatment approaches targeting T-cell immunoglobulin and mucin domain-3 (Tim-3)/Gal-9 and other immune checkpoint pathways can be considered, which may enhance the efficacy of host effector cells to attack leukemic cells.
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Affiliation(s)
- Cansu Yıldırım
- Atatürk Vocational School of Health Services, Afyonkarahisar Health Sciences University, Afyonkarahisar, Turkey.
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Francis ER, Vu J, Perez CO, Sun C. Vaccinations in patients with chronic lymphocytic leukemia. Semin Hematol 2024; 61:131-138. [PMID: 38302313 PMCID: PMC11162341 DOI: 10.1053/j.seminhematol.2024.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 12/04/2023] [Accepted: 01/02/2024] [Indexed: 02/03/2024]
Abstract
Chronic lymphocytic leukemia (CLL) is characterized by immune dysfunction resulting in heightened susceptibility to infections and elevated rates of morbidity and mortality. A key strategy to mitigate infection-related complications has been immunization against common pathogens. However, the immunocompromised status of CLL patients poses challenges in eliciting an adequate humoral and cellular immune response to vaccination. Most CLL-directed therapy disproportionately impairs humoral immunity. Vaccine responsiveness also depends on the phase and type of immune response triggered by immunization. In this review, we discuss the immune dysfunction, vaccine responsiveness, and considerations for optimizing vaccine response in patients with CLL.
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Affiliation(s)
| | - Jennifer Vu
- Rosalind Franklin University of Medicine and Science, Chicago Medical School
| | | | - Clare Sun
- National Institutes of Health, National Heart, Lung, and Blood Institute.
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Lopresti L, Capitani N, Tatangelo V, Tangredi C, Boncompagni G, Frezzato F, Visentin A, Marotta G, Ciofini S, Gozzetti A, Bocchia M, Trentin L, Baldari CT, Patrussi L. p66Shc deficiency in CLL cells enhances PD-L1 expression and suppresses immune synapse formation. Front Cell Dev Biol 2024; 12:1297116. [PMID: 38389706 PMCID: PMC10883382 DOI: 10.3389/fcell.2024.1297116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 01/08/2024] [Indexed: 02/24/2024] Open
Abstract
Introduction: Escape from immunosurveillance is a hallmark of chronic lymphocytic leukemia (CLL) cells. In the protective niche of lymphoid organs, leukemic cells suppress the ability of T lymphocytes to form the immune synapse (IS), thereby hampering T-cell mediated anti-tumoral activities. By binding its cognate receptor PD-1 at the surface of T lymphocytes, the inhibitory ligand PD-L1, which is overexpressed in CLL cells, mediates the T-cell suppressive activities of CLL cells. However, the molecular mechanism underlying PD-L1 overexpression in CLL cells remains unknown. We have previously reported a defective expression of the pro-apoptotic and pro-oxidant adaptor p66Shc in CLL cells, which is causally related to an impairment in intracellular reactive oxygen species (ROS) production and to the activation of the ROS-sensitive transcription factor NF-κB. The fact that PD-L1 expression is regulated by NF-κB suggests a mechanistic relationship between p66Shc deficiency and PD-L1 overexpression in CLL cells. Methods: 62 treatment-naive CLL patients and 43 healthy donors were included in this study. PD-L1 and p66Shc expression was quantified in B cells by flow cytometry and qRT-PCR. IS architecture and local signaling was assessed by flow cytometry and confocal microscopy. CD8+ cell killing activity was assessed by flow cytometry. Results: Here we show that residual p66Shc expression in leukemic cells isolated both from CLL patients and from the CLL mouse model Eμ-TCL1 inversely correlated with PD-L1 expression. We also show that the PD-L1 increase prevented leukemic cells from forming ISs with T lymphocytes. Reconstitution of p66Shc, but not of a ROS-defective mutant, in both CLL cells and the CLL-derived cell line MEC-1, enhanced intracellular ROS and decreased PD-L1 expression. Similar results were obtained following treatment of CLL cells with H2O2 as exogenous source of ROS, that normalized PD-L1 expression and recovered IS formation. Discussion: Our data provide direct evidence that the p66Shc-deficiency-related ROS depletion in CLL cells concurs to enhance PD-L1 expression and provides a mechanistic basis for the suppression of T cell-mediated anti-tumoral functions in the immunosuppressive lymphoid niche.
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Affiliation(s)
| | - Nagaja Capitani
- Department of Life Sciences, University of Siena, Siena, Italy
| | | | | | | | - Federica Frezzato
- Hematology and Clinical Immunology Unit, Department of Medicine, University of Padua, Padua, Italy
| | - Andrea Visentin
- Hematology and Clinical Immunology Unit, Department of Medicine, University of Padua, Padua, Italy
| | - Giuseppe Marotta
- Stem Cell Transplant and Cellular Therapy Unit, University Hospital, Siena, Italy
| | - Sara Ciofini
- Department of Medical Science, Surgery and Neuroscience, University of Siena, Siena, Italy
| | - Alessandro Gozzetti
- Department of Medical Science, Surgery and Neuroscience, University of Siena, Siena, Italy
| | - Monica Bocchia
- Department of Medical Science, Surgery and Neuroscience, University of Siena, Siena, Italy
| | - Livio Trentin
- Hematology and Clinical Immunology Unit, Department of Medicine, University of Padua, Padua, Italy
| | | | - Laura Patrussi
- Department of Life Sciences, University of Siena, Siena, Italy
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8
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Li H, Cao GM, Gu GL, Li SY, Yan Y, Fu Z, Du XH. Expression characteristics of peripheral lymphocyte programmed death 1 and FoxP3 + Tregs in gastric cancer during surgery and chemotherapy. World J Gastroenterol 2023; 29:5582-5592. [PMID: 37970473 PMCID: PMC10642441 DOI: 10.3748/wjg.v29.i40.5582] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 08/31/2023] [Accepted: 10/11/2023] [Indexed: 10/27/2023] Open
Abstract
BACKGROUND Programmed death 1 (PD-1) and CD4+CD25+FoxP3+ expression in peripheral blood T-cells has been previously reported in various types of cancer. However, the specific variation tendency during surgery and chemotherapy, as well as their relationship in gastric cancer patients, still remain unclear. Understanding this aspect may provide some novel insights for future studies on tumor recurrence and tumor immune escape, and also serve as a reference for determining the optimal timing and dose of clinical anti-PD-1 antibodies. AIM To observe and analyze the expression characteristics of peripheral lymphocyte PD-1 and FoxP3+ regulatory T cells (FoxP3+ Tregs) before and after surgery or chemotherapy in gastric cancer patients. METHODS Twenty-nine stomach cancer patients undergoing chemotherapy after a D2 gastrectomy provided 10 mL peripheral blood samples at each phase of the perioperative period and during chemotherapy. This study also included 29 age-matched healthy donors as a control group. PD-1 expression was detected on lymphocytes, including CD4+CD8+CD45RO+, CD4+CD45RO+, and CD8+CD45RO+ lymphocytes as well as regulatory T cells. RESULTS We observed a significant increase of PD-1 expression on immune subsets and a larger number of FoxP3+ Tregs in gastric cancer patients (P < 0.05). Following D2 gastrectomy, peripheral lymphocytes PD-1 expression and the number of FoxP3+ Tregs notably decrease (P < 0.05). However, during postoperative chemotherapy, we only observed a decrease in PD-1 expression on lymphocytes in the CD8+CD45RO+ and CD8+CD45RO+ populations. Additionally, linear correlation analysis indicated a positive correlation between PD-1 expression and the number of CD4+CD45RO+FoxP3high activated Tregs (aTregs) on the total peripheral lymphocytes (r = 0.5622, P < 0.0001). CONCLUSION The observed alterations in PD-1 expression and the activation of regulatory T cells during gastric cancer treatment may offer novel insights for future investigations into tumor immune evasion and the clinical application of anti-PD-1 antibodies in gastric cancer.
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Affiliation(s)
- Hao Li
- Graduate School, Medical School of Chinese People’s Liberation Army, Beijing 100039, China
- Department of General Surgery, Air Force Medical Center, Air Force Medical University, Beijing 100142, China
| | - Guan-Mei Cao
- Department of Radiology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Guo-Li Gu
- Department of General Surgery, Air Force Medical Center, Air Force Medical University, Beijing 100142, China
| | - Song-Yan Li
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100039, China
| | - Yang Yan
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100039, China
| | - Ze Fu
- Graduate School, Medical School of Chinese People’s Liberation Army, Beijing 100039, China
| | - Xiao-Hui Du
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100039, China
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9
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Gamal W, Sahakian E, Pinilla-Ibarz J. The role of Th17 cells in chronic lymphocytic leukemia: friend or foe? Blood Adv 2023; 7:2401-2417. [PMID: 36574293 PMCID: PMC10238851 DOI: 10.1182/bloodadvances.2022008985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 12/18/2022] [Indexed: 12/28/2022] Open
Abstract
T helper 17 (Th17) cells have a prominent role in autoimmune diseases. In contrast, the nature of these cells in cancer is controversial, with either pro- or antitumorigenic activities depending on various cancer settings. Chronic lymphocytic leukemia (CLL), a B-cell malignancy, is characterized by an imbalance in T-cell immune responses that contributes to disease progression and increased mortality. Many clinical reports indicate an increase in Th17 cells and/or interleukin 17 serum cytokine levels in patients with CLL compared with healthy individuals, which correlates with various prognostic markers and significant changes in the tumor microenvironment. The exact mechanisms by which Th17 cells might contribute to CLL progression remain poorly investigated. In this review, we provide an updated presentation of the clinical information related to the significance of Th17 cells in CLL and their interaction with the complex leukemic microenvironment, including various mediators, immune cells, and nonimmune cells. We also address the available data regarding the effects of CLL-targeted therapies on Th17 cells and the potential of using these cells in adoptive cell therapies. Having a sound understanding of the role played by Th17 cells in CLL is crucial for designing novel therapies that can achieve immune homeostasis and maximize clinical benefits.
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Affiliation(s)
- Wael Gamal
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL
| | - Eva Sahakian
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
- Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
| | - Javier Pinilla-Ibarz
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
- Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
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10
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Wang W, Ye CH, Deng ZF, Wang JL, Zhang L, Bao L, Xu BH, Zhu H, Guo Y, Wen Z. CD4 +CD25 + regulatory T cells decreased future liver remnant after associating liver partition and portal vein ligation for staged hepatectomy. World J Gastrointest Surg 2023; 15:917-930. [PMID: 37342857 PMCID: PMC10277939 DOI: 10.4240/wjgs.v15.i5.917] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 12/22/2022] [Accepted: 04/04/2023] [Indexed: 05/26/2023] Open
Abstract
BACKGROUND Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is an innovative surgical approach for the treatment of massive hepatocellular carcinoma (HCC), the key to successful planned stage 2 ALPPS is future liver remnant (FLR) volume growth, but the exact mechanism has not been elucidated. The correlation between regulatory T cells (Tregs) and postoperative FLR regeneration has not been reported. AIM To investigate the effect of CD4+CD25+ Tregs on FLR regeneration after ALPPS. METHODS Clinical data and specimens were collected from 37 patients who developed massive HCC treated with ALPPS. Flow cytometry was performed to detect changes in the proportion of CD4+CD25+ Tregs to CD4+ T cells in peripheral blood before and after ALPPS. To analyze the relationship between peripheral blood CD4+CD25+ Treg proportion and clinicopathological information and liver volume. RESULTS The postoperative CD4+CD25+ Treg proportion in stage 1 ALPPS was negatively correlated with the amount of proliferation volume, proliferation rate, and kinetic growth rate (KGR) of the FLR after stage 1 ALPPS. Patients with low Treg proportion had significantly higher KGR than those with high Treg proportion (P = 0.006); patients with high Treg proportion had more severe postoperative pathological liver fibrosis than those with low Treg proportion (P = 0.043). The area under the receiver operating characteristic curve between the percentage of Tregs and proliferation volume, proliferation rate, and KGR were all greater than 0.70. CONCLUSION CD4+CD25+ Tregs in the peripheral blood of patients with massive HCC at stage 1 ALPPS were negatively correlated with indicators of FLR regeneration after stage 1 ALPPS and may influence the degree of fibrosis in patients' livers. Treg percentage was highly accurate in predicting the FLR regeneration after stage 1 ALPPS.
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Affiliation(s)
- Wei Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Chun-Hui Ye
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Zhen-Feng Deng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Ji-Long Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Ling Zhang
- Department of Radiology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Li Bao
- Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300000, China
| | - Bang-Hao Xu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Hai Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Ya Guo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Zhang Wen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
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11
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Peng Y, Tao Y, Zhang Y, Wang J, Yang J, Wang Y. CD25: A potential tumor therapeutic target. Int J Cancer 2023; 152:1290-1303. [PMID: 36082452 DOI: 10.1002/ijc.34281] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 07/17/2022] [Accepted: 08/08/2022] [Indexed: 02/03/2023]
Abstract
CD25 is the alpha-chain of the heterotrimer IL-2 receptor. CD25 is expressed on the surface of both immune and non-immune cells with different frequencies. For cancers, CD25 is expressed at high levels in many types of hematological malignancies, but at low levels in most solid tumors. CD25 is also highly expressed in activated circulating immune cells and regulatory T cells (Tregs). Infiltration of Tregs in the tumor microenvironment can lead to an imbalanced ratio of effector T cells (Teffs) and Tregs, which is associated with the progression of cancers. A rescued Teff/Treg cell ratio indicates an efficient anti-tumor response to immunotherapy. CD25 as a potential target for the depletion of Tregs is critical in developing new immunotherapeutic strategies. Few articles have summarized the relationships between CD25 and tumors, or the recent progress of drugs targeting CD25. In this paper, we will discuss the structures of IL-2 and IL-2R, the biological function of CD25 and its important role in tumor therapy. In addition, the latest research on drugs targeting CD25 has been summarized, providing guidance for future drug development.
