Journal Articles

Immune suppression

Local and peripheral suppression of immune cell activity, immune escape and strategies to revert these pro-tumorigenic mechanisms; cell types with immunosuppressive function

Indoleamine 2,3-dioxygenase provides adaptive resistance to immune checkpoint inhibitors in hepatocellular carcinoma

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Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Immune checkpoint blockade with anti-CTLA-4 and anti-PD-1 antibodies has shown promising results in the treatment of patients with advanced HCC. The anti-PD-1 antibody, nivolumab, is now approved for patients who have had progressive disease on the current standard of care. However, a subset of patients with advanced HCC treated with immune checkpoint inhibitors failed to respond to therapy. Here, we provide evidence of adaptive resistance to immune checkpoint inhibitors through upregulation of indoleamine 2,3-dioxygenase (IDO) in HCC. Anti-CTLA-4 treatment promoted an induction of IDO1 in resistant HCC tumors but not in tumors sensitive to immune checkpoint blockade. Using both subcutaneous and hepatic orthotopic models, we found that the addition of an IDO inhibitor increases the efficacy of treatment in HCC resistant tumors with high IDO induction. Furthermore, in vivo neutralizing studies demonstrated that the IDO induction by immune checkpoint blockade was dependent on IFN-gamma. Similar findings were observed with anti-PD-1 therapy. These results provide evidence that IDO may play a role in adaptive resistance to immune checkpoint inhibitors in patients with HCC. Therefore, inhibiting IDO in combination with immune checkpoint inhibitors may add therapeutic benefit in tumors which overexpress IDO and should be considered for clinical evaluation in HCC.

Author Info: (1) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA

Author Info: (1) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. (2) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea. (3) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. (4) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. (5) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. (6) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. (7) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. (8) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. (9) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. (10) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. tim.greten@nih.gov. National Cancer Institute, Center for Cancer Research, Liver Cancer Program, Bethesda, USA. tim.greten@nih.gov.

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Intraperitoneal oxaliplatin administration inhibits the tumor immunosuppressive microenvironment in an abdominal implantation model of colon cancer

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Recent studies have demonstrated that some chemotherapeutic drugs can enhance antitumor immunity by eliminating and inactivating immunosuppressive cells. Oxaliplatin (OXP) induces immunogenic cell death by increasing the immunogenicity of cancer cells. However, the effects of OXP on the tumor immunosuppressive microenvironment remain unclear. The aim of the present study was to evaluate the antitumor activity of OXP by intraperitoneal (i.p.) administration in an abdominal implantation model of colon cancer and tested the tumor immune microenvironment to observe whether OXP affects the local immune inhibitory cell populations. Abdominal metastasis models were established by inoculation of CT26 cells. The antitumor efficacy of OXP and the tumor immune microenvironment were evaluated. The tumors and spleens of mice were harvested for flow cytometric analysis. Cluster of differentiation (CD)8+CD69+ T cells, regulatory T cells (Tregs), CD11b+F4/80high macrophages and myeloidderived suppressor cells (MDSCs) were evaluated by flow cytometric analysis. In vivo i.p. administration of OXP inhibited tumor growth in the abdominal metastasis model. Furthermore, OXP was observed to increase tumorinfiltrating activated CD8+ T cells in tumors, decrease CD11b+F4/80high macrophages in tumors and decrease MDSCs in the spleen. These results suggested that i.p. administration of OXP alone may inhibit tumor cell growth and induce the antitumor immunostimulatory microenvironment by eliminating immunosuppressive cells.

Author Info: (1) Department of Abdominal Cancer, Cancer Center, The State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041

Author Info: (1) Department of Abdominal Cancer, Cancer Center, The State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China. (2) Department of Abdominal Cancer, Cancer Center, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China. (3) Department of Abdominal Cancer, Cancer Center, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China. (4) Department of Hematology, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China.

