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Chen H, Zhu Y, Zhang C, Hu L, Yang K. Engineered bacteria in tumor immunotherapy. Cancer Lett 2024; 589:216817. [PMID: 38492769 DOI: 10.1016/j.canlet.2024.216817] [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: 12/14/2023] [Revised: 03/12/2024] [Accepted: 03/12/2024] [Indexed: 03/18/2024]
Abstract
As the limitations of cancer immunotherapy become increasingly apparent, there is considerable anticipation regarding the utilization of biological tools to enhance treatment efficacy, particularly bacteria and their derivatives. Leveraging advances in genetic and synthetic biology technologies, engineered bacteria now play important roles far beyond those of conventional immunoregulatory agents, and they could function as tumor-targeting vehicles and in situ pharmaceutical factories. In recent years, these engineered bacteria play a role in almost every aspect of immunotherapy. It is nothing short of impressive to keep seeing different strain of bacteria modified in diverse ways for unique immunological enhancement. In this review, we have scrutinized the intricate interplay between the immune system and these engineered bacteria. These interactions generate strategies that can directly or indirectly optimize immunotherapy and even modulate the effects of combination therapies. Collectively, these engineered bacteria present a promising novel therapeutic strategy that promises to change the current landscape of immunotherapy.
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Affiliation(s)
- Hua Chen
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X) and Collaborative Innovation Centre of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, 199 Renai Road, Suzhou, 215123, China
| | - Yinrui Zhu
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X) and Collaborative Innovation Centre of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, 199 Renai Road, Suzhou, 215123, China
| | - Chonghai Zhang
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X) and Collaborative Innovation Centre of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, 199 Renai Road, Suzhou, 215123, China
| | - Lin Hu
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X) and Collaborative Innovation Centre of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, 199 Renai Road, Suzhou, 215123, China.
| | - Kai Yang
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X) and Collaborative Innovation Centre of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, 199 Renai Road, Suzhou, 215123, China.
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Howell LM, Manole S, Reitter AR, Forbes NS. Controlled production of lipopolysaccharides increases immune activation in Salmonella treatments of cancer. Microb Biotechnol 2024; 17:e14461. [PMID: 38758181 PMCID: PMC11100551 DOI: 10.1111/1751-7915.14461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 03/12/2024] [Accepted: 03/17/2024] [Indexed: 05/18/2024] Open
Abstract
Immunotherapies have revolutionized cancer treatment. These treatments rely on immune cell activation in tumours, which limits the number of patients that respond. Inflammatory molecules, like lipopolysaccharides (LPS), can activate innate immune cells, which convert tumour microenvironments from cold to hot, and increase therapeutic efficacy. However, systemic delivery of lipopolysaccharides (LPS) can induce cytokine storm. In this work, we developed immune-controlling Salmonella (ICS) that only produce LPS in tumours after colonization and systemic clearance. We tuned the expression of msbB, which controls production of immunogenic LPS, by optimizing its ribosomal binding sites and protein degradation tags. This genetic system induced a controllable inflammatory response and increased dendritic cell cross-presentation in vitro. The strong off state did not induce TNFα production and prevented adverse events when injected into mice. The accumulation of ICS in tumours after intravenous injection focused immune responses specifically to tumours. Tumour-specific expression of msbB increased infiltration of immune cells, activated monocytes and neutrophils, increased tumour levels of IL-6, and activated CD8 T cells in draining lymph nodes. These immune responses reduced tumour growth and increased mouse survival. By increasing the efficacy of bacterial anti-cancer therapy, localized production of LPS could provide increased options to patients with immune-resistant cancers.
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Affiliation(s)
- Lars M. Howell
- Department of Chemical EngineeringUniversity of Massachusetts AmherstAmherstMassachusettsUSA
| | - Simin Manole
- Molecular and Cellular Biology ProgramUniversity of Massachusetts AmherstAmherstMassachusettsUSA
| | - Alec R. Reitter
- Department of Chemical EngineeringUniversity of Massachusetts AmherstAmherstMassachusettsUSA
| | - Neil S. Forbes
- Department of Chemical EngineeringUniversity of Massachusetts AmherstAmherstMassachusettsUSA
- Molecular and Cellular Biology ProgramUniversity of Massachusetts AmherstAmherstMassachusettsUSA
- Institute for Applied Life Sciences, University of Massachusetts AmherstAmherstMassachusettsUSA
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3
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Singh A, Chatterjee A, Rakshit S, Shanmugam G, Mohanty LM, Sarkar K. Neem Leaf Glycoprotein in immunoregulation of cancer. Hum Immunol 2022; 83:768-777. [DOI: 10.1016/j.humimm.2022.08.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 08/09/2022] [Accepted: 08/16/2022] [Indexed: 11/04/2022]
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Howell LM, Forbes NS. Bacteria-based immune therapies for cancer treatment. Semin Cancer Biol 2021; 86:1163-1178. [PMID: 34547442 DOI: 10.1016/j.semcancer.2021.09.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 09/03/2021] [Accepted: 09/12/2021] [Indexed: 12/23/2022]
Abstract
Engineered bacterial therapies that target the tumor immune landscape offer a new class of cancer immunotherapy. Salmonella enterica and Listeria monocytogenes are two species of bacteria that have been engineered to specifically target tumors and serve as delivery vessels for immunotherapies. Therapeutic bacteria have been engineered to deliver cytokines, gene silencing shRNA, and tumor associated antigens that increase immune activation. Bacterial therapies stimulate both the innate and adaptive immune system, change the immune dynamics of the tumor microenvironment, and offer unique strategies for targeting tumors. Bacteria have innate adjuvant properties, which enable both the delivered molecules and the bacteria themselves to stimulate immune responses. Bacterial immunotherapies that deliver cytokines and tumor-associated antigens have demonstrated clinical efficacy. Harnessing the diverse set of mechanisms that Salmonella and Listeria use to alter the tumor-immune landscape has the potential to generate many new and effective immunotherapies.
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Affiliation(s)
- Lars M Howell
- Department of Chemical Engineering, University of Massachusetts, Amherst, United States
| | - Neil S Forbes
- Department of Chemical Engineering, University of Massachusetts, Amherst, United States.
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Abstract
In patients with ulcerative colitis (UC), dysplasia develops in 10%–20% of cases. The persistence of low-grade dysplasia (LGD) in UC in 2 consecutive observations is still an indication for restorative proctocolectomy. Our hypothesis is that in the case of weak cytotoxic activation, dysplasia persists. We aimed to identify possible immunological markers of LGD presence and persistence.
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Liu X, Zhang Z, Liu J, Wang Y, Zhou Q, Wang S, Wang X. Ginsenoside Rg3 improves cyclophosphamide-induced immunocompetence in Balb/c mice. Int Immunopharmacol 2019; 72:98-111. [PMID: 30974284 DOI: 10.1016/j.intimp.2019.04.003] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 03/19/2019] [Accepted: 04/02/2019] [Indexed: 10/27/2022]
Abstract
Ginsenoside Rg3 (Rg3), which comprises Panax ginseng, is commonly used to improve the immunocompetence of cancer patients undergoing chemotherapy. This study was designed to elucidate the immunoenhancement effects of Rg3 in immunosuppressed mice induced by cyclophosphamide (CTX) treatment. Balb/c mice were administered Rg3 intragastrically once daily for 19 consecutive days and were intraperitoneally administered CTX (80 mg/kg) on days 15-19. Weight and immune organ indices were recorded. Hematological tests and cytokines were assessed using ELISA. We measured the activity of LDH and ACP, performed pathological and immunohistochemical staining of immune organs, and evaluated cytokines and transcription factors using RT-PCR. Immunosuppressed mice showed weight loss, decreased thymus and spleen indices and severe pathological damage. CTX attenuated macrophage phagocytosis by decreasing activity of LDH and ACP and decreased the release of related immune factors, IgG, IL-2 and G-CSF. Subsequently, we observed T lymphocyte expression on the surface of the thymus and spleen, which inhibited T cell activity. Further mechanistic analysis showed that CTX decreased the expression of T-bet and IFN-γ and increased the expression of GATA-3 and IL-4 in the thymus and spleen, which affected the Th1/Th2 balance. However, Rg3 treatment reversed CTX-induced immunosuppression. In summary, all the results suggest that Rg3 has protective effects on CTX-induced immunosuppression, which could be partially related to macrophages, T cells and Th1/Th2 balance. Although deeper studies of its mechanism are needed, these findings support the hypothesis that Rg3 can improve the reduced immunocompetence after CTX injury.
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Affiliation(s)
- Xiao Liu
- State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Zhaojian Zhang
- State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Jinghua Liu
- State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Yu Wang
- State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Qian Zhou
- Department of Anatomy, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishiku, Kitakyushu 807-8555, Japan
| | - Siwei Wang
- State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Xiaoying Wang
- State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
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Tumor mechanisms of resistance to immune attack. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2019; 164:61-100. [PMID: 31383409 DOI: 10.1016/bs.pmbts.2019.03.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The immune system plays a key role in the interactions between host and tumor. Immune selection pressure is a driving force behind the sculpting and evolution of malignant cancer cells to escape this immune attack. Several common tumor cell-based mechanisms of resistance to immune attack have been identified and can be broadly categorized into three main classes: loss of antigenicity, loss of immunogenicity, and creation of an immunosuppressive microenvironment. In this review, we will discuss in detail the relevant literature associated with each class of resistance and will describe the relevance of these mechanisms to human cancer patients. To conclude, we will outline the implications these mechanisms have for the treatment of cancer using currently available therapeutic approaches. Immunotherapy has been a successful addition to current treatment approaches, but many patients either do not respond or quickly become resistant. This reflects the ability of tumors to continue to adapt to immune selection pressure at all stages of development. Additional study of immune escape mechanisms and immunotherapy resistance mechanisms will be needed to inform future treatment approaches.
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Jović V, Konjević G, Radulović S, Jelić S, Spuzić I. Impaired Perforin-Dependent NK Cell Cytotoxicity and Proliferative Activity of Peripheral Blood T Cells is Associated with Metastatic Melanoma. TUMORI JOURNAL 2018; 87:324-9. [PMID: 11765182 DOI: 10.1177/030089160108700509] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Aims and Background Patients with metastatic melanoma often have defects in the percentage and function of peripheral blood NK cells, which are involved in the non-specific innate antitumor immune response, and T cells, which participate in the specific acquired antitumor immune response. The aim of this study was to investigate in more detail not only the percentage but also the activation status and function of NK and T cells in patients with metastatic melanoma prior to therapy. Methods The percentage of peripheral blood CD56+ NK cells, CD3+ T cells and their CD4+ and CD8+ subsets, as well as the expression of the activation antigens CD69, CD38 and HLA-DR were analyzed by flow cytometry. The functional capacity of NK cells was evaluated by the 51-chromium release cytotoxicity assay, while the proliferative activity of T cells was estimated by the lymphocyte transformation test to mitogen phytohemagglutinin. Results The results obtained in this study have revealed a new aspect of NK and T cell dysfunction that is not, as commonly reported, associated with a decrease in their percentage. Moreover, a significant number of the investigated patients had a higher percentage of NK cells that did not lead to improved NK ceil cytotoxicity as a result of the detected defect in the NK cell perforin-mediated cytotoxic mechanism of tumor cell lysis. The impaired proliferative response of T cells was associated with a decreased expression of the activation antigen HLA-DR. Conclusion The novel finding in this study of melanoma patients with metastatic disease is the impaired perforin-depen-dent NK cell cytotoxic mechanism, which was recently shown to be primarily responsible for preventing metastasis. Another interesting finding was the generally hyporeactive status of T cells, possibly resulting from persistent antigenic stimulation. The observed dysfunction of NK and T cells in patients with metastatic melanoma prior to therapy point to the need to supplement chemotherapy with appropriate immunotherapeutic agents in order to overcome the immunosuppression associated with advanced malignancy.