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Affiliation(s)
- Yujia Peng
- State Key Laboratory of Biotherapy, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease- related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.,West China-California Research Center for Predictive Intervention Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China.,Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yiran Tao
- State Key Laboratory of Biotherapy, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease- related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.,West China-California Research Center for Predictive Intervention Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China.,Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ya Zhang
- State Key Laboratory of Biotherapy, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease- related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.,College of Life Sciences, Sichuan University, Chengdu, Sichuan, China
| | - Jiaxing Wang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Jinliang Yang
- State Key Laboratory of Biotherapy, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease- related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yuxi Wang
- State Key Laboratory of Biotherapy, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease- related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.,Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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12
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Breast cancer tumor microenvironment affects Treg/IL-17-producing Treg/Th17 cell axis: Molecular and therapeutic perspectives. Mol Ther Oncolytics 2023; 28:132-157. [PMID: 36816749 PMCID: PMC9922830 DOI: 10.1016/j.omto.2023.01.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
The tumor microenvironment (TME) comprises a variety of immune cells, among which T cells exert a prominent axial role in tumor development or anti-tumor responses in patients with breast cancer (BC). High or low levels of anti-inflammatory cytokines, such as transforming growth factor β, in the absence or presence of proinflammatory cytokines, such as interleukin-6 (IL-6), delineate the fate of T cells toward either regulatory T (Treg) or T helper 17 (Th17) cells, respectively. The transitional state of RORγt+Foxp3+ Treg (IL-17-producing Treg) resides in the middle of this reciprocal polarization, which is known as Treg/IL-17-producing Treg/Th17 cell axis. TME secretome, including microRNAs, cytokines, and extracellular vesicles, can significantly affect this axis. Furthermore, immune checkpoint inhibitors may be used to reconstruct immune cells; however, some of these novel therapies may favor tumor development. Therefore, understanding secretory and cell-associated factors involved in their differentiation or polarization and functions may be targeted for BC management. This review discusses microRNAs, cytokines, and extracellular vesicles (as secretome), as well as transcription factors and immune checkpoints (as cell-associated factors), which influence the Treg/IL-17-producing Treg/Th17 cell axis in BC. Furthermore, approved or ongoing clinical trials related to the modulation of this axis in the TME of BC are described to broaden new horizons of promising therapeutic approaches.
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13
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N6-methyladenosine in hematological malignancies: a concise review. Curr Opin Hematol 2023; 30:4-13. [PMID: 36165537 DOI: 10.1097/moh.0000000000000741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
PURPOSE OF REVIEW Hematological malignancies are a kind of systemic cancers mostly related to abnormal differentiation of blood stem cells. Because of the poor prognosis, chemotherapy resistance and common recurrence, new mechanisms and treatment therapies are looking forward to be discovered. RECENT FINDINGS Over the years, epigenetic abnormalities have been known to act a key part in occurrence and development of hematological tumors. In the internal modifications on long noncoding eukaryotic mRNA, there is a common type called N6-methyladenosine that can change the expression of target genes and participate in the translation, degradation and splicing of mRNA. M6A is related to a wealth of cancers, such as HNRNPA2B1's elevation in multiple myeloma, METTLE3's elevation in acute myeloid leukemia and lung cancer. Immune cells, playing a significant role in hematological cancers, can also be regulated by m6A. SUMMARY In the review, we summarized the recent progress on hematological malignancies associating with m6A and immune cells, which may offer a new road for the treatment of them.
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14
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Bogacka J, Pawlik K, Ciapała K, Ciechanowska A, Mika J. CC Chemokine Receptor 4 (CCR4) as a Possible New Target for Therapy. Int J Mol Sci 2022; 23:ijms232415638. [PMID: 36555280 PMCID: PMC9779674 DOI: 10.3390/ijms232415638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 11/30/2022] [Accepted: 12/05/2022] [Indexed: 12/14/2022] Open
Abstract
Chemokines and their receptors participate in many biological processes, including the modulation of neuroimmune interactions. Approximately fifty chemokines are distinguished in humans, which are classified into four subfamilies based on the N-terminal conserved cysteine motifs: CXC, CC, C, and CX3C. Chemokines activate specific receptors localized on the surface of various immune and nervous cells. Approximately twenty chemokine receptors have been identified, and each of these receptors is a seven-transmembrane G-protein coupled receptor. Recent studies provide new evidence that CC chemokine receptor 4 (CCR4) is important in the pathogenesis of many diseases, such as diabetes, multiple sclerosis, asthma, dermatitis, and cancer. This review briefly characterizes CCR4 and its ligands (CCL17, CCL22, and CCL2), and their contributions to immunological and neoplastic diseases. The review notes a significant role of CCR4 in nociceptive transmission, especially in painful neuropathy, which accompanies many diseases. The pharmacological blockade of CCR4 seems beneficial because of its pain-relieving effects and its influence on opioid efficacy. The possibilities of using the CCL2/CCL17/CCL22/CCR4 axis as a target in new therapies for many diseases are also discussed.
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Affiliation(s)
| | | | | | | | - Joanna Mika
- Correspondence: or ; Tel.: +48-12-6623-298; Fax: +48-12-6374-500
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15
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Vodárek P, Écsiová D, Řezáčová V, Souček O, Šimkovič M, Vokurková D, Belada D, Žák P, Smolej L. A comprehensive assessment of lymphocyte subsets, their prognostic significance, and changes after first‐line therapy administration in patients with chronic lymphocytic leukemia. Cancer Med 2022; 12:6956-6970. [PMID: 36440594 PMCID: PMC10067047 DOI: 10.1002/cam4.5492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 10/03/2022] [Accepted: 11/18/2022] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND In chronic lymphocytic leukemia (CLL), changes in the peripheral blood lymphocyte subsets play an important role in disease progression and infectious complications. The impact of chemoimmunotherapy (CIT) on these changes has not been extensively studied METHODS: We used multi-color flow cytometry, to prospectively measure absolute and relative numbers of CD4+ and CD8+ T-cells and their subsets in 45 patients with indolent untreated CLL, 86 patients indicated for first-line treatment, and 34 healthy controls. In 55 patients, we analyzed the impact of CIT RESULTS: CLL patients had a significant increase in most cell populations in comparison to controls. Progression of CLL was characterized by significantly elevated counts with the exception of a lower percentage of naïve T-cells. After treatment, the percentage of naïve T-cells further decreased at the expense of effector memory T-cells (TEM). In patients with indolent CLL, higher percentages of naïve CD4+ (p = 0.0026) and naïve CD8+ (p = 0.023) T-cells were associated with a longer time to first treatment (TTFT). The elevation of CD4+ central memory T-cells (TCM) (p = 0.27) and TEM (p = 0.003) counts and a higher percentage of CD4+ TEM (p = 0.0047), were linked with shorter TTFT. In treated patients, increased regulatory T-cells count was associated with shorter time to next treatment (TTNT) (p = 0.042), while higher CD4+ TCM count with shorter TTNT (p = 0.035) and shorter overall survival (p = 0.041). CONCLUSION Our results indicate that naïve cell depletion and CD4+ TCM and TEM increases are detrimental to CLL patients' prognosis.
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Affiliation(s)
- Pavel Vodárek
- 4th Department of Internal Medicine – Hematology Faculty of Medicine University Hospital and Charles University Hradec Kralove Czech Republic
| | - Dominika Écsiová
- 4th Department of Internal Medicine – Hematology Faculty of Medicine University Hospital and Charles University Hradec Kralove Czech Republic
| | - Vladimíra Řezáčová
- Institute of Clinical Immunology and Allergology Faculty of Medicine University Hospital and Charles University Hradec Kralove Czech Republic
| | - Ondřej Souček
- Institute of Clinical Immunology and Allergology Faculty of Medicine University Hospital and Charles University Hradec Kralove Czech Republic
| | - Martin Šimkovič
- 4th Department of Internal Medicine – Hematology Faculty of Medicine University Hospital and Charles University Hradec Kralove Czech Republic
| | - Doris Vokurková
- Institute of Clinical Immunology and Allergology Faculty of Medicine University Hospital and Charles University Hradec Kralove Czech Republic
| | - David Belada
- 4th Department of Internal Medicine – Hematology Faculty of Medicine University Hospital and Charles University Hradec Kralove Czech Republic
| | - Pavel Žák
- 4th Department of Internal Medicine – Hematology Faculty of Medicine University Hospital and Charles University Hradec Kralove Czech Republic
| | - Lukáš Smolej
- 4th Department of Internal Medicine – Hematology Faculty of Medicine University Hospital and Charles University Hradec Kralove Czech Republic
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16
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Yano M, Byrd JC, Muthusamy N. Natural Killer Cells in Chronic Lymphocytic Leukemia: Functional Impairment and Therapeutic Potential. Cancers (Basel) 2022; 14:cancers14235787. [PMID: 36497266 PMCID: PMC9739887 DOI: 10.3390/cancers14235787] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 11/07/2022] [Accepted: 11/21/2022] [Indexed: 11/27/2022] Open
Abstract
Immunotherapy approaches have advanced rapidly in recent years. While the greatest therapeutic advances so far have been achieved with T cell therapies such as immune checkpoint blockade and CAR-T, recent advances in NK cell therapy have highlighted the therapeutic potential of these cells. Chronic lymphocytic leukemia (CLL), the most prevalent form of leukemia in Western countries, is a very immunosuppressive disease but still shows significant potential as a target of immunotherapy, including NK-based therapies. In addition to their antileukemia potential, NK cells are important immune effectors in the response to infections, which represent a major clinical concern for CLL patients. Here, we review the interactions between NK cells and CLL, describing functional changes and mechanisms of CLL-induced NK suppression, interactions with current therapeutic options, and the potential for therapeutic benefit using NK cell therapies.
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Affiliation(s)
- Max Yano
- Medical Science Training Program, The Ohio State University College of Medicine, Columbus, OH 43210, USA
| | - John C. Byrd
- Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
- Correspondence: (J.C.B.); (N.M.)
| | - Natarajan Muthusamy
- Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA
- Correspondence: (J.C.B.); (N.M.)
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17
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Zhu Y, Gan X, Qin R, Lin Z. Identification of Six Diagnostic Biomarkers for Chronic Lymphocytic Leukemia Based on Machine Learning Algorithms. JOURNAL OF ONCOLOGY 2022; 2022:3652107. [PMID: 36467501 PMCID: PMC9715328 DOI: 10.1155/2022/3652107] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 09/13/2022] [Accepted: 09/30/2022] [Indexed: 09/19/2023]
Abstract
BACKGROUND Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults. Thus, novel reliable biomarkers need to be further explored to increase diagnostic, therapeutic, and prognostic effectiveness. METHODS Six datasets containing CLL and control samples were downloaded from the Gene Expression Omnibus database. Differential gene expression analysis, weighted gene coexpression network analysis (WGCNA), and the least absolute shrinkage and selection operator (LASSO) regression were applied to identify potential diagnostic biomarkers for CLL using R software. The diagnostic performance of the hub genes was then measured by the receiver operating characteristic (ROC) curve analysis. Functional analysis was implemented to uncover the underlying mechanisms. Additionally, correlation analysis was performed to assess the relationship between the hub genes and immunity characteristics. RESULTS A total number of 47 differentially expressed genes (DEGs) and 25 candidate hub genes were extracted through differential gene expression analysis and WGCNA, respectively. Based on the 14 overlapped genes between the DEGs and the candidate hub genes, LASSO regression analysis was used, which identified a final number of six hub genes as potential biomarkers for CLL: ABCA6, CCDC88A, PMEPA1, EBF1, FILIP1L, and TEAD2. The ROC curves of the six genes showed reliable predictive ability in the training and validation cohorts, with all area under the curve (AUC) values over 0.80. Functional analysis revealed an abnormal immune status in the CLL patients. A significant correlation was found between the hub genes and the immune-related pathways, indicating a possible tight connection between the hub genes and tumor immunity in CLL. CONCLUSION This study was based on machine learning algorithms, and we identified six genes that could be possible CLL markers, which may be involved in CLL pathogenesis and progression through immune-related signal pathways.
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Affiliation(s)
- Yidong Zhu
- Department of Traditional Chinese Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Xinjin Gan
- Department of Hematology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Ruoyan Qin
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Zhikang Lin
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
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18
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Dwivedi M, Tiwari S, Kemp EH, Begum R. Implications of regulatory T cells in anti-cancer immunity: from pathogenesis to therapeutics. Heliyon 2022; 8:e10450. [PMID: 36082331 PMCID: PMC9445387 DOI: 10.1016/j.heliyon.2022.e10450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 05/08/2022] [Accepted: 08/22/2022] [Indexed: 11/25/2022] Open
Abstract
Regulatory T cells (Tregs) play an essential role in maintaining immune tolerance and suppressing inflammation. However, Tregs present major hurdle in eliciting potent anti-cancer immune responses. Therefore, curbing the activity of Tregs represents a novel and efficient way towards successful immunotherapy of cancer. Moreover, there is an emerging interest in harnessing Treg-based strategies for augmenting anti-cancer immunity in different types of the disease. This review summarises the crucial mechanisms of Tregs’ mediated suppression of anti-cancer immunity and strategies to suppress or to alter such Tregs to improve the immune response against tumors. Highlighting important clinical studies, the review also describes current Treg-based therapeutic interventions in cancer, and discusses Treg-suppression by molecular targeting, which may emerge as an effective cancer immunotherapy and as an alternative to detrimental chemotherapeutic agents.
Tregs are crucial in maintaining immune tolerance and suppressing inflammation. Tregs present a major obstacle to eliciting potent anti-tumor immune responses. The review summarizes current Treg-based therapeutic interventions in cancer. Treg can be an effective cancer immunotherapy target.
