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James CA, Baer JM, Zou C, Panni UY, Knolhoff BL, Hogg GD, Kingston NL, Kang LI, Lander VE, Luo J, Tao Y, Watson MA, Aft R, Fields RC, Hawkins WG, DeNardo DG. Systemic Alterations in Type-2 Conventional Dendritic Cells Lead to Impaired Tumor Immunity in Pancreatic Cancer. Cancer Immunol Res 2023; 11:1055-1067. [PMID: 37229629 PMCID: PMC10524961 DOI: 10.1158/2326-6066.cir-21-0946] [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: 11/05/2021] [Revised: 10/04/2022] [Accepted: 05/23/2023] [Indexed: 05/27/2023]
Abstract
Intratumoral T-cell dysfunction is a hallmark of pancreatic tumors, and efforts to improve dendritic cell (DC)-mediated T-cell activation may be critical in treating these immune therapy unresponsive tumors. Recent evidence indicates that mechanisms that induce dysfunction of type 1 conventional DCs (cDC1) in pancreatic adenocarcinomas (PDAC) are drivers of the lack of responsiveness to checkpoint immunotherapy. However, the impact of PDAC on systemic type 2 cDC2 development and function has not been well studied. Herein, we report the analysis of 3 cohorts, totaling 106 samples, of human blood and bone marrow (BM) from patients with PDAC for changes in cDCs. We found that circulating cDC2s and their progenitors were significantly decreased in the blood of patients with PDAC, and repressed numbers of cDC2s were associated with poor prognosis. Serum cytokine analyses identified IL6 as significantly elevated in patients with PDAC and negatively correlated with cDC numbers. In vitro, IL6 impaired the differentiation of cDC1s and cDC2s from BM progenitors. Single-cell RNA sequencing analysis of human cDC progenitors in the BM and blood of patients with PDAC showed an upregulation of the IL6/STAT3 pathway and a corresponding impairment of antigen processing and presentation. These results suggested that cDC2s were systemically suppressed by inflammatory cytokines, which was linked to impaired antitumor immunity.
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Affiliation(s)
- C. Alston James
- Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - John M. Baer
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Chong Zou
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Usman Y. Panni
- Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Brett L. Knolhoff
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Graham D. Hogg
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Natalie L Kingston
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Liang-I Kang
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Varintra E. Lander
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Jingqin Luo
- Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Yu Tao
- Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Mark A. Watson
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Rebecca Aft
- Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Ryan C. Fields
- Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - William G. Hawkins
- Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - David G. DeNardo
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
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2003-2013, a valuable study: Autologous tumor lysate-pulsed dendritic cell immunotherapy with cytokine-induced killer cells improves survival in stage IV breast cancer. Immunol Lett 2017; 183:37-43. [PMID: 28143792 DOI: 10.1016/j.imlet.2017.01.014] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 01/24/2017] [Accepted: 01/24/2017] [Indexed: 12/21/2022]
Abstract
Dendritic cells (DCs) and cytokine-induced killer (CIK) cells have both shown activity as immunotherapy in some malignancies. Our aim was to prospective assess the effect of this immunotherapy in patients with stage IV breast cancer. Between Aug 2003 and Dec 2013, we collected 368 patients who met inclusion criteria and divided into immunotherapy group (treatment group: 188 patients) and chemotherapy group (control group: 180 patients). DCs were prepared from the mononuclear cells isolated from patients in the treatment group using IL-2/GM-CSF and were loaded with tumour antigens; CIK cells were prepared by incubating peripheral blood lymphocytes with IL-2, IFN-γ, and CD3 antibodies. After the patients had received low-dose chemotherapy, those in the treatment group also received the DC-CIK therapy, which was repeated four times in a fortnight to form one cycle. At least three cycles of DC-CIK therapy were given. Immune function was measured in treatment group patients' sera. Disease-free survival (DFS) and Overall survival (OS) after the diagnosis of stage IV breast cancer was assessed after a 10-year follow-up. The result demonstrated that immune function is obviously enhanced after DC-CIK therapy. By Cox regression analysis, DC-CIK therapy reduced the risk of disease progression (p<0.01) with an increased OS (p<0.01). After low-dose chemotherapy, active immunization with DC-CIK immunotherapy is a potentially effective approach for the control of tumour growth in stage IV breast cancer patients.