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Affiliation(s)
- V Jović
- Institute for Oncology and Radiology of Serbia, Belgrade
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Hishiki T, Mise N, Harada K, Ihara F, Takami M, Saito T, Terui K, Nakata M, Komatsu S, Yoshida H, Motohashi S. Frequency and proliferative response of circulating invariant natural killer T cells in pediatric patients with malignant solid tumors. Pediatr Surg Int 2018; 34:169-176. [PMID: 29018953 DOI: 10.1007/s00383-017-4185-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/21/2017] [Indexed: 12/16/2022]
Abstract
BACKGROUND Invariant natural killer T (iNKT) cells play an important role in tumor immunity, enhancing both innate and acquired immunity. We have previously shown the enhancement of antibody-dependent cellular cytotoxicity against neuroblastoma by activated iNKT cells. As a first step towards clinical application, we studied the frequency and proliferative response of circulating iNKT cells in children with and without cancer. METHODS Blood samples were collected from 10 patients with pediatric malignant solid tumors and 11 patients with non-neoplastic diseases (control). The frequency of circulating iNKT cells was quantified by flow cytometry. Whole peripheral blood mononuclear cells were then stimulated with α-galactosylceramide (α-GalCer) for 7 days, and the expansion rate of the iNKT-cell fraction was assessed. RESULTS The frequency of iNKT cells in the patients of the cancer and control group did not differ to a statistically significant extent. The iNKT-cell population increased after α-GalCer stimulation in all cases. The iNKT cells of patients who had undergone intensive chemotherapy also had the potential to expand in vitro. CONCLUSIONS Unlike adult cancer patients, the numbers of circulating iNKT cells were not decreased in pediatric cancer patients. α-GalCer stimulation induced a proliferative response in all of the patients.
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Affiliation(s)
- Tomoro Hishiki
- Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan. .,Division of Surgical Oncology, Children's Cancer Center, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan. .,Division of Pediatric Surgical Oncology, National Cancer Center Hospital, Tokyo, Japan.
| | - Naoko Mise
- Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.,Department of Medical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kazuaki Harada
- Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.,Department of Medical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Fumie Ihara
- Department of Medical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Mariko Takami
- Department of Medical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Takeshi Saito
- Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Keita Terui
- Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Mitsuyuki Nakata
- Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Shugo Komatsu
- Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hideo Yoshida
- Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Shinichiro Motohashi
- Department of Medical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan
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Mahmoud F, Shields B, Makhoul I, Avaritt N, Wong HK, Hutchins LF, Shalin S, Tackett AJ. Immune surveillance in melanoma: From immune attack to melanoma escape and even counterattack. Cancer Biol Ther 2017; 18:451-469. [PMID: 28513269 DOI: 10.1080/15384047.2017.1323596] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Pharmacologic inhibition of the cytotoxic T lymphocyte antigen 4 (CTLA4) and the programmed death receptor-1 (PD1) has resulted in unprecedented durable responses in metastatic melanoma. However, resistance to immunotherapy remains a major challenge. Effective immune surveillance against melanoma requires 4 essential steps: activation of the T lymphocytes, homing of the activated T lymphocytes to the melanoma microenvironment, identification and episode of melanoma cells by activated T lymphocytes, and the sensitivity of melanoma cells to apoptosis. At each of these steps, there are multiple factors that may interfere with the immune surveillance machinery, thus allowing melanoma cells to escape immune attack and develop resistance to immunotherapy. We provide a comprehensive review of the complex immune surveillance mechanisms at play in melanoma, and a detailed discussion of how these mechanisms may allow for the development of intrinsic or acquired resistance to immunotherapeutic modalities, and potential avenues for overcoming this resistance.
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Affiliation(s)
- Fade Mahmoud
- a Department of Internal Medicine, Division of Hematology/Oncology , University of Arkansas for Medical Sciences , Little Rock , Arkansas , USA
| | - Bradley Shields
- b Department of Biochemistry and Molecular Biology , University of Arkansas for Medical Sciences , Little Rock , Arkansas , USA
| | - Issam Makhoul
- a Department of Internal Medicine, Division of Hematology/Oncology , University of Arkansas for Medical Sciences , Little Rock , Arkansas , USA
| | - Nathan Avaritt
- b Department of Biochemistry and Molecular Biology , University of Arkansas for Medical Sciences , Little Rock , Arkansas , USA
| | - Henry K Wong
- c Department of Dermatology , University of Arkansas for Medical Sciences , Little Rock , Arkansas , USA
| | - Laura F Hutchins
- a Department of Internal Medicine, Division of Hematology/Oncology , University of Arkansas for Medical Sciences , Little Rock , Arkansas , USA
| | - Sara Shalin
- d Departments of Pathology and Dermatology , University of Arkansas for Medical Sciences , Little Rock , Arkansas , USA
| | - Alan J Tackett
- b Department of Biochemistry and Molecular Biology , University of Arkansas for Medical Sciences , Little Rock , Arkansas , USA
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Lapeyre-Prost A, Terme M, Pernot S, Pointet AL, Voron T, Tartour E, Taieb J. Immunomodulatory Activity of VEGF in Cancer. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2016; 330:295-342. [PMID: 28215534 DOI: 10.1016/bs.ircmb.2016.09.007] [Citation(s) in RCA: 145] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The ability of tumor cells to escape tumor immunosurveillance contributes to cancer development. Factors produced in the tumor microenvironment create "tolerizing" conditions and thereby help the tumor to evade antitumoral immune responses. VEGF-A, already known for its major role in tumor vessel growth (neoangiogenesis), was recently identified as a key factor in tumor-induced immunosuppression. In particular, VEGF-A fosters the proliferation of immunosuppressive cells, limits T-cell recruitment into tumors, and promotes T-cell exhaustion. Antiangiogenic therapies have shown significant efficacy in patients with a variety of solid tumors, preventing tumor progression by limiting tumor-induced angiogenesis. VEGF-targeting therapies have also been shown to modulate the tumor-induced immunosuppressive microenvironment, enhancing Th1-type T-cell responses and increasing tumor infiltration by T cells. The immunomodulatory properties of VEGF-targeting therapies open up new perspectives for cancer treatment, especially through strategies combining antiangiogenic drugs with immunotherapy. Preclinical models and early clinical studies of these combined approaches have given promising results.
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Affiliation(s)
- A Lapeyre-Prost
- INSERM U970, PARCC (Paris Cardiovascular Research Center), Université Paris-Descartes, Paris, France
| | - M Terme
- INSERM U970, PARCC (Paris Cardiovascular Research Center), Université Paris-Descartes, Paris, France.
| | - S Pernot
- INSERM U970, PARCC (Paris Cardiovascular Research Center), Université Paris-Descartes, Paris, France; Service d'hépatogastroentérologie et d'oncologie digestive, Hôpital Européen Georges Pompidou, Paris, France
| | - A-L Pointet
- INSERM U970, PARCC (Paris Cardiovascular Research Center), Université Paris-Descartes, Paris, France; Service d'hépatogastroentérologie et d'oncologie digestive, Hôpital Européen Georges Pompidou, Paris, France
| | - T Voron
- INSERM U970, PARCC (Paris Cardiovascular Research Center), Université Paris-Descartes, Paris, France; Service de chirurgie digestive, Hôpital Européen Georges Pompidou, Paris, France
| | - E Tartour
- INSERM U970, PARCC (Paris Cardiovascular Research Center), Université Paris-Descartes, Paris, France; Service d'immunologie biologique. Hôpital Européen Georges Pompidou, Paris, France
| | - J Taieb
- INSERM U970, PARCC (Paris Cardiovascular Research Center), Université Paris-Descartes, Paris, France; Service d'hépatogastroentérologie et d'oncologie digestive, Hôpital Européen Georges Pompidou, Paris, France.
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Crucial Contributions by T Lymphocytes (Effector, Regulatory, and Checkpoint Inhibitor) and Cytokines (TH1, TH2, and TH17) to a Pathological Complete Response Induced by Neoadjuvant Chemotherapy in Women with Breast Cancer. J Immunol Res 2016; 2016:4757405. [PMID: 27777963 PMCID: PMC5061970 DOI: 10.1155/2016/4757405] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Revised: 08/19/2016] [Accepted: 08/24/2016] [Indexed: 02/07/2023] Open
Abstract
The tumour microenvironment consists of malignant cells, stroma, and immune cells. Prominent tumour-infiltrating lymphocytes (TILs) in breast cancer are associated with a good prognosis and are predictors of a pathological complete response (pCR) with neoadjuvant chemotherapy (NAC). The contribution of different T effector/regulatory cells and cytokines to tumour cell death with NAC requires further characterisation and was investigated in this study. Breast tumours from 33 women with large and locally advanced breast cancers undergoing NAC were immunohistochemically (intratumoural, stromal) assessed for T cell subsets and cytokine expression using labelled antibodies, employing established semiquantitative methods. Prominent levels of TILs and CD4+, CD8+, and CTLA-4+ (stromal) T cells and CD8+ : FOXP3+ ratios were associated with a significant pCR; no association was seen with FOXP3+, CTLA-4+ (intratumoural), and PD-1+ T cells. NAC significantly reduced CD4+, FOXP3+, CTLA-4+ (stromal) (concurrently blood FOXP3+, CTLA-4+ Tregs), and PD-1+ T cells; no reduction was seen with CD8+ and CTLA-4+ (intratumoural) T cells. High post-NAC tumour levels of FOXP3+ T cells, IL-10, and IL-17 were associated with a failed pCR. Our study has characterised further the contribution of T effector/regulatory cells and cytokines to tumour cell death with NAC.
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Roles of ROS mediated oxidative stress and DNA damage in 3-methyl-2-quinoxalin benzenevinylketo-1, 4-dioxide-induced immunotoxicity of Sprague–Dawley rats. Regul Toxicol Pharmacol 2015; 73:587-94. [DOI: 10.1016/j.yrtph.2015.09.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2014] [Revised: 09/01/2015] [Accepted: 09/02/2015] [Indexed: 10/23/2022]
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Yan H, Kamiya T, Suabjakyong P, Tsuji NM. Targeting C-Type Lectin Receptors for Cancer Immunity. Front Immunol 2015; 6:408. [PMID: 26379663 PMCID: PMC4547497 DOI: 10.3389/fimmu.2015.00408] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 07/26/2015] [Indexed: 12/21/2022] Open
Abstract
C-type lectin receptors (CLRs) are a large family of soluble and trans-membrane pattern recognition receptors that are widely and primarily expressed on myeloid cells. CLRs are important for cell-cell communication and host defense against pathogens through the recognition of specific carbohydrate structures. Similar to a family of Toll-like receptors, CLRs signaling are involved in the various steps for initiation of innate immune responses and promote secretion of soluble factors such as cytokines and interferons. Moreover, CLRs contribute to endocytosis and antigen presentation, thereby fine-tune adaptive immune responses. In addition, there may also be a direct activation of acquired immunity. On the other hand, glycans, such as mannose structures, Lewis-type antigens, or GalNAc are components of tumor antigens and ligate CLRs, leading to immunoregulation. Therefore, agonists or antagonists of CLRs signaling are potential therapeutic reagents for cancer immunotherapy. We aim to overview the current knowledge of CLRs signaling and the application of their ligands on tumor-associating immune response.