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Affiliation(s)
- Mitesh Dwivedi
- C. G. Bhakta Institute of Biotechnology, Faculty of Science, Uka Tarsadia University, Tarsadi, Surat, Gujarat, 394350, India
- Corresponding author.
| | - Sanjay Tiwari
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli, Lucknow, 226002, Uttar Pradesh, India
| | - E. Helen Kemp
- Department of Oncology and Metabolism, Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield, S10 2RX, UK
| | - Rasheedunnisa Begum
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, 390 002, Gujarat, India
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19
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Liu L, Cheng X, Yang H, Lian S, Jiang Y, Liang J, Chen X, Mo S, Shi Y, Zhao S, Li J, Jiang R, Yang DH, Wu Y. BCL-2 expression promotes immunosuppression in chronic lymphocytic leukemia by enhancing regulatory T cell differentiation and cytotoxic T cell exhaustion. Mol Cancer 2022; 21:59. [PMID: 35193595 PMCID: PMC8862474 DOI: 10.1186/s12943-022-01516-w] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 01/21/2022] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Chronic lymphocytic leukemia (CLL) results in increased susceptibility to infections. T cell dysfunction is not associated with CLL in all patients; therefore, it is important to identify CLL patients with T cell defects. The role of B-cell lymphoma-2 (BCL-2) in CLL has been explored; however, few studies have examined its role in T cells in CLL patients. Herein, we have investigated the regulatory role of BCL-2 in T cells in the CLL tumor microenvironment. METHODS The expression of BCL-2 in T cells was evaluated using flow cytometry. The regulatory roles of BCL-2 were investigated using single-cell RNA sequencing (scRNA-seq) and verified using multi-parameter flow cytometry on CD4 and CD8 T cells. The clinical features of BCL-2 expression in T cells in CLL were also explored. RESULTS We found a significant increase in BCL-2 expression in the T cells of CLL patients (n = 266). Single cell RNA sequencing (scRNA-seq) indicated that BCL-2+CD4+ T cells had the gene signature of increased regulatory T cells (Treg); BCL-2+CD8+ T cells showed the gene signature of exhausted cytotoxic T lymphocytes (CTL); and increased expression of BCL-2 was associated with T cell activation and cellular adhesion. The results from scRNA-seq were verified in peripheral T cells from 70 patients with CLL, wherein BCL-2+CD4+ T cells were enriched with Tregs and had higher expression of interleukin-10 and transforming growth factor-β than BCL-2-CD4+ T cells. BCL-2 expression in CD8+T cells was associated with exhausted cells (PD-1+Tim-3+) and weak expression of granzyme B and perforin. T cell-associated cytokine profiling revealed a negative association between BCL-2+ T cells and T cell activation. Decreased frequencies and recovery functions of BCL-2+T cells were observed in CLL patients in complete remission after treatment with venetoclax. CONCLUSION BCL-2 expression in the T cells of CLL patients is associated with immunosuppression via promotion of Treg abundance and CTL exhaustion.
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Affiliation(s)
- Lu Liu
- Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China.,Key Laboratory of Hematology of Nanjing Medical University, Nanjing, 210029, China
| | - Xianfeng Cheng
- Department of Clinical laboratory, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, 210042, China
| | - Hui Yang
- Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China.,Key Laboratory of Hematology of Nanjing Medical University, Nanjing, 210029, China
| | - Senlin Lian
- Jiangsu Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, China.,State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, Nanjing, 210093, China.,Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Yuegen Jiang
- Department of Clinical laboratory, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, 210042, China
| | - Jinhua Liang
- Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China.,Key Laboratory of Hematology of Nanjing Medical University, Nanjing, 210029, China
| | - Xiao Chen
- Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China.,Key Laboratory of Hematology of Nanjing Medical University, Nanjing, 210029, China
| | - Suo Mo
- Department of Clinical laboratory, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, 210042, China
| | - Yu Shi
- Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China.,Key Laboratory of Hematology of Nanjing Medical University, Nanjing, 210029, China
| | - Sishu Zhao
- Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China.,Key Laboratory of Hematology of Nanjing Medical University, Nanjing, 210029, China
| | - Jianyong Li
- Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China.,Key Laboratory of Hematology of Nanjing Medical University, Nanjing, 210029, China
| | - Runqiu Jiang
- Jiangsu Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, China. .,State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, Nanjing, 210093, China. .,Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China.
| | - Dong-Hua Yang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
| | - Yujie Wu
- Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China. .,Key Laboratory of Hematology of Nanjing Medical University, Nanjing, 210029, China.
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20
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Bonifacio M, Papayannidis C, Lussana F, Fracchiolla N, Annunziata M, Sica S, Delia M, Foà R, Pizzolo G, Chiaretti S. Real-World Multicenter Experience in Tumor Debulking Prior to Blinatumomab Administration in Adult Patients With Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia. Front Oncol 2022; 11:804714. [PMID: 35071008 PMCID: PMC8770323 DOI: 10.3389/fonc.2021.804714] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 12/14/2021] [Indexed: 12/20/2022] Open
Abstract
Blinatumomab is an immunotherapeutic agent with dual specificity for CD3 and CD19 that is approved for the treatment of relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R B-ALL). A steroid based pre-treatment is recommended before administering blinatumomab to patients with a high tumor burden to minimize the risk of tumor lysis syndrome, but the optimal debulking regimen and whether it can improve responses remain unclear. The present study retrospectively evaluated real-world outcomes following tumor debulking and blinatumomab infusion in R/R B-ALL adult patients treated at 7 Italian centers. Data were collected from 34 patients. The choice of the cytoreductive therapy was made by the treating clinician on an individual patient basis; regimens included chemotherapy (n=23), steroids (n=7) and tyrosine kinase inhibitors alone or in combination (n=4). The rate of complete responses (CR) and complete minimal residual disease (MRD) responses in CR patients were 67.6% and 81% respectively, after 2 cycles of blinatumomab. Moreover, among patients with a high tumor burden 50% obtained a CR, with 89% of them also achieving a complete MRD response. Favorable responses were also obtained in patients over 50 years of age at treatment initiation. Overall, 7 of 23 patients in CR after blinatumomab underwent hematopoietic stem cell transplantation. The results of this retrospective study highlight the heterogeneity in the use of pre-blinatumomab tumor debulking in real-life clinical practice. Nonetheless, debulking pre-treatment enhanced responses to blinatumomab compared to historic studies, indicating that this strategy may help to improve outcomes for R/R B-ALL patients.
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Affiliation(s)
| | - Cristina Papayannidis
- "Serágnoli" Institute of Hematology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Federico Lussana
- Hematology and Bone Marrow Transplant Unit, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Nicola Fracchiolla
- Oncohematology Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy
| | - Mario Annunziata
- Hematology Division, Azienda Ospedaliera di Rilievo Nazionale Cardarelli, Naples, Italy
| | - Simona Sica
- Department of Diagnostic Imaging, Oncological Radiotherapy and Hematology, Fondazione Policlinico A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy.,Department of Radiological and Hematological Sciences, Hematology Unit, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Mario Delia
- Hematology and Stem Cell Transplantation Unit, Azienda Ospedaliero-Universitaria Consorziale Policlinico, Bari, Italy
| | - Robin Foà
- Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Giovanni Pizzolo
- Department of Medicine, Section of Hematology, University of Verona, Verona, Italy
| | - Sabina Chiaretti
- Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
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21
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Jiménez-Morales S, Aranda-Uribe IS, Pérez-Amado CJ, Ramírez-Bello J, Hidalgo-Miranda A. Mechanisms of Immunosuppressive Tumor Evasion: Focus on Acute Lymphoblastic Leukemia. Front Immunol 2021; 12:737340. [PMID: 34867958 PMCID: PMC8636671 DOI: 10.3389/fimmu.2021.737340] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 10/27/2021] [Indexed: 01/05/2023] Open
Abstract
Acute lymphoblastic leukemia (ALL) is a malignancy with high heterogeneity in its biological features and treatments. Although the overall survival (OS) of patients with ALL has recently improved considerably, owing to the application of conventional chemo-therapeutic agents, approximately 20% of the pediatric cases and 40-50% of the adult patients relapse during and after the treatment period. The potential mechanisms that cause relapse involve clonal evolution, innate and acquired chemoresistance, and the ability of ALL cells to escape the immune-suppressive tumor response. Currently, immunotherapy in combination with conventional treatment is used to enhance the immune response against tumor cells, thereby significantly improving the OS in patients with ALL. Therefore, understanding the mechanisms of immune evasion by leukemia cells could be useful for developing novel therapeutic strategies.
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Affiliation(s)
- Silvia Jiménez-Morales
- Laboratorio de Genómica del Cáncer, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | - Ivan Sammir Aranda-Uribe
- Laboratorio de Genómica del Cáncer, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
- Departamento de Farmacología, División de Ciencias de la Salud, Universidad de Quintana Roo, Quintana Roo, Mexico
| | - Carlos Jhovani Pérez-Amado
- Laboratorio de Genómica del Cáncer, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
- Programa de Doctorado en Ciencias Bioquímicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Julian Ramírez-Bello
- Departamento de Endocrinología, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Alfredo Hidalgo-Miranda
- Laboratorio de Genómica del Cáncer, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
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Cuesta-Mateos C, Terrón F, Herling M. CCR7 in Blood Cancers - Review of Its Pathophysiological Roles and the Potential as a Therapeutic Target. Front Oncol 2021; 11:736758. [PMID: 34778050 PMCID: PMC8589249 DOI: 10.3389/fonc.2021.736758] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 10/12/2021] [Indexed: 11/23/2022] Open
Abstract
According to the classical paradigm, CCR7 is a homing chemokine receptor that grants normal lymphocytes access to secondary lymphoid tissues such as lymph nodes or spleen. As such, in most lymphoproliferative disorders, CCR7 expression correlates with nodal or spleen involvement. Nonetheless, recent evidence suggests that CCR7 is more than a facilitator of lymphatic spread of tumor cells. Here, we review published data to catalogue CCR7 expression across blood cancers and appraise which classical and novel roles are attributed to this receptor in the pathogenesis of specific hematologic neoplasms. We outline why novel therapeutic strategies targeting CCR7 might provide clinical benefits to patients with CCR7-positive hematopoietic tumors.
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Affiliation(s)
- Carlos Cuesta-Mateos
- Immunology Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria- Instituto la Princesa (IIS-IP), Madrid, Spain.,Immunological and Medicinal Products (IMMED S.L.), Madrid, Spain.,Catapult Therapeutics BV, Lelystad, Netherlands
| | - Fernando Terrón
- Immunological and Medicinal Products (IMMED S.L.), Madrid, Spain.,Catapult Therapeutics BV, Lelystad, Netherlands
| | - Marco Herling
- Clinic of Hematology and Cellular Therapy, University of Leipzig, Leipzig, Germany
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23
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Karabon L, Andrzejczak A, Ciszak L, Tomkiewicz A, Szteblich A, Bojarska-Junak A, Roliński J, Wołowiec D, Wróbel T, Kosmaczewska A. BTLA Expression in CLL: Epigenetic Regulation and Impact on CLL B Cell Proliferation and Ability to IL-4 Production. Cells 2021; 10:cells10113009. [PMID: 34831232 PMCID: PMC8616199 DOI: 10.3390/cells10113009] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/22/2021] [Accepted: 10/31/2021] [Indexed: 12/13/2022] Open
Abstract
In our previous study, while chronic lymphocytic leukemia (CLL) cases showed higher levels of B and T lymphocyte attenuator (BTLA) mRNA compared to controls, lower BTLA protein expression was observed in cases compared to controls. Hence we hypothesize that micro RNA (miR) 155-5p regulates BTLA expression in CLL. In line with earlier data, expression of BTLA mRNA and miR-155-5p is elevated in CLL (p = 0.034 and p = 0.0006, respectively) as well as in MEC-1 cell line (p = 0.009 and 0.016, respectively). Inhibition of miR-155-5p partially restored BTLA protein expression in CLL patients (p = 0.01) and in MEC-1 cell lines (p = 0.058). Additionally, we aimed to evaluate the significance of BTLA deficiency in CLL cells on proliferation and IL-4 production of B cells. We found that secretion of IL-4 is not dependent on BTLA expression, since fractions of BTLA positive and BTLA negative B cells expressing intracellular IL-4 were similar in CLL patients and controls. We demonstrated that in controls the fraction of proliferating cells is lower in BTLA positive than in BTLA negative B cells (p = 0.059), which was not observed in CLL. However, the frequency of BTLA positive Ki67+ B cells in CLL was higher compared to corresponding cells from controls (p = 0.055) while there were no differences between the examined groups regarding frequency of BTLA negative Ki67+ B cells. Our studies suggest that miR-155-5p is involved in BTLA deficiency, affecting proliferation of CLL B cells, which may be one of the mechanisms responsible for CLL pathogenesis.
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MESH Headings
- Aged
- Base Sequence
- Cell Line, Tumor
- Cell Proliferation/genetics
- Epigenesis, Genetic
- Female
- Gene Expression Regulation, Leukemic
- Humans
- Interleukin-4/biosynthesis
- Ki-67 Antigen/metabolism
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Male
- MicroRNAs/genetics
- MicroRNAs/metabolism
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Receptors, Immunologic/genetics
- Receptors, Immunologic/metabolism
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Affiliation(s)
- Lidia Karabon
- Laboratory of Genetics and Epigenetics of Human Diseases, Department of Experimental Therapy, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigl 12 Str., 53-114 Wroclaw, Poland; (A.A.); (A.T.)