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Gao D, Li C, Xie X, Zhao P, Wei X, Sun W, Liu HC, Alexandrou AT, Jones J, Zhao R, Li JJ. Autologous tumor lysate-pulsed dendritic cell immunotherapy with cytokine-induced killer cells improves survival in gastric and colorectal cancer patients. PLoS One 2014; 9:e93886. [PMID: 24699863 PMCID: PMC3974849 DOI: 10.1371/journal.pone.0093886] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Accepted: 03/10/2014] [Indexed: 12/22/2022] Open
Abstract
Gastric and colorectal cancers (GC and CRC) have poor prognosis and are resistant to chemo- and/or radiotherapy. In the present study, the prophylactic effects of dendritic cell (DC) vaccination are evaluated on disease progression and clinical benefits in a group of 54 GC and CRC patients treated with DC immunotherapy combined with cytokine-induced killer (CIK) cells after surgery with or without chemo-radiotherapy. DCs were prepared from the mononuclear cells isolated from patients using IL-2/GM-CSF and loaded with tumor antigens; CIK cells were prepared by incubating peripheral blood lymphocytes with IL-2, IFN-γ, and CD3 antibodies. The DC/CIK therapy started 3 days after low-dose chemotherapy and was repeated 3–5 times in 2 weeks as one cycle with a total of 188.3±79.8×106 DCs and 58.8±22.3×108 CIK cells. Cytokine levels in patients' sera before and after treatments were measured and the follow-up was conducted for 98 months to determine disease-free survival (DFS) and overall survival (OS). The results demonstrate that all cytokines tested were elevated with significantly higher levels of IFN-γ and IL-12 in both GC and CRC cohorts of DC/CIK treated patients. By Cox regression analysis, DC/CIK therapy reduced the risk of post-operative disease progression (p<0.01) with an increased OS (<0.01). These results demonstrate that in addition to chemo- and/or radiotherapy, DC/CIK immunotherapy is a potential effective approach in the control of tumor growth for post-operative GC and CRC patients.
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Affiliation(s)
- Daiqing Gao
- Biotherapy Center, Qingdao Center Hospital, The Second Affiliated Hospital, Qingdao University Medical College, Qingdao, China
- * E-mail: (DG); (JJL)
| | - Changyou Li
- Biotherapy Center, Qingdao Center Hospital, The Second Affiliated Hospital, Qingdao University Medical College, Qingdao, China
| | - Xihe Xie
- Biotherapy Center, Qingdao Center Hospital, The Second Affiliated Hospital, Qingdao University Medical College, Qingdao, China
| | - Peng Zhao
- Biotherapy Center, Qingdao Center Hospital, The Second Affiliated Hospital, Qingdao University Medical College, Qingdao, China
| | - Xiaofang Wei
- Biotherapy Center, Qingdao Center Hospital, The Second Affiliated Hospital, Qingdao University Medical College, Qingdao, China
| | - Weihong Sun
- Biotherapy Center, Qingdao Center Hospital, The Second Affiliated Hospital, Qingdao University Medical College, Qingdao, China
| | - Hsin-Chen Liu
- Department of Radiation Oncology, NCI-Designated Comprehensive Cancer Center, University of California at Davis Sacramento, Sacramento, California, United States of America
| | - Aris T. Alexandrou
- Department of Radiation Oncology, NCI-Designated Comprehensive Cancer Center, University of California at Davis Sacramento, Sacramento, California, United States of America
| | - Jennifer Jones
- Department of Medicine, University of Saskatchewan, Saskatoon, Canada
| | - Ronghua Zhao
- Department of Medicine, University of Saskatchewan, Saskatoon, Canada
| | - Jian Jian Li
- Department of Radiation Oncology, NCI-Designated Comprehensive Cancer Center, University of California at Davis Sacramento, Sacramento, California, United States of America
- * E-mail: (DG); (JJL)
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Park H, Cho JA, Kim SK, Kim JH, Lee SH. Hyperthermia on mesenchymal stem cells (MSCs) can sensitize tumor cells to undergo cell death†. Int J Hyperthermia 2009; 24:638-48. [DOI: 10.1080/02656730802253117] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
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Herrmann TL, Agrawal RS, Connolly SF, McCaffrey RL, Schlomann J, Kusner DJ. MHC Class II levels and intracellular localization in human dendritic cells are regulated by calmodulin kinase II. J Leukoc Biol 2007; 82:686-99. [PMID: 17586661 DOI: 10.1189/jlb.0107045] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Dendritic cells (DC) are professional APC, which activate the adaptive immune response. A Ca2+-calmodulin (CaM)-CaM kinase II (CaMKII) pathway regulates maturation and MHC Class II antigen presentation in human DC. The objective of this study was to characterize the mechanisms by which CaMKII modulates the levels and subcellular distribution of MHC Class II molecules. Inhibition of CaMKII via the highly specific, autoinhibitory peptide derived from the enzyme's regulatory domain resulted