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IL-33 Promotes the Development of Colorectal Cancer Through Inducing Tumor-Infiltrating ST2L(+) Regulatory T Cells in Mice

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Colorectal cancer, one of the most commonly diagnosed and lethal cancers worldwide, is accompanied by the disorders of immune system. However, the underlying mechanism is still not fully understood. In this study, our goal was to determine whether interleukin 33 promotes tumorigenesis and progression of colorectal cancer through increased recruitment of tumor-infiltrating ST2(+) regulatory T cells in CT26 tumor-bearing mice. We found that the mRNA or protein levels of interleukin 33, soluble ST2, and membrane ST2 were elevated in the serum of tumor-bearing mice when compared to WT mice. The mRNA levels of interleukin 33, soluble ST2, and membrane ST2 were also elevated in the tissue of tumor-bearing mice when compared to surrounding nontumor muscular tissues. In addition, the frequency of ST2L(+) regulatory T cells was significantly increased in both tumor tissue and spleen of tumor-bearing mice. Higher protein levels of interleukin-4, -10, and -13 were also observed in the serum or the tumor homogenates of tumor-bearing mice. We found exogenously administered recombinant mouse interleukin 33 promoted tumor size and induced tumor-infiltrating ST2L(+) regulatory T cells in tumor-bearing mice while neutralizing interleukin-33 or ST2L inhibited tumor size and decreased ST2L(+) regulatory T cells. Furthermore, ST2L(+) regulatory T cells from tumor tissue were also able to suppress CD4(+)CD25(-)T cell proliferation and interferon gamma production. Altogether, our findings demonstrate the critical roles of interleukin 33 in promoting colorectal cancer development through inducing tumor-infiltrating ST2L(+) regulatory T cells, and inhibition of interleukin-33/ST2L signaling maybe a potential target for the prevention of colorectal cancer.

Author Info: (1) 1 Department of Hepatobiliary Surgery, the Fifth Affiliated Hospital of Medical School of Nantong University, Nantong, China. (2) 2 Department of Cardiothoracic Surgery, Wuxi

Author Info: (1) 1 Department of Hepatobiliary Surgery, the Fifth Affiliated Hospital of Medical School of Nantong University, Nantong, China. (2) 2 Department of Cardiothoracic Surgery, Wuxi People's Hospital Affiliated to Nanjing Medical University, Nanjing, China. (3) 1 Department of Hepatobiliary Surgery, the Fifth Affiliated Hospital of Medical School of Nantong University, Nantong, China. (4) 3 Department of Hepatobiliary Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, China. (5) 1 Department of Hepatobiliary Surgery, the Fifth Affiliated Hospital of Medical School of Nantong University, Nantong, China.

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IL-23 secreted by myeloid cells drives castration-resistant prostate cancer

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Patients with prostate cancer frequently show resistance to androgen-deprivation therapy, a condition known as castration-resistant prostate cancer (CRPC). Acquiring a better understanding of the mechanisms that control the development of CRPC remains an unmet clinical need. The well-established dependency of cancer cells on the tumour microenvironment indicates that the microenvironment might control the emergence of CRPC. Here we identify IL-23 produced by myeloid-derived suppressor cells (MDSCs) as a driver of CRPC in mice and patients with CRPC. Mechanistically, IL-23 secreted by MDSCs can activate the androgen receptor pathway in prostate tumour cells, promoting cell survival and proliferation in androgen-deprived conditions. Intra-tumour MDSC infiltration and IL-23 concentration are increased in blood and tumour samples from patients with CRPC. Antibody-mediated inactivation of IL-23 restored sensitivity to androgen-deprivation therapy in mice. Taken together, these results reveal that MDSCs promote CRPC by acting in a non-cell autonomous manner. Treatments that block IL-23 can oppose MDSC-mediated resistance to castration in prostate cancer and synergize with standard therapies.