- Department and Clinic of Urology and Oncologic Urology, Wroclaw Medical University, Borowska Str. 213, 50-556 Wroclaw, Poland
- Correspondence:
| | - Anna Andrzejczak
- Laboratory of Genetics and Epigenetics of Human Diseases, Department of Experimental Therapy, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigl 12 Str., 53-114 Wroclaw, Poland; (A.A.); (A.T.)
| | - Lidia Ciszak
- Laboratory of Immunopathology, Department of Experimental Therapy, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigl 12 Str., 53-114 Wroclaw, Poland; (L.C.); (A.S.); (A.K.)
| | - Anna Tomkiewicz
- Laboratory of Genetics and Epigenetics of Human Diseases, Department of Experimental Therapy, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigl 12 Str., 53-114 Wroclaw, Poland; (A.A.); (A.T.)
| | - Aleksandra Szteblich
- Laboratory of Immunopathology, Department of Experimental Therapy, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigl 12 Str., 53-114 Wroclaw, Poland; (L.C.); (A.S.); (A.K.)
| | - Agnieszka Bojarska-Junak
- Department of Clinical Immunology, Medical University of Lublin, ul. Chodźki 4a, 20-093 Lublin, Poland; (A.B.-J.); (J.R.)
| | - Jacek Roliński
- Department of Clinical Immunology, Medical University of Lublin, ul. Chodźki 4a, 20-093 Lublin, Poland; (A.B.-J.); (J.R.)
| | - Dariusz Wołowiec
- Department and Clinic of Hematology, Blood Neoplasms, and Bone Marrow Transplantation, Medical University, Wybrzeże Ludwika Pasteura 4, 50-367 Wroclaw, Poland; (D.W.); (T.W.)
| | - Tomasz Wróbel
- Department and Clinic of Hematology, Blood Neoplasms, and Bone Marrow Transplantation, Medical University, Wybrzeże Ludwika Pasteura 4, 50-367 Wroclaw, Poland; (D.W.); (T.W.)
| | - Agata Kosmaczewska
- Laboratory of Immunopathology, Department of Experimental Therapy, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigl 12 Str., 53-114 Wroclaw, Poland; (L.C.); (A.S.); (A.K.)
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24
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Moatti A, Cohen JL. The TNF-α/TNFR2 Pathway: Targeting a Brake to Release the Anti-tumor Immune Response. Front Cell Dev Biol 2021; 9:725473. [PMID: 34712661 PMCID: PMC8546260 DOI: 10.3389/fcell.2021.725473] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 09/24/2021] [Indexed: 12/15/2022] Open
Abstract
Newly discovered anti-cancer immunotherapies, such as immune checkpoint inhibitors and chimeric antigen receptor T cells, focus on spurring the anti-tumor effector T cell (Teff) response. Although such strategies have already demonstrated a sustained beneficial effect in certain malignancies, a substantial proportion of treated patients does not respond. CD4+FOXP3+ regulatory T cells (Tregs), a suppressive subset of T cells, can impair anti-tumor responses and reduce the efficacy of currently available immunotherapies. An alternative view that has emerged over the last decade proposes to tackle this immune brake by targeting the suppressive action of Tregs on the anti-tumoral response. It was recently demonstrated that the tumor necrosis factor alpha (TNF-α) tumor necrosis factor receptor 2 (TNFR2) is critical for the phenotypic stabilization and suppressive function of human and mouse Tregs. The broad non-specific effects of TNF-α infusion in patients initially led clinicians to abandon this signaling pathway as first-line therapy against neoplasms. Previously unrecognized, TNFR2 has emerged recently as a legitimate target for anti-cancer immune checkpoint therapy. Considering the accumulation of pre-clinical data on the role of TNFR2 and clinical reports of TNFR2+ Tregs and tumor cells in cancer patients, it is now clear that a TNFR2-centered approach could be a viable strategy, once again making the TNF-α pathway a promising anti-cancer target. Here, we review the role of the TNFR2 signaling pathway in tolerance and the equilibrium of T cell responses and its connections with oncogenesis. We analyze recent discoveries concerning the targeting of TNFR2 in cancer, as well as the advantages, limitations, and perspectives of such a strategy.
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Affiliation(s)
- Audrey Moatti
- Université Paris-Est Créteil Val de Marne, INSERM, IMRB, Créteil, France.,AP-HP, Groupe Hospitalo-Universitaire Chenevier Mondor, Centre d'Investigation Clinique Biothérapie, Créteil, France
| | - José L Cohen
- Université Paris-Est Créteil Val de Marne, INSERM, IMRB, Créteil, France.,AP-HP, Groupe Hospitalo-Universitaire Chenevier Mondor, Centre d'Investigation Clinique Biothérapie, Créteil, France
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25
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Allegra A, Tonacci A, Musolino C, Pioggia G, Gangemi S. Secondary Immunodeficiency in Hematological Malignancies: Focus on Multiple Myeloma and Chronic Lymphocytic Leukemia. Front Immunol 2021; 12:738915. [PMID: 34759921 PMCID: PMC8573331 DOI: 10.3389/fimmu.2021.738915] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 09/29/2021] [Indexed: 12/19/2022] Open
Abstract
Secondary immunodeficiency is reported in most patients with hematological malignancies such as chronic lymphocytic leukemia and multiple myeloma. The aim of our review was to evaluate the existing literature data on patients with hematological malignancies, with regard to the effect of immunodeficiency on the outcome, the clinical and therapeutic approach, and on the onset of noninfectious complications, including thrombosis, pleural effusion, and orofacial complications. Immunodeficiency in these patients has an intense impact on their risk of infection, in turn increasing morbidity and mortality even years after treatment completion. However, these patients with increased risk of severe infectious diseases could be treated with adequate vaccination coverage, but the vaccines' administration can be associated with a decreased immune response and an augmented risk of adverse reactions. Probably, immunogenicity of the inactivated is analogous to that of healthy subjects at the moment of vaccination, but it undertakes a gradual weakening over time. However, the dispensation of live attenuated viral vaccines is controversial because of the risk of the activation of vaccine viruses. A particular immunization schedule should be employed according to the clinical and immunological condition of each of these patients to guarantee a constant immune response without any risks to the patients' health.
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MESH Headings
- Animals
- Humans
- Immunocompromised Host
- Immunogenicity, Vaccine
- Immunologic Deficiency Syndromes/epidemiology
- Immunologic Deficiency Syndromes/immunology
- Immunologic Deficiency Syndromes/therapy
- Incidence
- Leukemia, Lymphocytic, Chronic, B-Cell/epidemiology
- Leukemia, Lymphocytic, Chronic, B-Cell/immunology
- Leukemia, Lymphocytic, Chronic, B-Cell/therapy
- Multiple Myeloma/epidemiology
- Multiple Myeloma/immunology
- Multiple Myeloma/therapy
- Opportunistic Infections/epidemiology
- Opportunistic Infections/immunology
- Opportunistic Infections/prevention & control
- Risk Factors
- Vaccination
- Vaccine Efficacy
- Vaccines/administration & dosage
- Vaccines/adverse effects
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Affiliation(s)
- Alessandro Allegra
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, Messina, Italy
| | - Alessandro Tonacci
- Clinical Physiology Institute, National Research Council of Italy (IFC-CNR), Pisa, Italy
| | - Caterina Musolino
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, Messina, Italy
| | - Giovanni Pioggia
- Institute for Biomedical Research and Innovation (IRIB), National Research Council of Italy (CNR), Messina, Italy
| | - Sebastiano Gangemi
- School of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
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26
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Moreno C, Muñoz C, Terol MJ, Hernández-Rivas JÁ, Villanueva M. Restoration of the immune function as a complementary strategy to treat Chronic Lymphocytic Leukemia effectively. J Exp Clin Cancer Res 2021; 40:321. [PMID: 34654437 PMCID: PMC8517318 DOI: 10.1186/s13046-021-02115-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 09/24/2021] [Indexed: 12/02/2022] Open
Abstract
Chronic Lymphocytic Leukemia (CLL) is a hematological malignancy characterized by uncontrolled proliferation of B-cells and severe immune dysfunction. Chemo(immuno)therapies (CIT) have traditionally aimed to reduce tumor burden without fully understanding their effects on the immune system. As a consequence, CIT are usually associated with higher risk of infections, secondary neoplasms and autoimmune disorders. A better understanding of the biology of the disease has led to the development of therapeutic strategies which not only act against malignant B-cells but also reactivate and enhance the patient's own anti-tumor immune response. Here, we review the current understanding of the underlying interplay between the malignant cells and non-malignant immune cells that may promote tumor survival and proliferation. In addition, we review the available evidence on how different treatment options for CLL including CIT regimens, small molecular inhibitors (i.e, BTK inhibitors, PI3K inhibitors, BCL-2 inhibitors) and T-cell therapies, affect the immune system and their clinical consequences. Finally, we propose that a dual therapeutic approach, acting directly against malignant B-cells and restoring the immune function is clinically relevant and should be considered when developing future strategies to treat patients with CLL.
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Affiliation(s)
| | - Cecilia Muñoz
- Hospital Universitario de la Princesa, Madrid, Spain
| | | | - José-Ángel Hernández-Rivas
- Hospital Universitario Infanta Leonor, Universidad Complutense de Madrid, Madrid, Spain.
- Servicio de Hematología y Hemoterapia, Hospital Universitario Infanta Leonor, Departamento de Medicina, Universidad Complutense de Madrid, Madrid, España.
- , C/ Gran Vía del Este 80, 28031, Madrid, Spain.
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27
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Leiter U, Loquai C, Reinhardt L, Rafei-Shamsabadi D, Gutzmer R, Kaehler K, Heinzerling L, Hassel JC, Glutsch V, Sirokay J, Schlecht N, Rübben A, Gambichler T, Schatton K, Pfoehler C, Franklin C, Terheyden P, Haferkamp S, Mohr P, Bischof L, Livingstone E, Zimmer L, Weichenthal M, Schadendorf D, Meiwes A, Keim U, Garbe C, Becker JC, Ugurel S. Immune checkpoint inhibition therapy for advanced skin cancer in patients with concomitant hematological malignancy: a retrospective multicenter DeCOG study of 84 patients. J Immunother Cancer 2021; 8:jitc-2020-000897. [PMID: 33093156 PMCID: PMC7583786 DOI: 10.1136/jitc-2020-000897] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/27/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Skin cancers are known for their strong immunogenicity, which may contribute to a high treatment efficacy of immune checkpoint inhibition (ICI). However, a considerable proportion of patients with skin cancer is immuno-compromised by concomitant diseases. Due to their previous exclusion from clinical trials, the ICI treatment efficacy is poorly investigated in these patients. The present study analyzed the ICI treatment outcome in advanced patients with skin cancer with a concomitant hematological malignancy. METHODS This retrospective multicenter study included patients who were treated with ICI for locally advanced or metastatic melanoma (MM), cutaneous squamous cell carcinoma (cSCC), or Merkel cell carcinoma (MCC), and had a previous diagnosis of a hematological malignancy irrespective of disease activity or need of therapy at ICI treatment start. Comparator patient cohorts without concomitant hematological malignancy were extracted from the prospective multicenter skin cancer registry ADOREG. Treatment outcome was measured as best overall response, progression-free (PFS), and overall survival (OS). RESULTS 84 patients (MM, n=52; cSCC, n=15; MCC, n=17) with concomitant hematological malignancy were identified at 20 skin cancer centers. The most frequent concomitant hematological malignancies were non-Hodgkin's lymphoma (n=70), with chronic lymphocytic leukemia (n=32) being the largest entity. While 9 patients received ICI in an adjuvant setting, 75 patients were treated for advanced non-resectable disease (55 anti-PD-1; 8 anti-PD-L1; 5 anti-CTLA-4; 7 combinations). In the latter 75 patients, best objective response (complete response+partial response) was 28.0%, disease stabilization was 25.3%, and 38.6% showed progressive disease (PD). Subdivided by skin cancer entity, best objective response was 31.1% (MM), 26.7% (cSCC), and 18.8% (MCC). Median PFS was 8.4 months (MM), 4.0 months (cSCC), and 5.7 months (MCC). 1-year OS rates were 78.4% (MM), 65.8% (cSCC), and 47.4% (MCC). Comparison with respective ADOREG patient cohorts without hematological malignancy (n=392) revealed no relevant differences in ICI therapy outcome for MM and MCC, but a significantly reduced PFS for cSCC (p=0.002). CONCLUSIONS ICI therapy showed efficacy in advanced patients with skin cancer with a concomitant hematological malignancy. Compared with patients without hematological malignancy, the observed ICI therapy outcome was impaired in cSCC, but not in MM or MCC patients.