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Affiliation(s)
- Huimin Yan
- Immune Homeostasis Laboratory, Biomedical Research Institute, National Institute for Advanced Industrial Science and Technology (AIST) , Tsukuba , Japan ; Institute for Liver Disease, Fifth Hospital of Shijiazhuang , Shijiazhuang , China
| | - Tomomori Kamiya
- Immune Homeostasis Laboratory, Biomedical Research Institute, National Institute for Advanced Industrial Science and Technology (AIST) , Tsukuba , Japan ; Research Institute for Biomedical Sciences, Tokyo University of Science , Noda-shi , Japan
| | - Papawee Suabjakyong
- Immune Homeostasis Laboratory, Biomedical Research Institute, National Institute for Advanced Industrial Science and Technology (AIST) , Tsukuba , Japan ; Department of Clinical and Analytical Biochemistry, Graduate School of Pharmaceutical Sciences, Chiba University , Chiba-shi , Japan
| | - Noriko M Tsuji
- Immune Homeostasis Laboratory, Biomedical Research Institute, National Institute for Advanced Industrial Science and Technology (AIST) , Tsukuba , Japan
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Optimal treatment strategy for a tumor model under immune suppression. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2014; 2014:206287. [PMID: 25140193 PMCID: PMC4129922 DOI: 10.1155/2014/206287] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/24/2014] [Revised: 05/02/2014] [Accepted: 05/18/2014] [Indexed: 11/17/2022]
Abstract
We propose a mathematical model describing tumor-immune interactions under immune suppression. These days evidences indicate that the immune suppression related to cancer contributes to its progression. The mathematical model for tumor-immune interactions would provide a new methodology for more sophisticated treatment options of cancer. To do this we have developed a system of 11 ordinary differential equations including the movement, interaction, and activation of NK cells, CD8(+)T-cells, CD4(+)T cells, regulatory T cells, and dendritic cells under the presence of tumor and cytokines and the immune interactions. In addition, we apply two control therapies, immunotherapy and chemotherapy to the model in order to control growth of tumor. Using optimal control theory and numerical simulations, we obtain appropriate treatment strategies according to the ratio of the cost for two therapies, which suggest an optimal timing of each administration for the two types of models, without and with immunosuppressive effects. These results mean that the immune suppression can have an influence on treatment strategies for cancer.
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Scarpa M, Castagliuolo I, Castoro C, Pozza A, Scarpa M, Kotsafti A, Angriman I. Inflammatory colonic carcinogenesis: A review on pathogenesis and immunosurveillance mechanisms in ulcerative colitis. World J Gastroenterol 2014; 20:6774-6785. [PMID: 24944468 PMCID: PMC4051917 DOI: 10.3748/wjg.v20.i22.6774] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2013] [Accepted: 02/27/2014] [Indexed: 02/06/2023] Open
Abstract
Ulcerative colitis (UC) is characterized by repeated flare-ups of inflammation that can lead to oncogenic insults to the colonic epithelial. UC-associated carcinogenesis presents a different sequence of tumorigenic events compared to those that contribute to the development of sporadic colorectal cancer. In fact, in UC, the early events are represented by oxidative DNA damage and DNA methylation that can produce an inhibition of oncosuppressor genes, mutation of p53, aneuploidy, and microsatellite instability. Hypermethylation of tumor suppressor and DNA mismatch repair gene promoter regions is an epigenetic mechanism of gene silencing that contribute to tumorigenesis and may represent the first step in inflammatory carcinogenesis. Moreover, p53 is frequently mutated in the early stages of UC-associated cancer. Aneuploidy is an independent risk factor for forthcoming carcinogenesis in UC. Epithelial cell-T-cell cross-talk mediated by CD80 is a key factor in controlling the progression from low to high grade dysplasia in UC-associated carcinogenesis.
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MESH Headings
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/immunology
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Colitis, Ulcerative/complications
- Colitis, Ulcerative/genetics
- Colitis, Ulcerative/immunology
- Colitis, Ulcerative/metabolism
- Colitis, Ulcerative/pathology
- Colonic Neoplasms/etiology
- Colonic Neoplasms/genetics
- Colonic Neoplasms/immunology
- Colonic Neoplasms/metabolism
- Colonic Neoplasms/pathology
- DNA Damage
- DNA Methylation
- Disease Progression
- Epigenesis, Genetic
- Gene Expression Regulation, Neoplastic
- Humans
- Inflammation Mediators/metabolism
- Neoplasm Grading
- Oncogenes
- Oxidative Stress
- Risk Factors
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
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17
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Naujoks M, Weiß J, Riedel T, Hömberg N, Przewoznik M, Noessner E, Röcken M, Mocikat R. Alterations of costimulatory molecules and instructive cytokines expressed by dendritic cells in the microenvironment of an endogenous mouse lymphoma. Cancer Immunol Immunother 2014; 63:491-9. [PMID: 24638151 PMCID: PMC11029135 DOI: 10.1007/s00262-014-1538-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Accepted: 03/09/2014] [Indexed: 10/25/2022]
Abstract
Costimulatory surface molecules and instructive cytokines expressed by dendritic cells (DCs) determine the outcome of an immune response. In malignant disease, DCs are often functionally compromised. In most tumors studied so far, the deficient induction of effective T cell responses has been associated with a blockade of DC maturation, but little has been known on DCs infiltrating malignant B cell lymphoma. Here, we investigated for the first time the phenotypic and functional status of DCs in B cell lymphoma, and we analyzed the network of DCs, tumor cells, natural killer (NK) cells and cytokines present in the tumor micromilieu. Therefor, we used an endogenous myc-transgenic mouse lymphoma model, because transplanted tumor cells foster an IFN-γ-driven Th1 antitumor response rather than an immunosuppressive environment, which is observed in autochthonous neoplasias. Lymphoma-infiltrating DCs showed a mature phenotype and a Th2-inducing cytokine pattern. This situation is in contrast to most human malignancies and mouse models described. Cellular contacts between DCs and tumor cells, which involved CD62L on the lymphoma, caused upregulation of costimulatory molecules, whereas IL-10 primarily derived from lymphoma cells induced an IL-12/IL-10 shift in DCs. Thus, alteration of costimulatory molecules and instructive cytokines was mediated by distinct mechanisms. Normal NK cells were able to additionally modulate DC maturation but this effect was absent in the lymphoma environment where IFN-γ production by NK cells was severely impaired. These data are relevant for establishing novel immunotherapeutic approaches against B cell lymphoma.
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Affiliation(s)
- Marcella Naujoks
- Institut für Molekulare Immunologie, Helmholtz-Zentrum München, Marchioninistr. 25, 81377 Munich, Germany
| | - Jakob Weiß
- Institut für Molekulare Immunologie, Helmholtz-Zentrum München, Marchioninistr. 25, 81377 Munich, Germany
| | - Tanja Riedel
- Institut für Molekulare Immunologie, Helmholtz-Zentrum München, Marchioninistr. 25, 81377 Munich, Germany
| | - Nadine Hömberg
- Institut für Molekulare Immunologie, Helmholtz-Zentrum München, Marchioninistr. 25, 81377 Munich, Germany
| | - Margarethe Przewoznik
- Institut für Molekulare Immunologie, Helmholtz-Zentrum München, Marchioninistr. 25, 81377 Munich, Germany
| | - Elfriede Noessner
- Institut für Molekulare Immunologie, Helmholtz-Zentrum München, Marchioninistr. 25, 81377 Munich, Germany
| | - Martin Röcken
- Department of Dermatology, Eberhard-Karls-Universität, Tübingen, Germany
| | - Ralph Mocikat
- Institut für Molekulare Immunologie, Helmholtz-Zentrum München, Marchioninistr. 25, 81377 Munich, Germany
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18
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Koufos N, Michailidou D, Xynos ID, Tomos P, Athanasiadou K, Kosmas C, Tsavaris N. Modulation of peripheral immune responses by paclitaxel-ifosfamide-cisplatin chemotherapy in advanced non-small-cell lung cancer. J Cancer Res Clin Oncol 2013; 139:1995-2003. [PMID: 24072231 DOI: 10.1007/s00432-013-1514-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2013] [Accepted: 09/02/2013] [Indexed: 12/25/2022]
Abstract
PURPOSE The aim of this study was to assess systemic immunological responses in non-small-cell lung cancer (NSCLC) patients with stage III/IV disease during treatment with paclitaxel-ifosfamide-cisplatin (TIP) chemotherapy. METHODS Peripheral blood mononuclear cells (PBMCs) collected from healthy donors (HD) (n = 20) and chemotherapy-naive NSCLC patients treated with TIP (n = 32) were tested for production of IL-1, TNF-α, TNF-β, IL-6, IL-8, IL-10, IL-12 and IL-2 upon polyclonal stimulation with anti-CD3 mAb. They were further assessed over a treatment period of twelve weeks (i.e., four treatment cycles). RESULTS PBMCs from NSCLC patients produced higher IL-1, TNF-α, TNF-β, IL-6, IL-8, IL-10 and IL-12 levels, whereas IL-2 exhibited lower values compared to HD (p < 0.001 for all parameters). Of interest, patients who responded to treatment had significantly higher increases in IL-2 (p < 0.001) and significantly higher decreases in IL-1 (p < 0.001), TNF-α (p < 0.001), TNF-β (p < 0.001), IL-6 (p = 0.02), IL-8 (p < 0.001), IL-10 (p < 0.001) and IL-12 (p < 0.001) levels. Non-responders revealed post-therapeutically a significantly higher increase in IL-1, TNF-α, TNF-β, IL-6, IL-8, IL-10 and IL-12 secretion and a significantly higher decrease in IL-2 levels (p < 0.001 for all parameters). Patients who responded to treatment and had a significantly higher increase in IL-2 showed a significantly longer median survival (p value < 0.001, 26 vs. 7.5 months). CONCLUSION Our study indicates that monitoring cytokine dynamics in patients with advanced NSCLC and especially those of IL-2 in peripheral blood components in vitro could be used as a predictor of treatment-related outcome and overall survival in NSCLC.
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Affiliation(s)
- Nikolaos Koufos
- Oncology Unit, Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Agios Thomas 17, 11527, Athens, Greece
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19
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Riediger C, Wingender G, Knolle P, Aulmann S, Stremmel W, Encke J. Fms-like tyrosine kinase 3 receptor ligand (Flt3L)-based vaccination administered with an adenoviral vector prevents tumor growth of colorectal cancer in a BALB/c mouse model. J Cancer Res Clin Oncol 2013; 139:2097-110. [PMID: 24114287 DOI: 10.1007/s00432-013-1532-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2013] [Accepted: 09/21/2013] [Indexed: 12/22/2022]
Abstract
PURPOSE Colorectal cancer is the third most frequent cancer in industrial nations. Therapeutic strategies to treat metastatic disease and prevent recurrence are needed. Anti-tumor immunity can be induced by dendritic cells. Dendritic cells can be expanded by the fms-like tyrosine kinase 3 ligand (Flt3L) in vivo. The aim of this study was to develop an adenoviral-based immune-gene therapy of colorectal cancer with Flt3L in a BALB/c mouse model. METHODS A new Flt3L-encoding adenoviral vector (pAdFlt3L) was administered in two approaches in a CT26 colon cancer model in female BALB/c mice. In the therapeutic approach, pAdFlt3L was injected into the tail vein or directly into subcutaneous CT26 colon carcinoma tumors in BALB/c mice. In the vaccination protocol, mice were vaccinated with CT26 cell lysate and pAdFlt3L subcutaneous prior to subcutaneous application of vital CT26 cells. RESULTS Application of pAdFlt3L led to high levels of Flt3L in vitro and in vivo. Significant expansion of dendritic cells after application of pAdFlt3L in vivo was confirmed by the use of CD11c and CD11b surface markers in immunohistochemistry and flow cytometry (p = 0.019). In the therapeutic approach, neither intravenous nor intratumoral treatments with pAdFlt3L lead to regression of CT26 tumors. In the vaccination protocol, vaccination completely prevented tumor growth and resulted in superior survival compared to control mice (p < 0.001). CONCLUSIONS Our results demonstrate that immunostimulatory therapy with pAdFlt3L is effective to prevent tumor development through vaccination and may represent a therapeutic tool to prevent metastatic disease.