in rapid (60 min) and sustained (24 h) reduction of MHC Class II levels in antigen-stimulated, primary, human DC. The initial depletion of intracellular and cell surface MHC Class II was associated with its enhanced lysosomal trafficking and increased activity of specific proteases in the absence of effects on other transmembrane proteins (CD1b and CD34) or a detectable change in lysosomal degradation of exogenous protein. Inhibition of CaMKII also resulted in significant reductions in the level and stability of MHC Class II mRNA and the levels and nucleocytosolic localization of its major transcriptional regulator CIITA. These data support a model in which CaMKII regulates the levels and localization of MHC Class II protein in human DC via transcriptional, post-transcriptional, and post-translational mechanisms. These pathways are likely important to the physiologic regulation of MHC Class II as well as to its dysregulation in disease states associated with altered CaMKII function.
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Affiliation(s)
- Tara L Herrmann
- The Inflammation Program, Division of Infectious Diseases, University of Iowa Carver College of Medicine, 200 Hawkins Dr., SW 54-8, GH, Iowa City, IA 52242, USA
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Zhao YR, Gong L, He YL, Liu F, Lu C. Relationship between polymorphism of class II transactivator gene promoters and chronic hepatitis B. World J Gastroenterol 2005; 11:854-7. [PMID: 15682480 PMCID: PMC4250596 DOI: 10.3748/wjg.v11.i6.854] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the relationship between the polymorphism of class II transactivator (CIITA) gene promoters and chronic hepatitis B (CHB).
METHODS: Genomic DNA was prepared from peripheral blood leukocytes. Promoters I, III and IV of gene were analyzed respectively with polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) in 65 patients with CHB, 26 patients with acute hepatitis B (AHB) and 85 normal controls.
RESULTS: No abnormal migration was found in PCR-SSCP analysis of the three promoters in the three groups. Also, no sequential difference was observed at the three promoters among the CHB patients, AHB patients and normal controls.
CONCLUSION: No polymorphism in promoters I, III and IV of CIITA gene exists in CHB patients, ABH patients and normal controls, suggesting that the promoter of CIITA gene might be a conserved domain.
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Affiliation(s)
- Ying-Ren Zhao
- Department of Infectious Diseases, First Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.
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Kawakami Y, Curiel TJ, Curiel DT. Cancer gene therapy and immunotherapy. ACTA ACUST UNITED AC 2004; 21:327-37. [PMID: 15338753 DOI: 10.1016/s0921-4410(03)21016-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/30/2023]
Affiliation(s)
- Yosuke Kawakami
- Department of Medicine, Surgery and Pathology, University of Alabama at Birmingham, 35294-2172, USA
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Nagaraj S, Ziske C, Schmidt-Wolf IGH. Human cytokine-induced killer cells have enhanced in vitro cytolytic activity via non-viral interleukin-2 gene transfer. GENETIC VACCINES AND THERAPY 2004; 2:12. [PMID: 15329148 PMCID: PMC516021 DOI: 10.1186/1479-0556-2-12] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/11/2004] [Accepted: 08/25/2004] [Indexed: 11/21/2022]
Abstract
Modulation of the immune system by genetically modified immunological effector cells is of potential therapeutic value in the treatment of malignancies. Interleukin-2 (IL-2) is a crucial cytokine which induces potent antitumor response. Cytokine-induced killer cells (CIK) have been described as highly efficient cytotoxic effector cells capable of lysing tumor cell targets and are capable of recognizing these cells in a non-MHC restricted fashion. Dendritic cells (DC) are the major antigen presenting cells. This study evaluated the antitumor effect of CIK cells which were non-virally transfected with IL-2 and co-cultured with pulsed and unpulsed DC. Human CIK cells generated from peripheral blood were transfected in vitro with plasmid encoding for the human IL-2. Transfection involved a combination of electrical parameters and a specific solution to deliver plasmid directly to the cell nucleus by using the Nucleofector® electroporation system. Nucleofection resulted in the production of IL-2 with a mean of 478.5 pg/106 cells (range of 107.6–1079.3 pg /106 cells/24 h) compared to mock transfected CIK cells (31 pg/106 cells) (P = 0.05). After co-culturing with DC their functional ability was assessed in vitro by a cytotoxicity assay. On comparison with non-transfected CIK cells co-cultured with DCs (36.5 ± 5.3 %), transfected CIK cells co-cultured with DC had a significantly higher lytic activity of 58.5 ± 3.2% (P = 0.03) against Dan G cells, a human pancreatic carcinoma cell line.