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Affiliation(s)
- Ulrike Leiter
- Department of Dermatology, University Hospital Tübingen, Tübingen, Germany
| | - Carmen Loquai
- Department of Dermatology, Johannes Gutenberg University Hospital Mainz, Mainz, Germany
| | - Lydia Reinhardt
- Skin Cancer Center at the National Center for Tumor Diseases Dresden, Department of Dermatology, University Hospital Carl Gustav Carus, Dresden, Germany
| | - David Rafei-Shamsabadi
- Department of Dermatology and Venereology, University Medical Center Freiburg, Freiburg, Germany
| | - Ralf Gutzmer
- Skin Cancer Center, Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany
| | - Katharina Kaehler
- Department of Dermatology, University Hospital Schleswig-Holstein - Campus Kiel, Kiel, Germany
| | - Lucie Heinzerling
- Department of Dermatology, University Hospital Erlangen, Erlangen, Germany
| | - Jessica C Hassel
- Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - Valerie Glutsch
- Department of Dermatology, University Hospital Würzburg, Würzburg, Germany
| | - Judith Sirokay
- Department of Dermatology, University Hospital Bonn, Bonn, Germany
| | - Nora Schlecht
- Department of Dermatology, Hospital Dortmund, Dortmund, Germany
| | - Albert Rübben
- Department of Dermatology, University Hospital Aachen, Aachen, Germany
| | - Thilo Gambichler
- Department of Dermatology, Ruhr University Bochum, Bochum, Germany
| | - Kerstin Schatton
- Department of Dermatology, Heinrich Heine University Medical Faculty, Düsseldorf, Germany
| | - Claudia Pfoehler
- Department of Dermatology, Saarland University Medical Center, Homburg/Saar, Germany
| | - Cindy Franklin
- Department of Dermatology, University Hospital Cologne, Cologne, Germany
| | - Patrick Terheyden
- Department of Dermatology, Universitätsklinikum Schleswig-Holstein - Campus Lübeck, Lübeck, Germany
| | - Sebastian Haferkamp
- Department of Dermatology, University Hospital Regensburg, Regensburg, Germany
| | - Peter Mohr
- Department of Dermatology, Elbe Klinikum Buxtehude, Buxtehude, Germany
| | - Lena Bischof
- Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Elisabeth Livingstone
- Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Lisa Zimmer
- Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Michael Weichenthal
- Department of Dermatology, University Hospital Schleswig-Holstein - Campus Kiel, Kiel, Germany
| | - Dirk Schadendorf
- Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Andreas Meiwes
- Department of Dermatology, University Hospital Tübingen, Tübingen, Germany
| | - Ulrike Keim
- Department of Dermatology, University Hospital Tübingen, Tübingen, Germany
| | - Claus Garbe
- Department of Dermatology, University Hospital Tübingen, Tübingen, Germany
| | - Jürgen Christian Becker
- Translational Skin Cancer Research, Deutsches Konsortium für Translationale Krebsforschung (DKTK), Essen, Germany
| | - Selma Ugurel
- Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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28
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Yang S, Huang X, Gale RP. Cell therapy of chronic lymphocytic leukaemia: Transplants and chimeric antigen receptor (CAR)-T cells. Blood Rev 2021; 51:100884. [PMID: 34489116 DOI: 10.1016/j.blre.2021.100884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 08/17/2021] [Accepted: 08/20/2021] [Indexed: 11/24/2022]
Abstract
There is substantial progress in the therapy of chronic lymphocytic leukaemia (CLL), much of it the result of new drug development. As such the definition of high-risk CLL is changing. Nevertheless, few persons with CLL are cured with current therapy. Two types of cell therapies of CLL are currently being evaluated or re-evaluated in the context of these advances: haematopoietic cell transplants and chimeric antigen receptor (CAR)-T-cells. We discuss the potential role of these cell therapies in the context of the evolving therapy topography of CLL including how these therapies work and who, if anyone, is an appropriate candidate for cell therapy.
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Affiliation(s)
- Shenmiao Yang
- Peking University Peoples Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
| | - Xiaojun Huang
- Peking University Peoples Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China.
| | - Robert Peter Gale
- Centre for Haematology Research, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom.
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29
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Impact of Immune Parameters and Immune Dysfunctions on the Prognosis of Patients with Chronic Lymphocytic Leukemia. Cancers (Basel) 2021; 13:cancers13153856. [PMID: 34359757 PMCID: PMC8345723 DOI: 10.3390/cancers13153856] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/26/2021] [Accepted: 07/28/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary In chronic lymphocytic leukemia (CLL), immune alterations—affecting both the innate and adaptive immunity—are very common. As a clinical consequence, patients with CLL frequently present with autoimmune phenomena, increased risk of infections and second malignancies. The aim of this review article is to present available data on CLL-associated alterations of immune parameters that correlate with known prognostic markers and with clinical outcome. Also, data on the impact of immune-related clinical manifestations on the prognosis of patients with CLL will be discussed. Abstract Chronic lymphocytic leukemia (CLL) is characterized by a wide spectrum of immune alterations, affecting both the innate and adaptive immunity. These immune dysfunctions strongly impact the immune surveillance, facilitate tumor progression and eventually affect the disease course. Quantitative and functional alterations involving conventional T cells, γδ T cells, regulatory T cells, NK and NKT cells, and myeloid cells, together with hypogammaglobulinemia, aberrations in the complement pathways and altered cytokine signature have been reported in patients with CLL. Some of these immune parameters have been shown to associate with other CLL-related characteristics with a known prognostic relevance or to correlate with disease prognosis. Also, in CLL, the complex immune response dysfunctions eventually translate in clinical manifestations, including autoimmune phenomena, increased risk of infections and second malignancies. These clinical issues are overall the most common complications that affect the course and management of CLL, and they also may impact overall disease prognosis.
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30
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Zahran AM, Shibl A, Rayan A, Mohamed MAEH, Osman AMM, Saad K, Mahmoud KH, Ghandour AMA, Elsayh KI, El-Badawy O. Increase in polymorphonuclear myeloid-derived suppressor cells and regulatory T-cells in children with B-cell acute lymphoblastic leukemia. Sci Rep 2021; 11:15039. [PMID: 34294814 PMCID: PMC8298505 DOI: 10.1038/s41598-021-94469-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Accepted: 07/07/2021] [Indexed: 02/08/2023] Open
Abstract
Our study aimed to evaluate the levels of MDSCs and Tregs in pediatric B-cell acute lymphoblastic leukemia (B-ALL), their relation to patients' clinical and laboratory features, and the impact of these cells on the induction response. This study included 31 pediatric B-ALL patients and 27 healthy controls. All patients were treated according to the protocols of the modified St. Jude Children's Research Hospital total therapy study XIIIB for ALL. Levels of MDSCs and Tregs were analyzed using flow cytometry. We observed a reduction in the levels of CD4 + T-cells and an increase in both the polymorphonuclear MDSCs (PMN-MDSCs) and Tregs. The frequencies of PMN-MDSCs and Tregs were directly related to the levels of peripheral and bone marrow blast cells and CD34 + cells. Complete postinduction remission was associated with reduced percentages of PMN-MDSCs and Tregs, with the level of PMN-MDCs in this subpopulation approaching that of healthy controls. PMN-MDSCs and Tregs jointly play a critical role in maintaining an immune-suppressive state suitable for B-ALL tumor progression. Thereby, they could be independent predictors of B-ALL progress, and finely targeting both PMN-MDSCs and Tregs may be a promising approach for the treatment of B-ALL.
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Affiliation(s)
- Asmaa M Zahran
- Department of Clinical Pathology, South Egypt Cancer Institute, Assiut University, Assiut, Egypt
| | - Azza Shibl
- Pediatric Oncology Department, South Egypt Cancer Institute, Assiut University, Assiut, Egypt
| | - Amal Rayan
- Clinical Oncology Department, Faculty of Medicine, Assiut University, Assiut, 71516, Egypt
| | | | - Amira M M Osman
- Pediatric Oncology Department, South Egypt Cancer Institute, Assiut University, Assiut, Egypt
| | - Khaled Saad
- Pediatric Department, Faculty of Medicine, Assiut University, Assiut, Egypt.
| | | | - Aliaa M A Ghandour
- Medical Microbiology and Immunology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Khalid I Elsayh
- Pediatric Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Omnia El-Badawy
- Medical Microbiology and Immunology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
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31
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Pang N, Alimu X, Chen R, Muhashi M, Ma J, Chen G, Zhao F, Wang L, Qu J, Ding J. Activated Galectin-9/Tim3 promotes Treg and suppresses Th1 effector function in chronic lymphocytic leukemia. FASEB J 2021; 35:e21556. [PMID: 34137463 DOI: 10.1096/fj.202100013r] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 03/08/2021] [Accepted: 03/10/2021] [Indexed: 01/27/2023]
Abstract
Tim-3 is a negative immunoregulator in anti-tumor response, but its mechanism in chronic lymphocytic leukemia (CLL) is not yet clear. The aim of this study was to understand the role of Galectin-9/Tim-3 signaling pathway in the regulation of CD4+ T cell subsets in CLL patients. Flow cytometry results showed that the number of Treg cells obviously increased, and there was a significant Treg/Th17 imbalance in CLL patients. In addition, Tim-3 overexpressed on the surface of Th1 and Treg cells in CLL patients. The levels of Galectin-9 and IL-10 were significantly elevated in patients of CLL, especially in stages of Binet B, and C. However, IFN-γ decreased. Moreover, Galectin-9 in CLL patients was positively correlated with the number of Tim-3+ Treg cells and the level of IL-10. Interestingly, when the Tim-3/Galectin-9 pathway was blocked in vitro, the level of IL-10 in the culture supernatant of CD4+ T was significantly reduced, while the levels of IFN-γ and TNF-α were increased. After co-culture with activated Th1 cells, the apoptosis of CLL cells was significantly increased, and this effect was reversed after treatment with Tim-3+ Tregs. In summary, Galectin-9/Tim-3 are elevated in CLL and associated with disease progression. By the negative regulation of CD4+ T cells, activated Galectin-9/Tim-3 suppresses Th1 effector function and also promotes Treg to be involved in immune escape of CLL. This pathway might become the potential target of immunotherapy in CLL patients.
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MESH Headings
- Aged
- Case-Control Studies
- Female
- Galectins/genetics
- Galectins/metabolism
- Hepatitis A Virus Cellular Receptor 2/genetics
- Hepatitis A Virus Cellular Receptor 2/metabolism
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/immunology
- Leukemia, Lymphocytic, Chronic, B-Cell/metabolism
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Lymphocyte Activation/immunology
- Male
- Signal Transduction
- T-Lymphocytes, Regulatory/immunology
- Th1 Cells/immunology
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Affiliation(s)
- Nannan Pang
- Center of Hematology, The First Affiliated Hospital of Xinjiang Medical University, Hematology Institute of Xinjiang Uygur Autonomous Region, Urumqi, China
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Xierenguli Alimu
- Center of Hematology, The First Affiliated Hospital of Xinjiang Medical University, Hematology Institute of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Rong Chen
- Center of Hematology, The First Affiliated Hospital of Xinjiang Medical University, Hematology Institute of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Maliya Muhashi
- Center of Hematology, The First Affiliated Hospital of Xinjiang Medical University, Hematology Institute of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Jiajia Ma
- Center of Hematology, The First Affiliated Hospital of Xinjiang Medical University, Hematology Institute of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Gang Chen
- Center of Hematology, The First Affiliated Hospital of Xinjiang Medical University, Hematology Institute of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Fang Zhao
- Center of Hematology, The First Affiliated Hospital of Xinjiang Medical University, Hematology Institute of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Lei Wang
- Center of Hematology, The First Affiliated Hospital of Xinjiang Medical University, Hematology Institute of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Jianhua Qu
- Center of Hematology, The First Affiliated Hospital of Xinjiang Medical University, Hematology Institute of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Jianbing Ding
- Basic Medical College of Xinjiang Medical University, Urumqi, China
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Pochtar EV, Lugovskaya SA, Naumova EV, Dmitrieva EA, Kostin AI, Dolgov VV. Specific features of T- and NK-cellular immunity in chronic lymphocytic leukemia. Klin Lab Diagn 2021; 66:345-352. [PMID: 34105910 DOI: 10.51620/0869-2084-2021-66-6-345-352] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Profound immunological dysfunction is the key factor determining the development of infectious complications in chronic lymphocytic leukemia (CLL). The aim of this work is to assess the features of the subpopulation composition of T-lymphocytes (T-helpers (Th), cytotoxic T-lymphocytes (Tcyt), T regulatory cells (Treg), T-NK cells, naive Th, Th-memory, activated T-lymphocytes, TCRγδ cells) and NK cells in peripheral blood of patients with newly diagnosed chronic lymphocytic leukemia (CLL) and receiving ibrutinib therapy. Hematological and immunophenotypic studies have been performed in 30 patients with previously untreated CLL, 122 patients on ibrutinib therapy and 20 healthy donors. The subpopulation composition of T-lymphocytes (Th, Tcyt, Treg, T-NK, naive T-helpers, memory T-helpers, TCRγδ cells, activated T-lymphocytes) and NK cells has been assessed on flow cytometer (FACSCanto II (BD)) using the following panel of monoclonal antibodies: CD45, CD19, CD3, CD4, CD5, CD8, TCRγδ, CD127, CD16, CD56, CD57 CD45RA, CD45R0, HLA-DR, CD25. Compared to controls all CLL samples were found to have higher the absolute number of T-lymphocytes, NK cells and their subpopulations, T-helpers (especially of memory T-cells), cytotoxic T-cells, regulatory T-cells, TCRγδ T-cells, activated T-lymphocytes, increased cytotoxic potential of NK cells in previously untreated CLL patients. Patients who received ibrutinib therapy have registered a positive trend towards recovery of the subpopulation composition of T-lymphocytes and NK-cells. CLL patients have been found to have quantitative and functional changes in the subpopulations of T-lymphocytes and NK cells, indicating dysregulation of the immune response, and a high risk of developing infections. Monitoring of immunological parameters for ibrutinib therapy make possible to estimate impact of ibrutinib on the adaptive anti-CLL immune response.
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Affiliation(s)
| | - S A Lugovskaya
- Russian Medical Academy of professional continuous education
| | - E V Naumova
- Russian Medical Academy of professional continuous education
| | | | - A I Kostin
- Research Institute of emergency by Sklifosovsky
| | - V V Dolgov
- Russian Medical Academy of professional continuous education
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Regulatory T cells and vaccine effectiveness in older adults. Challenges and prospects. Int Immunopharmacol 2021; 96:107761. [PMID: 34162139 DOI: 10.1016/j.intimp.2021.107761] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 04/24/2021] [Accepted: 05/04/2021] [Indexed: 12/21/2022]
Abstract
Since the discovery of lymphocytes with immunosuppressive activity, increasing interest has arisen in their possible influence on the immune response induced by vaccines. Regulatory T cells (Tregs) are essential for maintaining peripheral tolerance, preventing autoimmune diseases, and limiting chronic inflammatory diseases. However, they also limit beneficial immune responses by suppressing anti-infectious and anti-tumor immunity. Mounting evidence suggests that Tregs are involved, at least in part, in the low effectiveness of immunization against various diseases where it has been difficult to obtain protective vaccines. Interestingly, increased activity of Tregs is associated with aging, suggesting a key role for these cells in the lower vaccine effectiveness observed in older people. In this review, we analyze the impact of Tregs on vaccination, with a focus on older adults. Finally, we address an overview of current strategies for Tregs modulation with potential application to improve the effectiveness of future vaccines targeting older populations.