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Affiliation(s)
- Carina Riediger
- Department of Internal Medicine IV and Otto-Meyerhof-Center for Medical Sciences, University of Heidelberg, Heidelberg, Germany,
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20
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Regulation of gap junctions in melanoma and their impact on Melan-A/MART-1-specific CD8⁺ T lymphocyte emergence. J Mol Med (Berl) 2013; 91:1207-20. [PMID: 23744108 DOI: 10.1007/s00109-013-1058-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2012] [Revised: 05/15/2013] [Accepted: 05/16/2013] [Indexed: 10/26/2022]
Abstract
UNLABELLED Gap junctions (GJs) enable intercellular communication between adjacent cells through channels of connexins. Using a three-dimensional construct, we previously showed that endothelial and tumor cells formed GJs, allowing melanoma-specific T lymphocytes to recognize and kill melanoma-derived endothelial cells. We demonstrate here on histological sections of melanoma biopsies that GJ formation occurs in vivo between tumor and endothelial cells and between T lymphocytes and target cells. We also show an in vitro increase of GJ formation in melanoma and endothelial cells following dacarbazin and interferon gamma (IFN-γ) treatment or hypoxic stress induction. Our data indicate that although connexin 43 (Cx43), the main GJ protein of the immune system, was localized at the immunological synapse between T lymphocyte and autologous melanoma cells, its over-expression or inhibition of GJs does not interfere with cytotoxic T lymphocyte (CTL) clone lytic function. In contrast, we showed that inhibition of GJs by oleamide during stimulation of resting PBMCs with Melan-A natural and analog peptides resulted in a decrease in antigen (Ag) specific CD8(+) T lymphocyte induction. These Ag-specific CD8(+) cells displayed paradoxically stronger reactivity as revealed by CD107a degranulation and IFN-γ secretion. These findings indicate that Cx43 does not affect lytic function of differentiated CTL, but reveal a major role for GJs in the regulation of antigen CD8(+)-naïve T lymphocyte activation. KEY MESSAGE GJ formation occurs in vivo between T lymphocytes and tumor cells Cx43 localized at the immunological synapse between T and autologous melanoma cells Inhibition of GJs resulted in a decrease in Ag-specific CD8(+) T lymphocyte induction A role for GJs in the regulation of antigen CD8(+)-naïve T lymphocyte activation.
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21
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Zhao H, Wu F, Cai Y, Chen Y, Wei L, Liu Z, Yuan W. Local antitumor effects of intratumoral delivery of rlL-2 loaded sustained-release dextran/PLGA-PLA core/shell microspheres. Int J Pharm 2013; 450:235-40. [PMID: 23624084 DOI: 10.1016/j.ijpharm.2013.04.051] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2013] [Revised: 03/25/2013] [Accepted: 04/09/2013] [Indexed: 12/13/2022]
Abstract
In this study, we formulated a rIL-2 loaded sustained-release dextran/PLGA-PLA core/shell microsphere, mimicking the paracrine mechanisms of cytokine action, to investigate its local antitumor efficacy. The presented microspheres were formed in two steps: rIL-2 was firstly loaded into dextran particles to keep its bioactivity by a unique method of stabilizing aqueous-aqueous "emulsion"; subsequently, the particles were encapsulated into poly(dl-lactide-co-glycolide)/polylactic acid (PLGA/PLA). A stable sustained release behavior in vitro was achieved for a period of about 25 days. In the subcutaneous colon carcinoma BALB/c mice models, a single dose of microspheres was introtumorally administrated and compared with multiple doses of rIL-2 solution to investigate the long acting effect of microspheres on tumor. The animal experiments showed the local efficacy at tumor site mediated by rIL-2 from a single dose of microspheres was better than that of multiple rIL-2 solution injections. Based on the experimental results, we conclude that rlL-2 loaded sustained-release dextran/PLGA-PLA core/shell microspheres represent a promising approach for local cancer treatment in animals.
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Affiliation(s)
- Haiping Zhao
- Department of Neurology, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, No. 1665, Kongjiang Road, Shanghai 200092, China
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22
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Eljaszewicz A, Wiese M, Helmin-Basa A, Jankowski M, Gackowska L, Kubiszewska I, Kaszewski W, Michalkiewicz J, Zegarski W. Collaborating with the enemy: function of macrophages in the development of neoplastic disease. Mediators Inflamm 2013; 2013:831387. [PMID: 23576856 PMCID: PMC3613099 DOI: 10.1155/2013/831387] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2012] [Revised: 12/26/2012] [Accepted: 01/13/2013] [Indexed: 01/15/2023] Open
Abstract
Due to the profile of released mediators (such as cytokines, chemokines, growth factors, etc.), neoplastic cells modulate the activity of immune system, directly affecting its components both locally and peripherally. This is reflected by the limited antineoplastic activity of the immune system (immunosuppressive effect), induction of tolerance to neoplastic antigens, and the promotion of processes associated with the proliferation of neoplastic tissue. Most of these responses are macrophages dependent, since these cells show proangiogenic properties, attenuate the adaptive response (anergization of naïve T lymphocytes, induction of Treg cell formation, polarization of immune response towards Th2, etc.), and support invasion and metastases formation. Tumor-associated macrophages (TAMs), a predominant component of leukocytic infiltrate, "cooperate" with the neoplastic tissue, leading to the intensified proliferation and the immune escape of the latter. This paper characterizes the function of macrophages in the development of neoplastic disease.
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Affiliation(s)
- Andrzej Eljaszewicz
- Chair of Immunology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University of Torun, Bydgoszcz, Poland.
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23
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Akalay I, Janji B, Hasmim M, Noman MZ, André F, De Cremoux P, Bertheau P, Badoual C, Vielh P, Larsen AK, Sabbah M, Tan TZ, Keira JH, Hung NTY, Thiery JP, Mami-Chouaib F, Chouaib S. Epithelial-to-mesenchymal transition and autophagy induction in breast carcinoma promote escape from T-cell-mediated lysis. Cancer Res 2013; 73:2418-27. [PMID: 23436798 DOI: 10.1158/0008-5472.can-12-2432] [Citation(s) in RCA: 236] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Epithelial-to-mesenchymal transition (EMT) mediates cancer cell invasion, metastasis, and drug resistance, but its impact on immune surveillance has not been explored. In this study, we investigated the functional consequences of this mode of epithelial cell plasticity on targeted cell lysis by cytotoxic T lymphocytes (CTL). Acquisition of the EMT phenotype in various derivatives of MCF-7 human breast cancer cells was associated with dramatic morphologic changes and actin cytoskeleton remodeling, with CD24(-)/CD44(+)/ALDH(+) stem cell populations present exhibiting a higher degree of EMT relative to parental cells. Strikingly, acquisition of this phenotype also associated with an inhibition of CTL-mediated tumor cell lysis. Resistant cells exhibited attenuation in the formation of an immunologic synapse with CTLs along with the induction of autophagy in the target cells. This response was critical for susceptibility to CTL-mediated lysis because siRNA-mediated silencing of beclin1 to inhibit autophagy in target cells restored their susceptibility to CTL-induced lysis. Our results argue that in addition to promoting invasion and metastasis EMT also profoundly alters the susceptibility of cancer cells to T-cell-mediated immune surveillance. Furthermore, they reveal EMT and autophagy as conceptual realms for immunotherapeutic strategies to block immune escape.
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Affiliation(s)
- Intissar Akalay
- Unité INSERM U753, Institut de Cancérologie Gustave Roussy, Villejuif, France
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24
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Gautam P, Deepak P, Kumar S, Acharya A. Role of Macrophage in Tumor Microenvironment: Prospect in Cancer Immunotherapy. EUR J INFLAMM 2013. [DOI: 10.1177/1721727x1301100101] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Current evidence suggests an increasing role of macrophages in inflammation and tumor progression. Most tumors contain an abundant number of macrophages as a major component of their leukocyte infiltrate, which co-exist with tumor cells at the tumor microenvironment. Upon activation with soluble tumor antigens, macrophages release a distinct repertoire of growth factor, cytokines, chemokines and enzymes that inhibit growth of the tumor. However, the anti-tumor immune response induced by macrophages does not always ensue. Tumor cells themselves are capable of down-regulating macrophage phenotype and functions and anti-tumor immune responses in the tumor-bearing host. The present review aims to elucidate the role of macrophages in tumor growth and progression, invasion, metastasis, and angiogenesis at the site of tumor growth. Moreover, the effect of tumor microenvironment on the phenotype and function of macrophages, which are altered due to the continuous exposure of various soluble and non-soluble tumor promoting factors secreted by tumor cells, and implication of macrophages in cancer immunotherapy have been discussed in detail.
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Affiliation(s)
- P.K. Gautam
- Department of zoology, Faculty of Science, Banaras Hindu University, Varanasi, U.P., India
| | - P. Deepak
- Department of zoology, Faculty of Science, Banaras Hindu University, Varanasi, U.P., India
| | - S. Kumar
- Department of zoology, Faculty of Science, Banaras Hindu University, Varanasi, U.P., India
| | - A. Acharya
- Department of zoology, Faculty of Science, Banaras Hindu University, Varanasi, U.P., India
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25
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Feng T, Zhou JH, Liu J, Ye F, Lu W, Xie X. Altered expression levels of HLA class Ⅱ and costimulatory molecules on circulating monocytes from patients with cervical intraepithelial neoplasia and squamous cervical cancer. Mol Med Rep 2012; 6:1301-4. [PMID: 22965188 DOI: 10.3892/mmr.2012.1068] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2012] [Accepted: 06/15/2012] [Indexed: 11/06/2022] Open
Abstract
The aim of this study was to investigate the role of the cell surface expression levels of HLA class I and II molecules, the costimulatory molecules CD80/B7-1 and CD86/B7-2, and the adhesion molecules CD54 and CD58 during cervical carcinogenesis. The expression levels of MHC class I and II molecules, the costimulatory molecules CD80/B7-1 and CD86/B7-2 and the adhesion molecules CD54 and CD58 on CD14+ peripheral blood monocytes (PBMs) from 21 cases of cervical intraepithelial neoplasia (CIN) II-III, 51 squamous cervical carcinomas (SCCs) and 18 healthy controls were analyzed using flow cytometry analysis. We found increased expression levels of HLA-DR (p=0.000), HLA-DQ (p=0.000), CD86/B7-2 (p=0.002) and CD58 (p=0.000) on PBMs from patients with SCC and CIN II-III, compared with healthy control subjects, whereas no significant difference existed in the expression levels of HLA class I antigens, HLA-DP CD80/B7-1 and CD54. Upregulated expression levels of HLA-DR, HLA-DQ, CD86/B7-2 and CD58 were associated with disease progression, indicating that an increased expression of HLA-DR, HLA-DQ, CD86/B7-2 and CD58 on PBMs may be correlated with the evolution of cervical cancer.
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Affiliation(s)
- Ting Feng
- Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, P.R. China
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26
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Bossard C, Bézieau S, Matysiak-Budnik T, Volteau C, Laboisse CL, Jotereau F, Mosnier JF. HLA-E/β2 microglobulin overexpression in colorectal cancer is associated with recruitment of inhibitory immune cells and tumor progression. Int J Cancer 2012; 131:855-63. [PMID: 21953582 DOI: 10.1002/ijc.26453] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2011] [Accepted: 09/05/2011] [Indexed: 01/13/2023]
Abstract
The host immune response plays a major role in colorectal carcinoma (CRC) progression. A mechanism of tumor immune escape might involve expression of the human leucocyte antigen (HLA)-E/β2m on tumor cells. The inhibitory effect of HLA-E/β2m on CD8+ cytotoxic T lymphocytes and natural killer (NK) cells is mediated by the main HLA-E receptor CD94/NKG2A. As the pathophysiological relevance of this mechanism in CRC remains unknown, this prompted us to examine, in situ, in a series of 80 CRC (i) the HLA-E and β2m coexpression by tumor cells, (ii) the density of CD8+, cytotoxic, CD244+ and NKP46+ intraepithelial tumor-infiltrating lymphocyte (IEL-TIL) and (iii) the expression of CD94/NKG2 receptor on IEL-TIL. These data were then correlated to patient survival. We provided (i) the in situ demonstration of HLA-E/β2m overexpression by tumor cells in 21% of CRC characterized by an overrepresentation of signet ring cell carcinomas, mucinous carcinomas and medullary carcinomas, (ii) the significant association between HLA-E/β2m overexpression by tumor cells and increased density of CD8+ cytotoxic, CD244+ and CD94+ IEL-TIL and (iii) finally, the unfavorable prognosis associated with HLA-E/β2m overexpression by tumor cells. Our findings show that HLA-E/β2m overexpression is a surrogate marker of poor prognosis and point to a novel mechanism of tumor immune escape in CRC in restraining inhibitory IEL-TIL.