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Affiliation(s)
- Srinivas Nagaraj
- Department of Internal Medicine I, General Internal Medicine Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany
| | - Carsten Ziske
- Department of Internal Medicine I, General Internal Medicine Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany
| | - Ingo GH Schmidt-Wolf
- Department of Internal Medicine I, General Internal Medicine Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany
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You Y, Zou P, Guo R. Expression of CII TA gene in five human malignant hematological cell lines and its significance. Curr Med Sci 2004; 24:338-41. [PMID: 15587393 DOI: 10.1007/bf02861862] [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: 12/27/2003] [Indexed: 10/19/2022]
Abstract
The role of MHC class II transactivator (C II TA) in constitutive or IFN-gamma inducible expression of HLA molecules in human malignant hematological cell lines was investigated. The expression of HLA molecules and C II TA protein was detected by Western blot, immunohistochemistry and flow cytometry. The expression of C II TA gene was determined by RT-PCR. The capability of peripheral blood T cell reaction stimulated by tumor cells was monitored by mixed lymphocyte reaction. It was found that the HLAII-positive tumor cells expressed the C II TA quite well, and the expression of HLA I + II was increased in the tumor cells with constitutive or inducible expression of C II TA after induced by IFN-gamma. The tumor cells which did not express C II TA after induced by IFN-gamma were not response to the expression of HLA II promoted by IFN-gamma. It suggests a correlation between the inability of some malignant hematological cell lines in response to IFN-gamma for HLA expression and the deficiency in the inducible expression of C II TA, indicating C II TA might take part in the regulation of HLA I + II expression in the tumor cells, which might play an important role in tumor immunologic escape.
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Affiliation(s)
- Yong You
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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Reinhard G, Märten A, Kiske SM, Feil F, Bieber T, Schmidt-Wolf IGH. Generation of dendritic cell-based vaccines for cancer therapy. Br J Cancer 2002; 86:1529-33. [PMID: 12085199 PMCID: PMC2746586 DOI: 10.1038/sj.bjc.6600316] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2001] [Revised: 03/15/2002] [Accepted: 03/27/2002] [Indexed: 12/13/2022] Open
Abstract
Dendritic cells play a major role in the generation of immunity against tumour cells. They can be grown under various culture conditions, which influence the phenotypical and functional properties of dendritic cells and thereby the consecutive immune response mainly executed by T cells. Here we discuss various conditions, which are important during generation and administration of dendritic cells to elicit a tumouricidal T cell-based immune response.
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Affiliation(s)
- G Reinhard
- Klinik und Poliklinik für Dermatologie der Rheinischen Friedrich-Wilhelms-Universität Bonn, Germany
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Abstract
The presentation of peptides to T cells by MHC class II molecules is of critical importance in specific recognition by the immune system. Expression of class II molecules is exquisitely controlled at the transcriptional level. A large set of proteins interact with the promoters of class II genes. The most important of these is CIITA, a master controller that orchestrates expression but does not bind directly to the promoter. The transcriptosome complex formed at class II promoters is a model for induction of gene expression.
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Affiliation(s)
- Jenny Pan-Yun Ting
- Department of Microbiology and Immunology and The Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
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