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34
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Pan Y, Wang H, An F, Wu F, Tao Q, Li Y, Ruan Y, Zhai Z. CD4 +CD25 +CD127 low regulatory T cells associated with the effect of CD19 CAR-T therapy for relapsed/refractory B-cell acute lymphoblastic leukemia. Int Immunopharmacol 2021; 96:107742. [PMID: 33984717 DOI: 10.1016/j.intimp.2021.107742] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 04/18/2021] [Accepted: 04/27/2021] [Indexed: 12/01/2022]
Abstract
BACKGROUND CD19-specific chimeric antigen receptor T-cell (CAR-T) therapy has shown promising clinical outcomes in relapsed/refractory acute B-cell lymphoblastic leukemia (R/R B-ALL) patients. However, some patients did not respond to this therapy or relapsed after remission. Regulatory T cells (Tregs) have shown great importance in promoting tumor escape, but little is known about their role in R/R B-ALL patients with CAR-T therapy. Our previous study has proved that higher Tregs before infusion was an independent high-risk factor for relapse-free survival (RFS). To further clarify the relationship between Tregs and the efficacy of CAR-T therapy, the present study tested the levels of CD4+CD25+CD127low Tregs in peripheral blood (PB) of R/R B-ALL patients at different stages of CD19 CAR-T therapy, and evaluate their impact on the efficacy and prognosis of CAR-T therapy. METHODS From November 2015 to May 2019, 47 R/R B-ALL patients successfully received CD19 CAR-T therapy at our institution and followed up for at least 1 month. Among them, one patient did not tested for Tregs, so 46 patients enrolled in this study. We collected clinical information of them and dynamically detected the frequency of CD4+CD25+CD127low Tregs within CD4 + T cells at different time points (before infusion and at 1 week after infusion) by flow cytometry, and validated the relationship of circulating Tregs with clinical efficacy, OS, and recurrence of CAR-T therapy. RESULTS Circulating Tregs of R/R B-ALL patients in pre-infusion group (median 6.67%) and in 1 week after infusion group (median 6.80%) were all higher than that of the healthy control group (median 5.04%), with statistical significance (P < 0.05). The frequencies of Tregs in not remission (NR) group at baseline (pre-infusion) and at 1 week after infusion were all significantly higher than those in remission group. With cut-off values of 11.54% (before infusion) and 13.56% (1 week after infusion), the specificity for Tregs were 94.6% and 100% , respectively. In remission group, 11 patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) after achieving remission by Sino 19 cell therapy. No significant differences of Tregs expression were found between transplantation and non-transplantation groups. Time-dependent Cox model showed that transplantation group had lower risk of relapse and death when compared with non-transplantation group (HR = 0.664 for RFS and HR = 0.364 for OS), however, no statistical significances were found (P = 0.403 and 0.106, respectively). Higher Tregs before infusion and at 1 week after infusion were significant associated with shorter RFS and OS by Kaplan-Meier analysis. Multivariate analysis showed that higher Tregs at 1 week after infusion was the independently factor for poor RFS (P = 0.032) and shorter OS (P = 0.025) in R/R B-ALL patients with CD19 CAR-T therapy. Besides, Tregs levels before and at 1 week after infusion were negatively correlated with the persistence time of Sino 19 cell. CONCLUSION Higher circulating Tregs, especially 1 week after CD19 CAR-T cell infusion, was a poor predict indicator for CD19 CAR-T therapy in R/R B-ALL patients.
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Affiliation(s)
- Ying Pan
- Hematology Department, the Second Hospital of Anhui Medical University (SHAMU), Hefei, Anhui Province, China; Hematologic Diseases Research Center of Anhui Medical University, Hefei, Anhui Province, China
| | - Huiping Wang
- Hematology Department, the Second Hospital of Anhui Medical University (SHAMU), Hefei, Anhui Province, China; Hematologic Diseases Research Center of Anhui Medical University, Hefei, Anhui Province, China
| | - Furun An
- Hematology Department, the Second Hospital of Anhui Medical University (SHAMU), Hefei, Anhui Province, China; Hematologic Diseases Research Center of Anhui Medical University, Hefei, Anhui Province, China
| | - Fan Wu
- Hematology Department, the Second Hospital of Anhui Medical University (SHAMU), Hefei, Anhui Province, China; Hematologic Diseases Research Center of Anhui Medical University, Hefei, Anhui Province, China
| | - Qianshan Tao
- Hematology Department, the Second Hospital of Anhui Medical University (SHAMU), Hefei, Anhui Province, China; Hematologic Diseases Research Center of Anhui Medical University, Hefei, Anhui Province, China
| | - Yingwei Li
- Hematology Department, the Second Hospital of Anhui Medical University (SHAMU), Hefei, Anhui Province, China; Hematologic Diseases Research Center of Anhui Medical University, Hefei, Anhui Province, China
| | - Yanjie Ruan
- Hematologic Diseases Research Center of Anhui Medical University, Hefei, Anhui Province, China
| | - Zhimin Zhai
- Hematology Department, the Second Hospital of Anhui Medical University (SHAMU), Hefei, Anhui Province, China; Hematologic Diseases Research Center of Anhui Medical University, Hefei, Anhui Province, China.
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35
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Ibrutinib Has Time-dependent On- and Off-target Effects on Plasma Biomarkers and Immune Cells in Chronic Lymphocytic Leukemia. Hemasphere 2021; 5:e564. [PMID: 33912812 PMCID: PMC8078281 DOI: 10.1097/hs9.0000000000000564] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 03/22/2021] [Indexed: 02/07/2023] Open
Abstract
Supplemental Digital Content is available in the text. Ibrutinib is a covalently binding inhibitor of the B-cell receptor signaling-mediator Bruton’s tyrosine kinase (BTK) with great efficacy in chronic lymphocytic leukemia (CLL). Common side effects like atrial fibrillation (AF), bleeding and infections might be caused by ibrutinib’s inhibition of other kinases in non-B cells. Five-year follow-up of plasma biomarkers by proximity extension assay and immune cell numbers by flow cytometry during ibrutinib treatment revealed that 86 of the 265 investigated plasma biomarkers significantly changed during treatment, 74 of which decreased. Among the 12 markers that increased, 6 are associated with cardiovascular diseases and therefore potentially involved in ibrutinib-induced AF. Comparison between healthy donors and X-linked agammaglobulinemia (XLA) patients, who have nonfunctional BTK and essentially lack B cells, showed indicative changes in 53 of the 265 biomarkers while none differed significantly. Hence, neither B cells nor BTK-dependent pathways in other cells seem to influence the levels of the studied plasma biomarkers in healthy donors. Regarding immune cells, the absolute number of T cells, including subsets, decreased, paralleling the decreasing tumor burden. T helper 1 (Th1) cell numbers dropped strongly, while Th2 cells remained relatively stable, causing Th2-skewing. Thus, long-term ibrutinib treatment has a profound impact on the plasma proteome and immune cells in patients with CLL.
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36
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Immunological Prognostic Factors in Multiple Myeloma. Int J Mol Sci 2021; 22:ijms22073587. [PMID: 33808304 PMCID: PMC8036885 DOI: 10.3390/ijms22073587] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/25/2021] [Accepted: 03/29/2021] [Indexed: 12/11/2022] Open
Abstract
Multiple myeloma (MM) is a plasma cell neoplasm characterized by an abnormal proliferation of clonal, terminally differentiated B lymphocytes. Current approaches for the treatment of MM focus on developing new diagnostic techniques; however, the search for prognostic markers is also crucial. This enables the classification of patients into risk groups and, thus, the selection of the most optimal treatment method. Particular attention should be paid to the possible use of immune factors, as the immune system plays a key role in the formation and course of MM. In this review, we focus on characterizing the components of the immune system that are of prognostic value in MM patients, in order to facilitate the development of new diagnostic and therapeutic directions.
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37
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Cuesta-Mateos C, Brown JR, Terrón F, Muñoz-Calleja C. Of Lymph Nodes and CLL Cells: Deciphering the Role of CCR7 in the Pathogenesis of CLL and Understanding Its Potential as Therapeutic Target. Front Immunol 2021; 12:662866. [PMID: 33841445 PMCID: PMC8024566 DOI: 10.3389/fimmu.2021.662866] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 03/09/2021] [Indexed: 01/13/2023] Open
Abstract
The lymph node (LN) is an essential tissue for achieving effective immune responses but it is also critical in the pathogenesis of chronic lymphocytic leukemia (CLL). Within the multitude of signaling pathways aberrantly regulated in CLL the homeostatic axis composed by the chemokine receptor CCR7 and its ligands is the main driver for directing immune cells to home into the LN. In this literature review, we address the roles of CCR7 in the pathophysiology of CLL, and how this chemokine receptor is of critical importance to develop more rational and effective therapies for this malignancy.
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MESH Headings
- Animals
- B-Lymphocytes/metabolism
- Biomarkers, Tumor
- Chemotaxis/genetics
- Chemotaxis/immunology
- Disease Susceptibility
- Gene Expression
- Humans
- Immune Tolerance
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Leukemia, Lymphocytic, Chronic, B-Cell/etiology
- Leukemia, Lymphocytic, Chronic, B-Cell/metabolism
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Ligands
- Lymph Nodes/immunology
- Lymph Nodes/metabolism
- Molecular Targeted Therapy
- Protein Binding
- Receptors, CCR7/antagonists & inhibitors
- Receptors, CCR7/genetics
- Receptors, CCR7/metabolism
- Tumor Microenvironment
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Affiliation(s)
- Carlos Cuesta-Mateos
- Immunology Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria- Instituto de La Princesa (IIS-IP), Madrid, Spain
- IMMED S.L., Immunological and Medicinal Products, Madrid, Spain
- Catapult Therapeutics BV, Lelystad, Netherlands
| | - Jennifer R. Brown
- Chronic Lymphocytic Leukemia (CLL) Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Fernando Terrón
- IMMED S.L., Immunological and Medicinal Products, Madrid, Spain
- Catapult Therapeutics BV, Lelystad, Netherlands
| | - Cecilia Muñoz-Calleja
- Immunology Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria- Instituto de La Princesa (IIS-IP), Madrid, Spain
- School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain
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38
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Deng B, Zhang W, Zhu Y, Li Y, Li D, Li B. FOXP3 + regulatory T cells and age-related diseases. FEBS J 2021; 289:319-335. [PMID: 33529458 DOI: 10.1111/febs.15743] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 01/29/2021] [Indexed: 12/17/2022]
Abstract
Regulatory T (Treg) cells are critical for the maintenance of immune homeostasis. Dysregulation of Treg cells has been implicated in the pathogenesis of autoimmunity and chronic inflammation, while aging is characterized by an accumulation of inflammatory markers in the peripheral blood, a phenomenon known as 'inflammaging'. The relationship between Treg cells and age-related diseases remains to be further studied. Increasing evidence revealed that Treg cells' dysfunction occurs in aged patients, suggesting that immune therapies targeting Treg cells may be a promising approach to treat diseases such as cancers and autoimmune diseases. Furthermore, drugs targeting Treg cells show encouraging results and contribute to CD8+ T-cell-mediated cytotoxic killing of tumor and infected cells. In general, a better understanding of Treg cell function may help us to develop new immune therapies against aging. In this review, we discuss potential therapeutic strategies to modify immune responses of relevance for aging to prevent and treat age-related diseases, as well as the challenges posed by the translation of novel immune therapies into clinical practice.
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Affiliation(s)
- Biaolong Deng
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, China.,Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, China
| | - Weiqi Zhang
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, China.,Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, China
| | - Yicheng Zhu
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, China.,Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, China
| | - Yangyang Li
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, China.,Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, China
| | - Dan Li
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, China.,Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, China
| | - Bin Li
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, China.,Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, China
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39
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Ghasemi Z, Kalantar K, Amirghofran Z. The role of FOXP3 rs3761548 and rs2294021 polymorphisms in pediatrics acute lymphoblastic leukemia: association with risk and response to therapy. Mol Biol Rep 2021; 48:1139-1150. [PMID: 33517519 DOI: 10.1007/s11033-021-06154-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 01/12/2021] [Indexed: 12/07/2022]
Abstract
FOXP3 X-linked gene has crucial roles in the development and function of regulatory T cells. We investigated the association of FOXP3 rs3761548, rs3761549 and rs2294021 single nucleotide polymorphisms (SNPs) with acute lymphoblastic leukemia (ALL) susceptibility and response to therapy. Genotyping was performed in 247 patients and 210 healthy subjects. We observed a higher frequency of rs3761548 A carriers and rs2294021 C carriers (p < 0.04) in male patients, and lower frequencies of rs3761548 AC genotype (p = 0.04) and rs2294021 CT genotype (p = 0.01) in female patients compared to controls. ACC (p = 0.04) and ATC haplotypes (p = 0.002) were associated with susceptibility to ALL. There was a significant correlation between the genotypes of rs3761548 and rs2294021 SNPs with event-free survival (EFS) and overall survival (OS). The rs3761548 A genotype in male patients was associated with increased risk of relapse (p < 0.0001), shorter EFS, increased death rate (p = 0.002) and shorter OS compared to C genotype (p = 0.001). Similar significant results were observed for the relation of rs2294021 C genotype with response to therapy in male patients. In females, patients with rs3761548 AC genotype had longer EFS (p = 0.02) and those with rs2294021 CT had longer EFS and OS (p < 0.005). According to haplotype analysis, patients carrying ACC or ATC haplotypes had the highest number of WBCs and shorter EFS or OS, and patients with CCT haplotype had the lowest number of WBCs and longer EFS or OS. These results provided evidence for the impact of these polymorphisms on susceptibility and response to therapy in children with ALL.
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Affiliation(s)
- Zahra Ghasemi
- Department of Immunology, Medical School, Shiraz University of Medical Sciences, Shiraz, 71345-1798, Iran
| | - Kurosh Kalantar
- Department of Immunology, Medical School, Shiraz University of Medical Sciences, Shiraz, 71345-1798, Iran
| | - Zahra Amirghofran
- Department of Immunology, Medical School, Shiraz University of Medical Sciences, Shiraz, 71345-1798, Iran. .,Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, 71345-1798, Iran.