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27
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Srivastava MK, Zhu L, Harris-White M, Kar U, Huang M, Johnson MF, Lee JM, Elashoff D, Strieter R, Dubinett S, Sharma S. Myeloid suppressor cell depletion augments antitumor activity in lung cancer. PLoS One 2012; 7:e40677. [PMID: 22815789 PMCID: PMC3398024 DOI: 10.1371/journal.pone.0040677] [Citation(s) in RCA: 169] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2012] [Accepted: 06/12/2012] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Myeloid derived suppressor cells (MDSC) are important regulators of immune responses. We evaluated the mechanistic role of MDSC depletion on antigen presenting cell (APC), NK, T cell activities and therapeutic vaccination responses in murine models of lung cancer. PRINCIPAL FINDINGS Individual antibody mediated depletion of MDSC (anti-Gr1 or anti-Ly6G) enhanced the antitumor activity against lung cancer. In comparison to controls, MDSC depletion enhanced the APC activity and increased the frequency and activity of the NK and T cell effectors in the tumor. Compared to controls, the anti-Gr1 or anti-Ly6G treatment led to increased: (i) CD8 T cells, (ii) NK cells, (iii) CD8 T or NK intracytoplasmic expression of IFNγ, perforin and granzyme (iv) CD3 T cells expressing the activation marker CD107a and CXCR3, (v) reduced CD8 T cell IL-10 production in the tumors (vi) reduced tumor angiogenic (VEGF, CXCL2, CXCL5, and Angiopoietin1&2) but enhanced anti-angiogenic (CXCL9 and CXCL10) expression and (vii) reduced tumor staining of endothelial marker Meca 32. Immunocytochemistry of tumor sections showed reduced Gr1 expressing cells with increased CD3 T cell infiltrates in the anti-Gr1 or anti-Ly6G groups. MDSC depletion led to a marked inhibition in tumor growth, enhanced tumor cell apoptosis and reduced migration of the tumors from the primary site to the lung compared to controls. Therapeutic vaccination responses were enhanced in vivo following MDSC depletion with 50% of treated mice completely eradicating established tumors. Treated mice that rejected their primary tumors acquired immunological memory against a secondary tumor challenge. The remaining 50% of mice in this group had 20 fold reductions in tumor burden compared to controls. SIGNIFICANCE Our data demonstrate that targeting MDSC can improve antitumor immune responses suggesting a broad applicability of combined immune based approaches against cancer. This multifaceted approach may prove useful against tumors where MDSC play a role in tumor immune evasion.
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MESH Headings
- Angiogenesis Inhibitors/pharmacology
- Angiogenesis Inhibitors/therapeutic use
- Animals
- Antigen-Presenting Cells/drug effects
- Antigen-Presenting Cells/immunology
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Apoptosis/drug effects
- Biomarkers, Tumor/metabolism
- Bone Marrow Cells/drug effects
- Bone Marrow Cells/pathology
- Carcinoma, Lewis Lung/blood supply
- Carcinoma, Lewis Lung/drug therapy
- Carcinoma, Lewis Lung/immunology
- Carcinoma, Lewis Lung/pathology
- Cell Adhesion/drug effects
- Cell Proliferation/drug effects
- Cytotoxicity, Immunologic/drug effects
- Disease Models, Animal
- Killer Cells, Natural/drug effects
- Killer Cells, Natural/immunology
- Mice
- Mice, Inbred C57BL
- Myeloid Cells/drug effects
- Myeloid Cells/immunology
- Myeloid Cells/pathology
- Neoplasm Metastasis
- Ovalbumin/immunology
- Spleen/drug effects
- Spleen/immunology
- T-Lymphocytes/drug effects
- T-Lymphocytes/immunology
- Treatment Outcome
- Tumor Burden
- Vaccination
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Affiliation(s)
- Minu K. Srivastava
- Department of Medicine, UCLA Lung Cancer Research Program, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
- Molecular Gene Medicine Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, United States of America
| | - Li Zhu
- Department of Medicine, UCLA Lung Cancer Research Program, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
- Molecular Gene Medicine Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, United States of America
| | - Marni Harris-White
- Molecular Gene Medicine Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, United States of America
| | - Upendra Kar
- Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
| | - Min Huang
- Molecular Gene Medicine Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, United States of America
| | - Ming F. Johnson
- Molecular Gene Medicine Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, United States of America
| | - Jay M. Lee
- Department of Medicine, UCLA Lung Cancer Research Program, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
| | - David Elashoff
- Department of Medicine, UCLA Lung Cancer Research Program, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
| | - Robert Strieter
- Department of Medicine, University of Virginia, Charlottesville, Virginia, United States of America
| | - Steven Dubinett
- Department of Medicine, UCLA Lung Cancer Research Program, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
- Molecular Gene Medicine Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, United States of America
| | - Sherven Sharma
- Department of Medicine, UCLA Lung Cancer Research Program, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
- Molecular Gene Medicine Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, United States of America
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Srivastava MK, Andersson Å, Zhu L, Harris-White M, Lee JM, Dubinett S, Sharma S. Myeloid suppressor cells and immune modulation in lung cancer. Immunotherapy 2012; 4:291-304. [PMID: 22401635 DOI: 10.2217/imt.11.178] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Many tumors, including lung cancers, promote immune tolerance to escape host immune surveillance and facilitate tumor growth. Tumors utilize numerous pathways to inhibit immune responses, including the elaboration of immune-suppressive mediators such as PGE2, TGF-β, IL-10, VEGF, GM-CSF, IL-6, S100A8/A9 and SCF, which recruit and/or activate myeloid-derived suppressor cells (MDSCs). MDSCs, a subset of heterogeneous bone marrow-derived hematopoietic cells, are found in the peripheral blood of cancer patients and positively correlate to malignancy. Solid tumors contain MDSCs that maintain an immune-suppressive network in the tumor microenvironment. This review will focus on the interaction of tumors with MDSCs that lead to dysregulation of antigen presentation and T-cell activities in murine tumor models. Specific genetic signatures in lung cancer modulate the activities of MDSCs and impact tumor progression. Targeting MDSCs may have a long-term antitumor benefit and is at the forefront of anticancer therapeutic strategies.
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Affiliation(s)
- Minu K Srivastava
- University of California Los Angeles & Veterans Affairs Greater Los Angeles, CA, USA
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29
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A mathematical model of tumor-immune interactions. J Theor Biol 2011; 294:56-73. [PMID: 22051568 DOI: 10.1016/j.jtbi.2011.10.027] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2010] [Revised: 07/01/2011] [Accepted: 10/19/2011] [Indexed: 12/31/2022]
Abstract
A mathematical model of the interactions between a growing tumor and the immune system is presented. The equations and parameters of the model are based on experimental and clinical results from published studies. The model includes the primary cell populations involved in effector T-cell mediated tumor killing: regulatory T cells, helper T cells, and dendritic cells. A key feature is the inclusion of multiple mechanisms of immunosuppression through the main cytokines and growth factors mediating the interactions between the cell populations. Decreased access of effector cells to the tumor interior with increasing tumor size is accounted for. The model is applied to tumors with different growth rates and antigenicities to gauge the relative importance of various immunosuppressive mechanisms. The most important factors leading to tumor escape are TGF-β-induced immunosuppression, conversion of helper T cells into regulatory T cells, and the limitation of immune cell access to the full tumor at large tumor sizes. The results suggest that for a given tumor growth rate, there is an optimal antigenicity maximizing the response of the immune system. Further increases in antigenicity result in increased immunosuppression, and therefore a decrease in tumor killing rate. This result may have implications for immunotherapies which modulate the effective antigenicity. Simulation of dendritic cell therapy with the model suggests that for some tumors, there is an optimal dose of transfused dendritic cells.
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Noman MZ, Janji B, Kaminska B, Van Moer K, Pierson S, Przanowski P, Buart S, Berchem G, Romero P, Mami-Chouaib F, Chouaib S. Blocking hypoxia-induced autophagy in tumors restores cytotoxic T-cell activity and promotes regression. Cancer Res 2011; 71:5976-86. [PMID: 21810913 DOI: 10.1158/0008-5472.can-11-1094] [Citation(s) in RCA: 204] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The relationship between hypoxic stress, autophagy, and specific cell-mediated cytotoxicity remains unknown. This study shows that hypoxia-induced resistance of lung tumor to cytolytic T lymphocyte (CTL)-mediated lysis is associated with autophagy induction in target cells. In turn, this correlates with STAT3 phosphorylation on tyrosine 705 residue (pSTAT3) and HIF-1α accumulation. Inhibition of autophagy by siRNA targeting of either beclin1 or Atg5 resulted in impairment of pSTAT3 and restoration of hypoxic tumor cell susceptibility to CTL-mediated lysis. Furthermore, inhibition of pSTAT3 in hypoxic Atg5 or beclin1-targeted tumor cells was found to be associated with the inhibition Src kinase (pSrc). Autophagy-induced pSTAT3 and pSrc regulation seemed to involve the ubiquitin proteasome system and p62/SQSTM1. In vivo experiments using B16-F10 melanoma tumor cells indicated that depletion of beclin1 resulted in an inhibition of B16-F10 tumor growth and increased tumor apoptosis. Moreover, in vivo inhibition of autophagy by hydroxychloroquine in B16-F10 tumor-bearing mice and mice vaccinated with tyrosinase-related protein-2 peptide dramatically increased tumor growth inhibition. Collectively, this study establishes a novel functional link between hypoxia-induced autophagy and the regulation of antigen-specific T-cell lysis and points to a major role of autophagy in the control of in vivo tumor growth.
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Affiliation(s)
- Muhammad Zaeem Noman
- Unité INSERM U753, Institut de Cancérologie Gustave Roussy, Villejuif Cedex, France
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31
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Zhao R, Chen Z, Jia G, Li J, Cai Y, Shao X. Protective effects of diosmetin extracted from Galium verum L. on the thymus of U14-bearing mice. Can J Physiol Pharmacol 2011; 89:665-73. [DOI: 10.1139/y11-058] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Diosmetin (DGVL) extracted from the traditional Chinese herb Galium verum L. has been found to have anticancer activity. In this study, the effects of DGVL on the thymus of U14-bearing mice were investigated. Using flow cytometry, peripheral blood lymphocytes were characterized based on the expression of surface markers for T helper cells (CD4+) and T suppressor cells (CD8+). Serum levels of tumor necrosis factor α (TNF-α), interleukin-2 (IL-2), IL-10, and transforming growth factor β1 (TGF-β1) and a cell proliferation assay were determined with an enzyme-linked immunosorbent assay. The expression of Fas and Fas ligand (FasL) on the thymus was determined by Western blotting. Our results showed that DGVL inhibited tumor growth and significantly increased the thymus weight compared with the control. Also, DGVL elevated serum levels of IL-2 and significantly reduced levels of TNF-α, TGF-β1, and IL-10 in a dose-dependent manner. Histological study and terminal dUTP nick end labeling staining results showed that DGVL protected thymus tissue against the onslaught of tumor growth by inhibiting thymus lymphocyte apoptosis. The cell proliferation assay revealed that DGVL might promote more thymus lymphocytes towards proliferation. Furthermore, the ratio of CD4+/CD8+ T lymphocytes was significantly increased from 0.69 to 2.29 by treatment with DGVL. Immunoblotting analyses revealed that the expression of Fas and FasL on the thymus was lower in mice in the DGVL treatment group than in the control mice. In conclusion, DGVL can inhibit tumor growth and protect tumor-induced apoptosis of the thymus, and the mechanism is closely associated with reduced cell death in the thymus and a Fas–FasL-dependent pathway.
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Affiliation(s)
- Rui Zhao
- Department of Pharmaceutical Engineering, College of Life Science and Biotechnology, Heilongjiang August First Land Reclamation University, Daqing High-Tech Industrial Development Zone, 163319, P.R. China
| | - Zhibao Chen
- Department of Pharmaceutical Engineering, College of Life Science and Biotechnology, Heilongjiang August First Land Reclamation University, Daqing High-Tech Industrial Development Zone, 163319, P.R. China
| | - Guiyan Jia
- Department of Pharmaceutical Engineering, College of Life Science and Biotechnology, Heilongjiang August First Land Reclamation University, Daqing High-Tech Industrial Development Zone, 163319, P.R. China
| | - Jian Li
- Department of Biological Engineering, School of Environment and Chemistry Engineering, Yanshan University, 438 Hebei Street, Qinhuangdao 066004, P.R. China
| | - Yaping Cai
- Department of Pharmaceutical Engineering, College of Life Science and Biotechnology, Heilongjiang August First Land Reclamation University, Daqing High-Tech Industrial Development Zone, 163319, P.R. China
| | - Xingyue Shao
- Department of Gynaecology and Obstetrics, Daqing Oilfield Hospital, Daqing 163311, P.R China
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32
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Chen LJ, Sun J, Wu HY, Zhou SM, Tan Y, Tan M, Shan BE, Lu BF, Zhang XG. B7-H4 expression associates with cancer progression and predicts patient's survival in human esophageal squamous cell carcinoma. Cancer Immunol Immunother 2011; 60:1047-55. [PMID: 21519829 PMCID: PMC11029661 DOI: 10.1007/s00262-011-1017-3] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2010] [Accepted: 04/07/2011] [Indexed: 12/12/2022]
Abstract
A retrospective cohort study including 112 patients suffering from esophageal squamous cell carcinoma (ESCC) was performed to investigate the expression of B7-H4 in ESCC and determine its association with patient's clinicopathological parameters and survival. Expression levels of B7-H4 on tumor cells and densities of tumor infiltrating lymphocytes (TILs) in the surgical specimens of ESCC tissues were characterized using immunohistochemical assays. Uni- and multivariate analyses were performed to evaluate the prognostic value of B7-H4 expression levels and densities of TILs in tumor sections. Positive B7-H4 immunostaining was observed in 107 of 112 (95.5%) of ESCC tissue sections. We further divided all patients into two major subgroups, a lower B7-H4 expression group with 46 patients and a higher B7-H4 expression group with 66 patients. We found that expression levels of B7-H4 on tumor cells were significantly correlated with patient's gender (P = 0.0288), distant metastasis (P = 0.0500), and TNM stage (P = 0.0258). Moreover, tumor cell B7-H4 expression was inversely correlated with densities of CD3(+) T cells in tumor nest (P = 0.0424) and CD8(+) T cells in tumor stroma (P = 0.0229). The overall survival rate of the patients with higher B7-H4 expression was significantly worse than that of the patients with lower B7-H4 expression (P = 0.0105, Hazard Ratio: 1.854, 95%CI:1.152-2.902). Markers of cell-mediated immune responses such as CD3, CD8, and T-bet were associated with better patient survival. The present study demonstrated that B7-H4 expression in human ESCC is associated with cancer progression, reduced tumor immunosurveillance and worse patient outcomes. B7-H4 can serve as a novel prognostic predictor for human ESCC and a potential target for the immune therapy against this malignancy.
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Affiliation(s)
- Lu-jun Chen
- Institute of Medical Biotechnology, Medical College of Suzhou University, 708 Renmin Road, 215007 Suzhou, Jiangsu China
| | - Jing Sun
- Institute of Medical Biotechnology, Medical College of Suzhou University, 708 Renmin Road, 215007 Suzhou, Jiangsu China
| | - Hong-ya Wu
- Clinical Immunology Laboratory, The First Affiliated Hospital of Suzhou University, Suzhou, Jiangsu China
| | - Shu-ming Zhou
- Department of Tumor Biological Treatment, Yixing Tumor Hospital, Wuxi, Jiangsu China
| | - Yan Tan
- Department of Pathology, The Third Affiliated Hospital of Suzhou University, Changzhou, Jiangsu China
| | - Ming Tan
- Department of Tumor Biological Treatment, Yixing Tumor Hospital, Wuxi, Jiangsu China
| | - Bao-en Shan
- Tumor Research Institute, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei China
| | - Bin-feng Lu
- Department of Immunology, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213 USA
| | - Xue-guang Zhang
- Institute of Medical Biotechnology, Medical College of Suzhou University, 708 Renmin Road, 215007 Suzhou, Jiangsu China
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Pro-inflammatory type-1 and anti-inflammatory type-2 macrophages differentially modulate cell survival and invasion of human bladder carcinoma T24 cells. Mol Immunol 2011; 48:1556-67. [DOI: 10.1016/j.molimm.2011.04.022] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2011] [Revised: 04/27/2011] [Accepted: 04/27/2011] [Indexed: 11/20/2022]
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Mucosal immune environment in colonic carcinogenesis: CD80 up-regulation in colonic dysplasia in ulcerative colitis. Eur J Cancer 2010; 47:611-9. [PMID: 21067914 DOI: 10.1016/j.ejca.2010.10.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2010] [Accepted: 10/11/2010] [Indexed: 12/16/2022]
Abstract
BACKGROUND In patients with ulcerative colitis (UC) the inconsistency between the rate of dysplasia and actual cancer incidence suggests the presence of an immunosurveillance mechanism. The aim of our study was to analyse the expression of CD80 and CD86 during the different stages of UC-associated and in non-inflammatory carcinogenesis. PATIENTS AND METHODS Sixty-two patients affected with UC, UC with colonic dysplasia, UC and cancer, colonic adenoma, or colonic cancer and 11 healthy subjects were enrolled in our study. Tissue samples were taken from surgical specimens during colonic resection or during colonoscopy. Mucosal mRNA expression of CD80 and CD86 was quantified with real time polymerase chain reaction (RT-PCR). CD80, CD86 and p53 expressions and lamina propria mononuclear cell populations (CD3, CD20 and CD68) were analysed by immunohistochemistry. Mucosal levels of IL-1β, IL-2 and IFN-γ were measured with immunometric assays. RESULTS Among UC patients, CD80 protein expression was higher in those with dysplasia (p=0.017). In non-inflammatory carcinogenesis pathway CD80 protein and mRNA expressions were lower compared to the corresponding steps in the UC pathway. CD80 expression was directly correlated with the lamina propria mononuclear cell populations (T and B lymphocytes and monocytes). CD80 protein, but not CD80 mRNA, expression was significantly and directly correlated with IL-2 expression. CONCLUSION CD80 resulted to be up-regulated in UC with dysplasia, while it was down-regulated in cancer. CD80 mucosal levels correlate with lamina propria T-cell and with IL-2 expression suggesting that it may elicit an active role in the immunosurveillance mechanism.
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35
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Miroux C, Vausselin T, Delhem N. Regulatory T cells in HBV and HCV liver diseases: implication of regulatory T lymphocytes in the control of immune response. Expert Opin Biol Ther 2010; 10:1563-72. [PMID: 20932226 DOI: 10.1517/14712598.2010.529125] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
IMPORTANCE OF THE FIELD Hepatic cirrhosis is a frequent consequence of chronic hepatitis infection (HBV and HCV) or alcohol abuse and the most common cause of hepatocellular carcinoma (HCC). Currently, liver transplantation remains the only effective therapeutic approach for cirrhosis-related HCC patients. The evolution of the pathology strongly depends on immunological mechanisms. AREAS COVERED IN THIS REVIEW Despite the presence of specific T cells, viral chronic infection and continuous tumor growth suggest a failure of immune control. It appears that direct suppression of antiviral or antitumor effector cells by regulatory T cells plays a pivotal role in the impairment of immune response. Several types of regulatory T cells have been described, natural regulatory T cells (nTreg) and induced-type 1 regulatory T cells (Tr1) being the best characterized. WHAT THE READER WILL GAIN Currently, there is no evidence for a direct implication of regulatory T cells in the evolution of hepatitis, especially concerning chronic infection, cirrhosis late stage and HCC progress. However, recent studies show that regulatory T cells are implicated in the modulation of HBV- and HCV-associated immune response, thus, promoting HCC progress. TAKE HOME MESSAGE Therefore, nTreg and Tr1 cells seem to play an important role in the control of immune response leading to chronic hepatitis infection and progression of the pathology to cirrhosis and HCC.
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Affiliation(s)
- Céline Miroux
- CNRS UMR 8161, Institut de Biologie de Lille, 1 rue du Professeur Calmette, Lille 59021, France
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36
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Hamaï A, Benlalam H, Meslin F, Hasmim M, Carré T, Akalay I, Janji B, Berchem G, Noman MZ, Chouaib S. Immune surveillance of human cancer: if the cytotoxic T-lymphocytes play the music, does the tumoral system call the tune? ACTA ACUST UNITED AC 2010; 75:1-8. [PMID: 20196816 DOI: 10.1111/j.1399-0039.2009.01401.x] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Accumulating evidence indicates that the innate and adaptive immune systems participate in the recognition and destruction of cancer cells by a process known as cancer immunosurveillance. Tumor antigen-specific cytotoxic T-lymphocytes (CTL) are the major effectors in the immune response against tumor cells. The identification of tumor-associated antigen (TAA) recognized primarily by CD 8(+) T-lymphocytes has led to the development of several vaccination strategies that induce or potentiate specific immune responses. However, large established tumors, which are associated with the acquisition of tumor resistance to specific lysis, are usually not fully controlled by the immune system. Recently, it has become clear that the immune system not only protects the host against tumor development but also sculpts the immunogenic phenotype of a developing tumor and can favor the emergence of resistant tumor cell variants. Moreover, it has become obvious that the evasion of immunosurveillance by tumor cells is under the control of the tumor microenvironment complexity and plasticity. In this review, we will focus on some new mechanisms associated with the acquisition of tumor resistance to specific lysis during tumor progression, involving genetic instability, structural changes in cytoskeleton, and hypoxic stress. We will also discuss the interaction between CTLs and tumor endothelial cells, a major component of tumor stroma.
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Affiliation(s)
- A Hamaï
- INSERM, U753, Laboratoire d'Immunologie des Tumeurs Humaines: Interaction Effecteurs Cytotoxiques-Système Tumoral, Institut Gustave-Roussy PR1 and IFR 54, Villejuif, France
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Kohler ME, Hallett WHD, Chen QR, Khan J, Johnson BD, Orentas RJ. Early expression of stem cell-associated genes within the CD8 compartment after treatment with a tumor vaccine. Cell Immunol 2010; 265:65-73. [PMID: 20692654 DOI: 10.1016/j.cellimm.2010.07.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2010] [Revised: 05/26/2010] [Accepted: 07/14/2010] [Indexed: 10/19/2022]
Abstract
Using a mouse neuroblastoma cell line, we have demonstrated that vaccination of tumor-free mice with a cell-based vaccine leads to productive immunity and resistance to tumor challenge, while vaccination of tumor-bearing mice does not. The T cell immunity induced by this vaccine, as measured by in vitro assays, is amplified by the depletion of Treg. Our goal is to understand this barrier to the development of protective cellular immunity. mRNA microarray analyses of CD8(+) T cells from naïve or tumor-bearing mice undergoing vaccination were carried out with or without administering anti-CD25 antibody. Gene-expression pathway analysis revealed the presence of CD8(+) T cells expressing stem cell-associated genes early after induction of productive anti-tumor immunity in tumor-free mice, prior to any phenotypic changes, but not in tumor-bearing mice. These data demonstrate that early after the induction of productive immune response, cells within the CD8(+) T cell compartment adopt a stem cell-related genetic phenotype that correlates with increased anti-tumor function.