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40
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Lambrou GI, Adamaki M, Hatziagapiou K, Vlahopoulos S. Gene Expression and Resistance to Glucocorticoid-Induced Apoptosis in Acute Lymphoblastic Leukemia: A Brief Review and Update. Curr Drug Res Rev 2021; 12:131-149. [PMID: 32077838 DOI: 10.2174/2589977512666200220122650] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 12/29/2019] [Accepted: 01/23/2020] [Indexed: 01/18/2023]
Abstract
BACKGROUND Resistance to glucocorticoid (GC)-induced apoptosis in Acute Lymphoblastic Leukemia (ALL), is considered one of the major prognostic factors for the disease. Prednisolone is a corticosteroid and one of the most important agents in the treatment of acute lymphoblastic leukemia. The mechanics of GC resistance are largely unknown and intense ongoing research focuses on this topic. AIM The aim of the present study is to review some aspects of GC resistance in ALL, and in particular of Prednisolone, with emphasis on previous and present knowledge on gene expression and signaling pathways playing a role in the phenomenon. METHODS An electronic literature search was conducted by the authors from 1994 to June 2019. Original articles and systematic reviews selected, and the titles and abstracts of papers screened to determine whether they met the eligibility criteria, and full texts of the selected articles were retrieved. RESULTS Identification of gene targets responsible for glucocorticoid resistance may allow discovery of drugs, which in combination with glucocorticoids may increase the effectiveness of anti-leukemia therapies. The inherent plasticity of clinically evolving cancer justifies approaches to characterize and prevent undesirable activation of early oncogenic pathways. CONCLUSION Study of the pattern of intracellular signal pathway activation by anticancer drugs can lead to development of efficient treatment strategies by reducing detrimental secondary effects.
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Affiliation(s)
- George I Lambrou
- First Department of Pediatrics, National and Kapodistrian University of Athens, Choremeio Research Laboratory, Athens, Greece
| | - Maria Adamaki
- First Department of Pediatrics, National and Kapodistrian University of Athens, Choremeio Research Laboratory, Athens, Greece
| | - Kyriaki Hatziagapiou
- First Department of Pediatrics, National and Kapodistrian University of Athens, Choremeio Research Laboratory, Athens, Greece
| | - Spiros Vlahopoulos
- First Department of Pediatrics, National and Kapodistrian University of Athens, Choremeio Research Laboratory, Athens, Greece
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Cuesta-Mateos C, Juárez-Sánchez R, Mateu-Albero T, Loscertales J, Mol W, Terrón F, Muñoz-Calleja C. Targeting cancer homing into the lymph node with a novel anti-CCR7 therapeutic antibody: the paradigm of CLL. MAbs 2021; 13:1917484. [PMID: 33944659 PMCID: PMC8098074 DOI: 10.1080/19420862.2021.1917484] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 03/29/2021] [Accepted: 04/12/2021] [Indexed: 11/25/2022] Open
Abstract
Lymph node (LN) is a key tissue in the pathophysiology of mature blood cancers, especially for chronic lymphocytic leukemia (CLL). Within the multiple de-regulated pathways affecting CLL homeostasis, the CC-chemokine receptor 7 (CCR7) grants homing of CLL cells into the LN where protective environments foster tumor progression. To cover the lack of specific therapies targeting the CCR7-dependence of CLL to enter into the LN, and aiming to displace the disease from LN, we generated CAP-100, an antibody that specifically binds to hCCR7 and neutralizes its ligand-binding site and signaling. In various in vitro and in vivo preclinical models CAP-100 strongly inhibited CCR7-induced migration, extravasation, homing, and survival in CLL samples. Moreover, it triggered potent tumor cell killing, mediated by host immune mechanisms, and was effective in xenograft models of high-risk disease. Additionally, CAP-100 showed a favorable toxicity profile on relevant hematopoietic subsets. Our results validated CAP-100 as a novel therapeutic tool to prevent the access of CLL cells, and other neoplasia with nodal-dependence, into the LN niches, thus hitting a central hub in the pathogenesis of cancer. The first-in-human clinical trial (NCT04704323), which will evaluate this novel therapeutic approach in CLL patients, is pending.
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Affiliation(s)
- Carlos Cuesta-Mateos
- Immed S.L., Immunological and Medicinal Products, Madrid, Spain
- Catapult Therapeutics, Lelystad, The Netherlands
- Immunology Department, Hospital Universitario De La Princesa, IIS-IP, Madrid, Spain
| | - Raquel Juárez-Sánchez
- Immed S.L., Immunological and Medicinal Products, Madrid, Spain
- Immunology Department, Hospital Universitario De La Princesa, IIS-IP, Madrid, Spain
| | - Tamara Mateu-Albero
- Immunology Department, Hospital Universitario De La Princesa, IIS-IP, Madrid, Spain
| | - Javier Loscertales
- Hematology Department, Hospital Universitario De La Princesa, IIS-IP, Madrid, Spain
| | - Wim Mol
- Catapult Therapeutics, Lelystad, The Netherlands
- Pepscan, Lelystad, The Netherlands
| | - Fernando Terrón
- Immed S.L., Immunological and Medicinal Products, Madrid, Spain
- Catapult Therapeutics, Lelystad, The Netherlands
| | - Cecilia Muñoz-Calleja
- Immunology Department, Hospital Universitario De La Princesa, IIS-IP, Madrid, Spain
- Medicine Faculty, Universidad Autónoma De Madrid, Madrid, Spain
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Smithy JW, Pianko MJ, Maher C, Postow MA, Shoushtari AN, Momtaz P, Chapman PB, Wolchok JD, Park JH, Callahan MK. Checkpoint Blockade in Melanoma Patients With Underlying Chronic Lymphocytic Leukemia. J Immunother 2021; 44:9-15. [PMID: 33290361 PMCID: PMC7727280 DOI: 10.1097/cji.0000000000000345] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Chronic lymphocytic leukemia (CLL) is associated with immune dysfunction and an increased risk of melanoma. For patients with metastatic melanoma, immunotherapy with checkpoint blocking antibodies is a standard of care. In patients with concomitant CLL and metastatic melanoma, it is not known whether CLL might influence the antimelanoma efficacy or immune-related toxicities of immune checkpoint blockade. Fifteen patients with locally advanced or metastatic melanoma and a concomitant diagnosis of CLL who received pembrolizumab or ipilimumab with or without nivolumab for the treatment of their melanoma at Memorial Sloan Kettering Cancer Center between January 1, 2010, and January 1, 2017, were retrospectively identified. Clinical characteristics including absolute lymphocyte counts during therapy were recorded along with a response to treatment (objective radiographic response, progression-free survival, and adverse events) for each patient. Of 9 response-evaluable patients treated with ipilimumab, 3 (33%) had a partial response, 1 (11%) had stable disease, and 5 (56%) developed progressive disease. Objective tumor responses were also observed with single-agent therapy pembrolizumab and with combination therapy of nivolumab and ipilimumab. Grade 3 or 4 toxicity was observed in 6 of 15 patients (40%), including diarrhea, transaminitis, rash, and hemolytic anemia. Although our retrospective assessment was limited, there was no evidence that CLL responded to the checkpoint blockade. This case series demonstrates that ipilimumab, pembrolizumab, and combined ipilimumab and nivolumab therapies show clinical activity in patients with melanoma and concomitant CLL, at rates consistent with those previously reported. This population may warrant closer surveillance for hematologic immune-related toxicities such as autoimmune hemolytic anemia.
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Affiliation(s)
- James W. Smithy
- Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | | | - Colleen Maher
- Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Michael A. Postow
- Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medical College, New York, NY
| | - Alexander N. Shoushtari
- Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medical College, New York, NY
- Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Parisa Momtaz
- Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medical College, New York, NY
| | - Paul B. Chapman
- Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medical College, New York, NY
| | - Jedd D. Wolchok
- Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medical College, New York, NY
- Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY
- Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Jae H. Park
- Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medical College, New York, NY
| | - Margaret K. Callahan
- Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medical College, New York, NY
- Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY
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van Bruggen JAC, Martens AWJ, Tonino SH, Kater AP. Overcoming the Hurdles of Autologous T-Cell-Based Therapies in B-Cell Non-Hodgkin Lymphoma. Cancers (Basel) 2020; 12:cancers12123837. [PMID: 33353234 PMCID: PMC7765898 DOI: 10.3390/cancers12123837] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 12/15/2020] [Accepted: 12/16/2020] [Indexed: 01/10/2023] Open
Abstract
Simple Summary The activity of novel therapies that utilize patient’s own T-cells to induce remission of B-cell non-Hodgkin lymphoma (B-NHL), including chronic lymphocytic leukemia (CLL), is still suboptimal. In this review, we summarize the clinical efficacy of T-cell-based therapies in B-NHL and provide a biologic rationale for the observed (lack of) responses. We describe and compare the acquired T-cell dysfunctions that occur in the different subtypes of B-NHL. Furthermore, we discuss new insights that could enhance the efficacy of T-cell-based therapies for B-NHL and CLL. Abstract The next frontier towards a cure for B-cell non-Hodgkin lymphomas (B-NHL) is autologous cellular immunotherapy such as immune checkpoint blockade (ICB), bispecific antibodies (BsAbs) and chimeric antigen receptor (CAR) T-cells. While highly successful in various solid malignancies and in aggressive B-cell leukemia, this clinical success is often not matched in B-NHL. T-cell subset skewing, exhaustion, expansion of regulatory T-cell subsets, or other yet to be defined mechanisms may underlie the lack of efficacy of these treatment modalities. In this review, a systematic overview of results from clinical trials is given and is accompanied by reported data on T-cell dysfunction. From these results, we distill the underlying pathways that might be responsible for the observed differences in clinical responses towards autologous T-cell-based cellular immunotherapy modalities between diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). By integration of the clinical and biological findings, we postulate strategies that might enhance the efficacy of autologous-based cellular immunotherapy for the treatment of B-NHL.
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Affiliation(s)
- Jaco A. C. van Bruggen
- Department of Hematology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (J.A.C.v.B.); (A.W.J.M.); (S.H.T.)
- Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Amsterdam Infection & Immunity Institute, 1105 AZ Amsterdam, The Netherlands
- Lymphoma and Myeloma Center Amsterdam, LYMMCARE, 1105 AZ Amsterdam, The Netherlands
| | - Anne W. J. Martens
- Department of Hematology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (J.A.C.v.B.); (A.W.J.M.); (S.H.T.)
- Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Amsterdam Infection & Immunity Institute, 1105 AZ Amsterdam, The Netherlands
- Lymphoma and Myeloma Center Amsterdam, LYMMCARE, 1105 AZ Amsterdam, The Netherlands
| | - Sanne H. Tonino
- Department of Hematology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (J.A.C.v.B.); (A.W.J.M.); (S.H.T.)
- Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Amsterdam Infection & Immunity Institute, 1105 AZ Amsterdam, The Netherlands
- Lymphoma and Myeloma Center Amsterdam, LYMMCARE, 1105 AZ Amsterdam, The Netherlands
| | - Arnon P. Kater
- Department of Hematology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (J.A.C.v.B.); (A.W.J.M.); (S.H.T.)
- Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Amsterdam Infection & Immunity Institute, 1105 AZ Amsterdam, The Netherlands
- Lymphoma and Myeloma Center Amsterdam, LYMMCARE, 1105 AZ Amsterdam, The Netherlands
- Correspondence:
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Augé H, Notarantonio AB, Morizot R, Quinquenel A, Fornecker LM, Hergalant S, Feugier P, Broséus J. Microenvironment Remodeling and Subsequent Clinical Implications in Diffuse Large B-Cell Histologic Variant of Richter Syndrome. Front Immunol 2020; 11:594841. [PMID: 33381116 PMCID: PMC7767850 DOI: 10.3389/fimmu.2020.594841] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 11/03/2020] [Indexed: 12/16/2022] Open
Abstract
Introduction Richter Syndrome (RS) is defined as the development of an aggressive lymphoma in the context of Chronic Lymphocytic Leukemia (CLL), with a Diffuse Large B-Cell Lymphoma (DLBCL) histology in 95% cases. RS genomic landscape shares only a few features with de novo DLBCLs and is marked by a wide spectrum of cytogenetic abnormalities. Little is known about RS microenvironment. Therapeutic options and efficacy are limited, leading to a 12 months median overall survival. The new targeted treatments usually effective in CLL fail to obtain long-term remissions in RS. Methods We reviewed available PubMed literature about RS genomics, PD-1/PD-L1 (Programmed Death 1/Programmed Death Ligand 1) pathway triggering and subsequent new therapeutic options. Results Data from about 207 patients from four landmark papers were compiled to build an overview of RS genomic lesions and point mutations. A number of these abnormalities may be involved in tumor microenvironment reshaping. T lymphocyte exhaustion through PD-L1 overexpression by tumor cells and subsequent PD-1/PD-L1 pathway triggering is frequently reported in solid cancers. This immune checkpoint inhibitor is also described in B lymphoid malignancies, particularly CLL: PD-1 expression is reported in a subset of prolymphocytes from the CLL lymph node proliferation centers. However, there is only few data about PD-1/PD-L1 pathway in RS. In RS, PD-1 expression is a hallmark of recently described « Regulatory B-cells », which interact with tumor microenvironment by producing inhibiting cytokines such as TGF-β and IL-10, impairing T lymphocytes anti-tumoral function. Based upon the discovery of high PD-1 expression on tumoral B lymphocyte from RS, immune checkpoint blockade therapies such as anti-PD-1 antibodies have been tested on small RS cohorts and provided heterogeneous but encouraging results. Conclusion RS genetic landscape and immune evasion mechanisms are being progressively unraveled. New protocols using targeted treatments such as checkpoint inhibitors as single agents or in combination with immunochemotherapy are currently being evaluated.