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Affiliation(s)
- M Eric Kohler
- Dept. Pediatrics, Section of Hematology Oncology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226, United States
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38
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Tomihari M, Chung JS, Akiyoshi H, Cruz PD, Ariizumi K. DC-HIL/glycoprotein Nmb promotes growth of melanoma in mice by inhibiting the activation of tumor-reactive T cells. Cancer Res 2010; 70:5778-87. [PMID: 20570888 DOI: 10.1158/0008-5472.can-09-2538] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
DC-HIL/glycoprotein nmb (Gpnmb) expressed on antigen-presenting cells attenuates T-cell activation by binding to syndecan-4 (SD-4) on activated T cells. Because DC-HIL/Gpnmb is expressed abundantly by mouse and human melanoma lines, we posited that melanoma-associated DC-HIL/Gpnmb exerts similar inhibitory function on melanoma-reactive T cells. We generated small interfering RNA-transfected B16F10 melanoma cells to completely knock down DC-HIL/Gpnmb expression, with no alteration in cell morphology, melanin synthesis, or MHC class I expression. This knockdown had no effect on B16F10 proliferation in vitro or entry into the cell cycle following growth stimulation, but it markedly reduced the growth of these cells in vivo following their s.c. injection into syngeneic immunocompetent (but not immunodeficient) mice. This reduction in tumor growth was due most likely to an augmented capacity of DC-HIL-knocked down B16F10 cells (compared with controls) to activate melanoma-reactive T cells as documented in vitro and in mice. Whereas DC-HIL knockdown had no effect on susceptibility of melanoma to killing by cytotoxic T cells, blocking SD-4 function enhanced the reactivity of CD8(+) T cells to melanoma-associated antigens on parental B16F10 cells. Using an assay examining the spread to the lung following i.v. injection, DC-HIL-knocked down cells produced lung foci at similar numbers compared with that produced by control cells, but the size of the former foci was significantly smaller than the latter. We conclude that DC-HIL/Gpnmb confers upon melanoma the ability to downregulate the activation of melanoma-reactive T cells, thereby allowing melanoma to evade immunologic recognition and destruction. As such, the DC-HIL/SD-4 pathway is a potentially useful target for antimelanoma immunotherapy.
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Affiliation(s)
- Mizuki Tomihari
- Department of Dermatology, The University of Texas Southwestern Medical Center and Dermatology Section Medical Service, Dallas Veterans Affairs Medical Center, Dallas, Texas 75390-9069, USA
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Chemical diversity of biologically active metabolites in the sclerotia of Inonotus obliquus and submerged culture strategies for up-regulating their production. Appl Microbiol Biotechnol 2010; 87:1237-54. [DOI: 10.1007/s00253-010-2682-4] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2010] [Revised: 05/11/2010] [Accepted: 05/11/2010] [Indexed: 01/10/2023]
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40
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Iida T, Shiba H, Misawa T, Ohashi T, Eto Y, Yanaga K. Immunogene therapy against colon cancer metastasis using an adenovirus vector expressing CD40 ligand. Surgery 2010; 148:925-35. [PMID: 20378141 DOI: 10.1016/j.surg.2010.02.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2008] [Accepted: 02/05/2010] [Indexed: 11/15/2022]
Abstract
BACKGROUND Colon cancer is one of the most common cancers worldwide, and liver metastasis is a poor prognostic factor for all types of digestive cancers, including colon cancer. We studied CD40 ligand (CD40L)-mediated immunogene therapy for metastatic liver cancer in rats. METHODS We studied whether in vitro infection of a rat colon cancer cell line (RCN9) with an adenoviral-vector that expresses the CD40L (AxCAmCD40L) induced CD40L expression. In vivo to confirm the antitumor effect induced by AxCAmCD40L, the tumor cells that had been transduced by AxCAmCD40L were implanted into the subcutaneous tissues of syngenic rats (prevention model) or AxCAmCD40L was injected into the tumor tissues of the rats (treatment model). Furthermore, immune cells including NK cells, cytotoxic T cells, and tumor-specific antibodies induced by AxCAmCD40L were examined. RESULTS Immunogene therapy using AxCAmCD40L suppressed the tumor growth strongly or reduced tumor size in the prevention model and treatment model. NK cells, cytotoxic T cells, and tumor-specific antibodies contributed to this antitumor effect in both groups. CONCLUSION These observations suggest that CD40L-mediated immunogene therapy for metastatic colon cancer in the liver and lungs is effective and is mediated by the activation of both the cellular and humoral immune systems.
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Affiliation(s)
- Tomonori Iida
- Department of Surgery, Institute of DNA Medicine, The Jikei University School of Medicine, Tokyo, Japan.
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41
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Deepak P, Kumar S, Kishore D, Acharya A. IL-13 from Th2-type cells suppresses induction of antigen-specific Th1 immunity in a T-cell lymphoma. Int Immunol 2009; 22:53-63. [PMID: 19951958 DOI: 10.1093/intimm/dxp114] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Dalton's lymphoma (DL) is a transplantable T-cell lymphoma of spontaneous origin, characterized by highly invasive and immunosuppressive property. Progression of DL cells results into an imbalance of T helper type 1 (T(h)1)/T helper type 2 (T(h)2)-type cytokine in the host, which is partly responsible for DL-induced severe immunosuppression and DL cell progression. In this study, we have shown the role of IL-13 in the regulation of T(h)1 immunity in both normal healthy and DL-bearing host. IL-13 pre-treatment inhibits the induction of 2,4-dinitro-1-fluorobenzene-induced contact hypersensitivity and delayed-type hypersensitivity (DTH) in antigen-challenged mice, which have been confirmed by neutralizing IL-13 by systemic delivery of non-signaling decoy receptor IL-13Ralpha2. Furthermore, IL-13 neutralization enhances the splenocyte proliferation, which has been inhibited by IL-13 administration. Adoptive transfer of splenocyte from IL-13-pre-treated mice and macrophages incubated with IL-13 and pulsed with antigens suppresses the DTH as well in antigen-challenged recipient mice. In addition, it also suppresses the production of pro-inflammatory cytokine and C-C chemokine in DTH footpad. Furthermore, IL-13 neutralization not only enhances the DTH reaction but also increases longevity and survival of DL-bearing host, which suggests that blocking/inactivating systemic IL-13 enhances T(h)1 immunity, and therefore, effects to diminish IL-13 production may have therapeutic value in a host bearing T-cell lymphoma.
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Affiliation(s)
- Praveen Deepak
- Centre of Advanced Study in Zoology, Department of Zoology, Faculty of Science, Banaras Hindu University, Varanasi 221 005, Uttar Pradesh, India
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42
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Dubinett S, Sharma S. Towards effective immunotherapy for lung cancer: simultaneous targeting of tumor-initiating cells and immune pathways in the tumor microenvironment. Immunotherapy 2009; 1:721-5. [DOI: 10.2217/imt.09.56] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Affiliation(s)
- Steven Dubinett
- Division of Pulmonary and Critical Care Medicine, UCLA Lung Cancer Program, School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095-1690, USA
- Veterans Affairs Greater Los Angeles Healthcare System, CA, USA
| | - Sherven Sharma
- Division of Pulmonary and Critical Care Medicine, UCLA Lung Cancer Program, School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095-1690, USA
- Veterans Affairs Greater Los Angeles Healthcare System, CA, USA
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43
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Gonçalves MAG, Soares EG, Donadi EA. The influence of human papillomavirus type and HIV status on the lymphomononuclear cell profile in patients with cervical intraepithelial lesions of different severity. Infect Agent Cancer 2009; 4:11. [PMID: 19689792 PMCID: PMC2736163 DOI: 10.1186/1750-9378-4-11] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2006] [Accepted: 08/18/2009] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Immunological alterations are implicated in the increased prevalence of high-grade squamous intraepithelial lesions (HG-SIL) and persistent human papillomavirus (HPV) infection. This study evaluated the expression of CD4, CD8, CD25 (IL-2Ralpha) and CD28 antigens from SIL biopsies, stratified by HIV status and HPV-type. Biopsies specimens from 82 (35 HIV+) women with a normal cervix, low-grade (LG-SIL) or high-grade lesions (HG-SIL) were studied. CD molecule expression was evaluated by immunohistochemistry and HPV detection/typing performed using PCR techniques. RESULTS CD4 stromal staining was increased in patients with HPV18. Women with HPV16 infection showed decreased: a) CD8 and CD25 stromal staining, b) CD25 staining in LG-SIL epithelium and in HG-SIL stroma. In HIV- women samples, CD28 epithelial staining and CD8 stromal staining surrounding metaplastic epithelium were less intense and even absent, as compared to HIV+ women. Both epithelial and stromal CD8 staining was more intense in the HG-SIL/HIV+ group than in the HG-SIL/HIV- group. Positive correlations were observed between CD4/CD25, CD4/CD28 and CD25/CD28 in the stroma and CD25/CD28 in the epithelium. CONCLUSION HIV status and HPV-type may influence the lymphomononuclear cell profile present in the spectrum of cervical lesions. The knowledge of the infiltrating cell profile in cervical tumours may help the development of specific anti-tumoural strategies.
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Affiliation(s)
- Maria Alice G Gonçalves
- Division of Clinical Immunology, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
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Deepak P, Kumar S, Acharya A. Overexpression of Interleukin-13 in a Murine T-Cell Lymphoma: A Possible Factor of DL-Induced Immunosuppression and Tumor Progression. Cancer Invest 2009; 27:641-9. [DOI: 10.1080/07357900802622758] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Imataki O, Heike Y, Makiyama H, Iizuka A, Ikarashi Y, Ishida T, Wakasugi H, Takaue Y. Insufficient ex vivo expansion of Valpha24(+) natural killer T cells in malignant lymphoma patients related to the suppressed expression of CD1d molecules on CD14(+) cells. Cytotherapy 2009; 10:497-506. [PMID: 18608348 DOI: 10.1080/14653240802072747] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
BACKGROUND Valpha24(+) natural killer T (NKT) cell is a human counterpart of mice Valpha14(+) NKT cell that has a regulatory role for innate and acquired potential antitumor activity. The efficient expansion of NKT cells is an obstacle to the clinical application of Valpha24(+) NKT cells for immunotherapy. METHODS We used mononuclear cells (MNC) obtained from the peripheral blood (PB) of normal healthy donor (HD) and malignant lymphoma (ML) patients before and after granulocyte colony-stimulating factor (G-CSF) treatment. MNC were cultured for 12 days with alpha-galactosylceramide (100 ng/mL) and interleukin-2 (IL-2; 100 U/mL). RESULTS The fold expansion of Valpha24(+) NKT cells was higher in HD than in ML patients (208 versus 0.00), despite comparable numbers of Valpha24(+) NKT cells before culture. G-CSF administration enhanced the predominance of Valpha24(+) NKT cell fold expansion in HD compared with ML patients (1935 versus 1.95). After treatment with G-CSF, the expression of CD1d molecules was up-regulated in CD14(+) cells from HD but not ML patients. The fold expansion of Valpha24(+) NKT cells and CD1d expression on CD14(+) cells was strongly correlated in both HD and ML patients (r(2)=0.84). However, replacement of a patient's CD14(+) cells with HD cells did not increase the efficacy of Valpha24(+) NKT cell expansion. DISCUSSION G-CSF-mobilized PB from ML patients has inhibitory characteristics for Valpha24(+) NKT cell expansion as a result of both monocytes and Valpha24(+) NKT cells. Multiple procedures would be needed for the expansion of patients' Valpha24(+) NKT cells.
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Affiliation(s)
- O Imataki
- Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan
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Neem leaf glycoprotein induces perforin-mediated tumor cell killing by T and NK cells through differential regulation of IFNgamma signaling. J Immunother 2009; 32:42-53. [PMID: 19307993 DOI: 10.1097/cji.0b013e31818e997d] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
We have demonstrated augmentation of the CD3-CD56+ natural killer (NK) and CD8+CD56_ T-cell-mediated tumor cell cytotoxicity by neem leaf glycoprotein (NLGP). These NK and T cells were isolated from the peripheral blood of head and neck squamous cell carcinoma patients with a state of immunosuppression. NLGP induces TCRalphabeta-associated cytotoxic T lymphocyte (CTL) reaction to kill oral cancer (KB) cells. This CTL reaction is assisted by NLGP-mediated up-regulation of CD28 on T cells and HLA-ABC, CD80/86 on monocytes. CTL-mediated killing of KB cells and NK-cell-mediated killing of K562 (erythroleukemic) cells are associated with activation of these cells by NLGP. This activation is evidenced by increased expression of early activation marker CD69 with altered expression of CD45RO/CD45RA. NLGP is a strong inducer of IFNgamma from both T and NK cells; however, IFNgamma regulates the T-cell-mediated cytotoxicity only without affecting NK-cell-mediated one. Reason of this differential regulation may lie within up-regulated expression of IFNgamma-receptor on T-cell surface, not on NK cells. This NLGP-induced cytotoxicity is dependent on up-regulated perforin/granzyme B expression in killer cells, which is again IFNgamma dependent in T cells and independent in NK cells. Although, FasL expression is increased by NLGP, it may not be truly linked with the cytotoxic functions, as brefeldin A could not block such NLGP-mediated cytotoxicity, like, concanamycin A, a perforin inhibitor. On the basis of these results, we conclude that NLGP might be effective to recover the suppressed cytotoxic functions of NK and T cells from head and neck squamous cell carcinoma patients.
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Noman MZ, Buart S, Van Pelt J, Richon C, Hasmim M, Leleu N, Suchorska WM, Jalil A, Lecluse Y, El Hage F, Giuliani M, Pichon C, Azzarone B, Mazure N, Romero P, Mami-Chouaib F, Chouaib S. The cooperative induction of hypoxia-inducible factor-1 alpha and STAT3 during hypoxia induced an impairment of tumor susceptibility to CTL-mediated cell lysis. THE JOURNAL OF IMMUNOLOGY 2009; 182:3510-21. [PMID: 19265129 DOI: 10.4049/jimmunol.0800854] [Citation(s) in RCA: 143] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Hypoxia is an essential component of tumor microenvironment. In this study, we investigated the influence of hypoxia (1% PO(2)) on CTL-mediated tumor cell lysis. We demonstrate that exposure of target tumor cells to hypoxia has an inhibitory effect on the CTL clone (Heu171)-induced autologous target cell lysis. Such inhibition correlates with hypoxia-inducible factor-1alpha (HIF-1alpha) induction but is not associated with an alteration of CTL reactivity as revealed by granzyme B polarization or morphological change. Western blot analysis indicates that although hypoxia had no effect on p53 accumulation, it induced the phosphorylation of STAT3 in tumor cells by a mechanism at least in part involving vascular endothelial growth factor secretion. We additionally show that a simultaneous nuclear translocation of HIF-1alpha and phospho-STAT3 was observed. Interestingly, gene silencing of STAT3 by small interfering RNA resulted in HIF-1alpha inhibition and a significant restoration of target cell susceptibility to CTL-induced killing under hypoxic conditions by a mechanism involving at least in part down-regulation of AKT phosphorylation. Moreover, knockdown of HIF-1alpha resulted in the restoration of target cell lysis under hypoxic conditions. This was further supported by DNA microarray analysis where STAT3 inhibition resulted in a partly reversal of the hypoxia-induced gene expression profile. The present study demonstrates that the concomitant hypoxic induction of phospho-STAT3 and HIF-1alpha are functionally linked to the alteration of non-small cell lung carcinoma target susceptibility to CTL-mediated killing. Considering the eminent functions of STAT3 and HIF-1alpha in the tumor microenvironment, their targeting may represent novel strategies for immunotherapeutic intervention.
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Affiliation(s)
- Muhammad Zaeem Noman
- Institut National de la Santé et de la Recherche Médicale, Unité 753, Villejuif, France
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Brignole C, Marimpietri D, Pastorino F, Di Paolo D, Pagnan G, Loi M, Piccardi F, Cilli M, Tradori-Cappai A, Arrigoni G, Pistoia V, Ponzoni M. Anti-IL-10R antibody improves the therapeutic efficacy of targeted liposomal oligonucleotides. J Control Release 2009; 138:122-7. [PMID: 19427884 DOI: 10.1016/j.jconrel.2009.05.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2009] [Revised: 04/29/2009] [Accepted: 05/02/2009] [Indexed: 01/22/2023]
Abstract
High-risk Neuroblastoma (NB) has still a poor prognosis. Liposomes targeted to NB cells and encapsulating antisense CpG-containing oligonucleotides (TL-asCpG) had increased anti-tumour efficacy in NB xenografts compared to free asCpG. Interleukin 10 (IL-10) suppresses antigen presenting cell activation contributing to tumour-mediated immune suppression. In principle, combination of TL-asCpG and antibodies against IL-10 receptor (aIL-10R) could prolong immune system activation, leading to better therapeutic results. Mice treated with TL-asCpG 4 h after human NB cell inoculation survived significantly longer than controls. An increased life span was achieved also in mice receiving TL-asCpG 24 and 72 h after NB cell challenge. The addition of aIL-10R to TL-asCpG in the 4-h protocol significantly increased the percentage of long term survivors compared to TL-asCpG only. Surviving mice treated with the combined strategy were completely cured. In contrast, long term surviving mice treated only with TL-asCpG presented lymph node infiltration with NB cells. TL-asCpG plus aIL-10R treatment was significantly superior to TL-asCpG alone also for the 24-h protocol. Ex vivo experiments demonstrated that the combined therapy evoked a stronger and more prolonged immune system activation compared to monotherapy. These results support the feasibility of a clinical trial with TL-asCpG and aIL-10R in advanced NB patients.
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Affiliation(s)
- Chiara Brignole
- Laboratory of Oncology, G. Gaslini Children's Hospital, 16147 Genoa, Italy.
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Jiang YF, Ma J, He Y, Zhang YH, Xu Y, Gong GZ. Cationic liposome-mediated transfection of CD40 ligand gene inhibits hepatic tumor growth of hepatocellular carcinoma in mice. J Zhejiang Univ Sci B 2009; 10:7-13. [PMID: 19198017 DOI: 10.1631/jzus.b0820178] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
OBJECTIVE To evaluate the efficacy of cationic liposome-mediated CD40 ligand (CD40L) gene therapy for hepatocellular carcinoma. METHODS 1x10(6) of parental H22 cells or H22 cells transfected with the expression vector containing murine CD40L cDNA encoding the entire coding region (pcDNA3.1(+)-mCD40L) were inoculated subcutaneously into the left flanks of syngenic BALB/C mice. The tumor-bearing mice (tumor nodules 10 mm in maximal diameter) received the treatment of the intratumoral injection of pcDNA3.1(+)-mCD40L/Transfectam, pcDNA3.1(+), or phosphate-buffered saline (PBS), or no treatment. The mice were monitored for tumor growth weekly. We examined mCD40L messenger ribonucleic acid (mRNA) expression by reverse transcription polymerase chain reaction (RT-PCR) and the histologic changes in tumors at two weeks after intratumoral injection using immunohistochemical staining of tumor tissues. RESULTS All mice inoculated with parental H22 cells developed a tumor subcutaneously, and the tumor size increased progressively within three weeks. However, the mice receiving H22-CD40L cells exhibited complete regression of the tumor two weeks after tumor cell inoculation. The tumor-bearing animals with the treatment of pcDNA3.1(+) or PBS, or without treatment had progressive tumor growth, while those mice treated with pcDNA3.1(+)-mCD40L exhibited a significant inhibition of tumor growth. RT-PCR analysis showed that 783-bp fragments corresponding to the mCD40L mRNA were amplified only from pcDNA3.1(+)-mCD40L treated tumors. The tumor samples from pcDNA3.1(+)-mCD40L-treated mice showed significant lymphocyte infiltration, apoptotic bodies, and confluent necrosis in the tumor tissues. CONCLUSION The tumorigenicity of CD40L-expressing cells was abrogated when the cells were implanted subcutaneously. In vivo gene therapy of established liver tumor nodules in mice by the intratumoral injection of pcDNA3.1(+)-mCD40L led to significant tumor inhibition. There was mCD40L mRNA expression in the tissues from pcDNA3.1(+)-mCD40L-treated tumors. The intratumoral injection of pcDNA3.1(+)-mCD40L induced a strong inflammatory, mainly lymphocytic infiltration of the tumor, and increased the necrotic rate of the neoplastic cells.
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Affiliation(s)
- Yong-fang Jiang
- Center for Liver Diseases, the Second Xiangya Hospital, Central South University, Changsha, China.
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Hamaï A, Meslin F, Benlalam H, Jalil A, Mehrpour M, Faure F, Lecluse Y, Vielh P, Avril MF, Robert C, Chouaib S. ICAM-1 has a critical role in the regulation of metastatic melanoma tumor susceptibility to CTL lysis by interfering with PI3K/AKT pathway. Cancer Res 2009; 68:9854-64. [PMID: 19047166 DOI: 10.1158/0008-5472.can-08-0719] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Human primary melanoma cells (T1) were found to be more susceptible to lysis by a Melan-A/MART-1-specific CTL clone (LT12) than their metastatic derivative (G1). We show that this differential susceptibility does not involve antigen presentation by target cells, synapse formation between the metastatic target and CTL clone, or subsequent granzyme B (GrB) polarization. Although PI-9, an inhibitor of GrB, was found to be overexpressed in metastatic G1 cells, knockdown of the PI-9 gene did not result in the attenuation of G1 resistance to CTL-induced killing. Interestingly, we show that whereas T1 cells express high levels of intercellular adhesion molecule-1 (ICAM-1), a dramatically reduced expression was noted on G1 cells. We also showed that sorted ICAM-1+ G1 cells were highly sensitive to CTL-induced lysis compared with ICAM-1- G1 cells. Furthermore, incubation of metastatic G1 cells with IFN-gamma resulted in the induction of ICAM-1 and the potentiation of their susceptibility to lysis by LT12. More importantly, we found that the level of ICAM-1 expression by melanoma cells correlated with decreased PTEN activity. ICAM-1 knockdown in T1 cells resulted in increased phosphorylation of PTEN and the subsequent activation of AKT. We have additionally shown that inhibition of the phosphatidylinositol (3,4,5)-triphosphate kinase (PI3K)/AKT pathway by the specific inhibitor wortmannin induced a significant potentiation of susceptibility of G1 and ICAM-1 small interfering RNA-treated T1 cells to CTL-induced lysis. The present study shows that a shift in ICAM-1 expression, which was associated with an activation of the PI3K/AKT pathway, can be used by metastatic melanoma cells to escape CTL-mediated killing.
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Affiliation(s)
- Ahmed Hamaï
- Institut National de la Santé et de la Recherche Médicale, U753, Laboratoire d'Immunologie des Tumeurs Humaines: Interaction effecteurs cytotoxiques-système tumoral, Institut Gustave Roussy PR1 and IFR 54, Villejuif, France
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