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Affiliation(s)
- Hélène Augé
- Inserm UMRS1256 Nutrition-Génétique et Exposition aux Risque Environnementaux (N-GERE), Université de Lorraine, Nancy, France.,Université de Lorraine, CHRU-Nancy, service d'hématologie clinique, pôle spécialités médicales, Nancy, France
| | - Anne-Béatrice Notarantonio
- Université de Lorraine, CHRU-Nancy, service d'hématologie clinique, pôle spécialités médicales, Nancy, France.,UMR7365 Ingénierie Moléculaire et Physiopathologie Articulaire (IMOPA), CNRS, Université de Lorraine, Nancy, France
| | - Romain Morizot
- Inserm UMRS1256 Nutrition-Génétique et Exposition aux Risque Environnementaux (N-GERE), Université de Lorraine, Nancy, France.,Université de Lorraine, CHRU-Nancy, service d'hématologie clinique, pôle spécialités médicales, Nancy, France
| | - Anne Quinquenel
- Département d'hématologie, Université de Reims Champagne-Ardenne, Reims, France.,Département d'hématologie clinique, Centre Hospitalier Universitaire de Reims, Reims, France
| | - Luc-Matthieu Fornecker
- Université de Strasbourg, Inserm, IRFAC/UMR-S1113, Strasbourg, France.,Département d'hématologie clinique, Institut de Cancérologie Strasbourg Europe, Strasbourg, France
| | - Sébastien Hergalant
- Inserm UMRS1256 Nutrition-Génétique et Exposition aux Risque Environnementaux (N-GERE), Université de Lorraine, Nancy, France
| | - Pierre Feugier
- Inserm UMRS1256 Nutrition-Génétique et Exposition aux Risque Environnementaux (N-GERE), Université de Lorraine, Nancy, France.,Université de Lorraine, CHRU-Nancy, service d'hématologie clinique, pôle spécialités médicales, Nancy, France
| | - Julien Broséus
- Inserm UMRS1256 Nutrition-Génétique et Exposition aux Risque Environnementaux (N-GERE), Université de Lorraine, Nancy, France.,Université de Lorraine, CHRU-Nancy, service d'hématologie biologique, pôle laboratoires, Nancy, France
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Griggio V, Perutelli F, Salvetti C, Boccellato E, Boccadoro M, Vitale C, Coscia M. Immune Dysfunctions and Immune-Based Therapeutic Interventions in Chronic Lymphocytic Leukemia. Front Immunol 2020; 11:594556. [PMID: 33312177 PMCID: PMC7708380 DOI: 10.3389/fimmu.2020.594556] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 10/14/2020] [Indexed: 01/01/2023] Open
Abstract
Chronic lymphocytic leukemia (CLL) is a B-cell malignancy characterized by a wide range of tumor-induced alterations, which affect both the innate and adaptive arms of the immune response, and accumulate during disease progression. In recent years, the development of targeted therapies, such as the B-cell receptor signaling inhibitors and the Bcl-2 protein inhibitor venetoclax, has dramatically changed the treatment landscape of CLL. Despite their remarkable anti-tumor activity, targeted agents have some limitations, which include the development of drug resistance mechanisms and the inferior efficacy observed in high-risk patients. Therefore, additional treatments are necessary to obtain deeper responses and overcome drug resistance. Allogeneic hematopoietic stem cell transplantation (HSCT), which exploits immune-mediated graft-versus-leukemia effect to eradicate tumor cells, currently represents the only potentially curative therapeutic option for CLL patients. However, due to its potential toxicities, HSCT can be offered only to a restricted number of younger and fit patients. The growing understanding of the complex interplay between tumor cells and the immune system, which is responsible for immune escape mechanisms and tumor progression, has paved the way for the development of novel immune-based strategies. Despite promising preclinical observations, results from pilot clinical studies exploring the safety and efficacy of novel immune-based therapies have been sometimes suboptimal in terms of long-term tumor control. Therefore, further advances to improve their efficacy are needed. In this context, possible approaches include an earlier timing of immunotherapy within the treatment sequencing, as well as the possibility to improve the efficacy of immunotherapeutic agents by administering them in combination with other anti-tumor drugs. In this review, we will provide a comprehensive overview of main immune defects affecting patients with CLL, also describing the complex networks leading to immune evasion and tumor progression. From the therapeutic standpoint, we will go through the evolution of immune-based therapeutic approaches over time, including i) agents with broad immunomodulatory effects, such as immunomodulatory drugs, ii) currently approved and next-generation monoclonal antibodies, and iii) immunotherapeutic strategies aiming at activating or administering immune effector cells specifically targeting leukemic cells (e.g. bi-or tri-specific antibodies, tumor vaccines, chimeric antigen receptor T cells, and checkpoint inhibitors).
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Affiliation(s)
- Valentina Griggio
- University Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy.,Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Francesca Perutelli
- University Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy.,Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Chiara Salvetti
- University Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy.,Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Elia Boccellato
- University Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy.,Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Mario Boccadoro
- University Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy.,Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Candida Vitale
- University Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy.,Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Marta Coscia
- University Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy.,Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
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Roessner PM, Seiffert M. T-cells in chronic lymphocytic leukemia: Guardians or drivers of disease? Leukemia 2020; 34:2012-2024. [PMID: 32457353 PMCID: PMC8318881 DOI: 10.1038/s41375-020-0873-2] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 05/12/2020] [Accepted: 05/13/2020] [Indexed: 12/11/2022]
Abstract
Chronic lymphocytic leukemia (CLL) is a B-cell malignancy, which is associated with profound alterations and defects in the immune system and a prevalent dependency on the microenvironmental niche. An abnormal T-cell compartment in the blood of CLL patients was already reported 40 years ago. Since then, our knowledge of T-cell characteristics in CLL has grown steadily, but the question of whether T-cells act as pro-tumoral bystander cells or possess anti-tumoral activity is still under debate. Increased numbers of CD4+ T-helper cell subsets are present in the blood of CLL patients, and T-helper cell cytokines have been shown to stimulate CLL cell survival and proliferation in vitro. In line with this, survival and growth of CLL cells in murine xenograft models have been shown to rely on activated CD4+ T-cells. This led to the hypothesis that T-cells are tumor-supportive in CLL. In recent years, evidence for an enrichment of antigen-experienced CD8+ T-cells in CLL has accumulated, and these cells have been shown to control leukemia in a CLL mouse model. Based on this, it was suggested that CD8+ T-cells recognize CLL-specific antigens and exert an anti-leukemia function. As described for other cancer entities, T-cells in CLL express multiple inhibitory receptors, such as PD-1, and lose their functional capacity, leading to an exhaustion phenotype which has been shown to be more severe in T-cells from secondary lymphoid organs compared with peripheral blood. This exhausted phenotype has been suggested to be causative for the poor response of CLL patients to CAR T-cell therapies. In addition, T-cells have been shown to be affected by drugs that are used to treat CLL, which likely impacts therapy response. This review provides an overview of the current knowledge about alterations of T-cells in CLL, including their distribution, function, and exhaustion state in blood and lymphoid organs, and touches also on the topic of how CLL drugs impact on the T-cell compartment and recent results of T-cell-based immunotherapy. We will discuss potential pathological roles of T-cell subsets in CLL and address the question of whether they foster progression or control of disease.
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Affiliation(s)
- Philipp M Roessner
- Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Martina Seiffert
- Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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Abnormal Expression of BTLA and CTLA-4 Immune Checkpoint Molecules in Chronic Lymphocytic Leukemia Patients. J Immunol Res 2020; 2020:6545921. [PMID: 32775467 PMCID: PMC7407019 DOI: 10.1155/2020/6545921] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 02/07/2020] [Accepted: 02/11/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic lymphocytic leukemia (CLL) is characterized by the peripheral accumulation of neoplastic B cells and is frequently complicated by the systemic immunosuppression associated with an impairment in B and T lymphocyte activation. We hypothesized that the expression of immune checkpoint suppressors B and T lymphocyte attenuator (BTLA) and cytotoxic T lymphocyte antigen (CTLA-4) is disturbed in both lymphocyte subpopulations in CLL. The expression of CTLA-4 and BTLA mRNA was determined by real-time PCR, while CTLA-4 protein expression (surface or intracellular) was estimated in BTLA+ lymphocytes by flow cytometry. In CLL patients, we observed a higher gene transcript level of BTLA and CTLA-4 than in healthy individuals in both freshly isolated and PMA stimulated B and T cells. Remarkably, lower amounts of both inhibitory proteins were found in peripheral blood (PB) CLL B cells, whereas normal BTLA and elevated CTLA-4 were found in T cells. Consistently, there was a prevalence of CTLA-4+ cells within circulating BTLA+ T cells cells of patients confronting PB healthy cells. After in vitro stimulation, the only change found in CLL patients was a decrease in BTLA expression in B and T lymphocytes. In contrast, healthy lymphocytes responded more vigorously as regards the BTLA and CTLA expression with substantially higher frequency of CD69+ cells under the stimulating condition compared to corresponding cells from the CLL group. Our results indicate that CLL development is associated with the affected expression of BTLA and CTLA-4 checkpoint receptors in PB and its impaired expression might be associated with lowering of the threshold for B cell activation and proliferation, while upregulated CTLA-4 expression in CLL peripheral BTLA+ T cells may contribute to suppressed T cell effector functions. This hypothesis needs to be validated in future studies, which would allow us to explain how the increased or decreased expression of these molecules affects the cell function.
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48
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Shariati A, Moradabadi A, Chegini Z, Khoshbayan A, Didehdar M. An Overview of the Management of the Most Important Invasive Fungal Infections in Patients with Blood Malignancies. Infect Drug Resist 2020; 13:2329-2354. [PMID: 32765009 PMCID: PMC7369308 DOI: 10.2147/idr.s254478] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Accepted: 06/26/2020] [Indexed: 12/12/2022] Open
Abstract
In patients with hematologic malignancies due to immune system disorders, especially persistent febrile neutropenia, invasive fungal infections (IFI) occur with high mortality. Aspergillosis, candidiasis, fusariosis, mucormycosis, cryptococcosis and trichosporonosis are the most important infections reported in patients with hematologic malignancies that undergo hematopoietic stem cell transplantation. These infections are caused by opportunistic fungal pathogens that do not cause severe issues in healthy individuals, but in patients with hematologic malignancies lead to disseminated infection with different clinical manifestations. Prophylaxis and creating a safe environment with proper filters and air pressure for patients to avoid contact with the pathogens in the surrounding environment can prevent IFI. Furthermore, due to the absence of specific symptoms in IFI, rapid and accurate diagnosis reduces the mortality rate of these infections and using molecular techniques along with standard mycological methods will improve the diagnosis of disseminated fungal infection in patients with hematologic disorders. Amphotericin B products, extended-spectrum azoles, and echinocandins are the essential drugs to control invasive fungal infections in patients with hematologic malignancies, and according to various conditions of patients, different results of treatment with these drugs have been reported in different studies. On the other hand, drug resistance in recent years has led to therapeutic failures and deaths in patients with blood malignancies, which indicates the need for antifungal susceptibility tests to use appropriate therapies. Life-threatening fungal infections have become more prevalent in patients with hematologic malignancies in recent years due to the emergence of new risk factors, new species, and increased drug resistance. Therefore, in this review, we discuss the different dimensions of the most critical invasive fungal infections in patients with hematologic malignancies and present a list of these infections with different clinical manifestations, treatment, and outcomes.
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Affiliation(s)
- Aref Shariati
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alireza Moradabadi
- Department of Medical Parasitology and Mycology, Arak University of Medical Sciences, Arak, Iran
| | - Zahra Chegini
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Amin Khoshbayan
- Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
| | - Mojtaba Didehdar
- Department of Medical Parasitology and Mycology, Arak University of Medical Sciences, Arak, Iran
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Repurposing Food and Drug Administration-Approved Drugs to Promote Antitumor Immunity. ACTA ACUST UNITED AC 2020; 25:88-99. [PMID: 30896530 DOI: 10.1097/ppo.0000000000000368] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
There has been a major resurgence of interest in immune-based approaches to treat cancer, based largely on the success of checkpoint inhibitors (anti-cytotoxic T-lymphocyte-associated antigen 4, anti-programmed cell death 1, and anti-programmed cell death ligand 1 antibodies) in several malignancies. However, not all tumors respond to checkpoint therapy, and there is clearly a need for additional approaches for enhancing tumor immunity. We summarize the critical elements necessary for mounting an efficacious T-cell response to a tumor. We cite drugs approved by the Food and Drug Administration for no-cancer indications that could be repurposed and used as part of an antitumor immune cocktail. We also list cancer drugs not initially intended to impact tumor immunity (soft repurposing) but that have been found to modulate the immune system. We highlight those drugs that might be used in combination with checkpoint inhibitors to increase response rates and survival of cancer patients. Our focus will be on drugs for which there are limited but existing human data. We cite supporting mechanistic mouse data as well. Repurposing drugs to modulate antitumor immunity is an opportunity to rapidly bring new, effective, and affordable treatments to cancer patients.
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50
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Ringelstein-Harlev S. Immune dysfunction complexity in chronic lymphocytic leukemia ‒ an issue to consider when designing novel therapeutic strategies. Leuk Lymphoma 2020; 61:2050-2058. [PMID: 32336174 DOI: 10.1080/10428194.2020.1755857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
A complex interplay between chronic lymphocytic leukemia (CLL) cells and different constituents of the immune system generally results in immune tolerance. As targeted therapies are gaining a critical role in the therapeutic landscape of this disease, their impact on the already perturbed immune milieu needs to be considered. This review addresses the issues of basic immune dysfunction in CLL which is further complicated by the effects of a number of novel targeted therapies used for this malignancy. These new approaches may simultaneously facilitate both anti- and pro-cancer activity, potentially compromising the depth of response to therapy. Current evidence suggests that exploiting combination therapy could potentially overcome at least part of these deleterious effects, thereby prolonging response to treatment and helping to restore immune activity.
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Affiliation(s)
- Shimrit Ringelstein-Harlev
- Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel.,The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
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