Author Info: (1) Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. (2) Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona

Author Info: (1) Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. (2) Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. (3) Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. (4) Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. (5) The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK. (6) The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK. (7) Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. (8) Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. (9) Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. (10) Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. (11) Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. (12) The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK. (13) The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK. (14) The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK. (15) Division of Oncology, Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy. (16) Division of Oncology, Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy. (17) The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK. (18) The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK. (19) Department of Urology, University of Padova, Padova, Italy. (20) The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK. (21) Division of Oncology, Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy. (22) Experimental Imaging Center, San Raffaele Scientific Institute, Milan, Italy. (23) IMED Oncology AstraZeneca, Li Ka Shing Centre, Cambridge, UK. (24) The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK. (25) The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK. (26) The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK. (27) Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. andrea.alimonti@ior.iosi.ch. Universita della Svizzera italiana, Faculty of Biomedical Sciences, Lugano, Switzerland. andrea.alimonti@ior.iosi.ch. Faculty of Biology and Medicine, University of Lausanne UNIL, Lausanne, Switzerland. andrea.alimonti@ior.iosi.ch. Department of Medicine, Venetian Institute of Molecular Medicine, University of Padova, Padova, Italy. andrea.alimonti@ior.iosi.ch.

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Increased exhausted CD8(+) T cells with programmed death-1, T-cell immunoglobulin and mucin-domain-containing-3 phenotype in patients with multiple myeloma

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AIM: The immunosuppressive microenvironment plays a crucial role in T-cell immunodeficiency in multiple myeloma (MM). Overexpression of T-cell immunosuppressive receptors, including programmed death-1 (PD-1) and T-cell immunoglobulin and mucin-domain-containing-3 (Tim-3), may be related to tumor immunosuppression and poor prognosis, and the malignant bone marrow (BM) microenvironment may contribute to such immunosuppression. The purpose of this study was to analyze the distribution of PD-1(+) and/or Tim-3(+) T cells in different T-cell subset in patients with MM. METHODS: The expression of PD-1 and Tim-3 with exhausted (CD244(+) and CD57(+) ) CD3(+) , CD4(+) and CD8(+) T cells between BM and peripheral blood (PB) from 10 patients with untreated MM was detected by multicolor flow cytometry assay. RESULTS: A significant increase in both PD-1(+) CD57(+) and Tim-3(+) CD57(+) CD3(+) T cells and PD-1(+) Tim-3(+) CD3(+) T cells was detected in PB from patients with MM compared with 10 healthy individuals (HIs), and the alteration was mostly in the CD8(+) T-cell subset. Significant higher percentage of PD-1(+) CD3(+) T cells was found in BM compared with PB from patients with MM. The level of PD-1(+) Tim-3(+) CD3(+) , CD4(+) , and CD8(+) T cells was high in BM group compared with PB. Moreover, PD-1(+) CD244(+) or PD-1(+) CD57(+) CD3(+) T cells, particularly PD-1(+) CD244(+) and PD-1(+) CD57(+) CD8(+) T cells were significantly higher in BM than in PB. In addition, limited dynamic detection data from three MM cases who achieved complete remission after treatment showed that the numbers of either PD-1(+) or PD-1(+) Tim-3(+) T cells in different T-cell subsets were decreased in both BM and PB. CONCLUSION: We characterized the distribution of PD-1 and TIM-3 concurrent with exhausted CD3(+) , CD4(+) and CD8(+) T cells between BM and PB from patients with MM. Higher numbers of PD-1(+) CD244(+) or PD-1(+) CD57(+) CD3(+) T cells in BM from patients with MM may contribute to mediate the BM immunosuppressive microenvironment. Although heterogeneous alterations in Tim-3(+) T cells may represent a complex immunosuppressive pattern in MM. Overall, higher levels of PD-1(+) CD244(+) or PD-1/Tim-3(+) CD57(+) CD8(+) T cells may be a major reason for lower T-cell activation and T-cell immunodeficiency in MM.

Author Info: (1) Department of Hematology, First Affiliated Hospital, Institute of Hematology, School of Medicine, Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou

Author Info: (1) Department of Hematology, First Affiliated Hospital, Institute of Hematology, School of Medicine, Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, China. (2) Department of Hematology, First Affiliated Hospital, Institute of Hematology, School of Medicine, Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, China. (3) Department of Hematology, First Affiliated Hospital, Institute of Hematology, School of Medicine, Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, China. (4) Department of Hematology, First Affiliated Hospital, Institute of Hematology, School of Medicine, Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, China. (5) Department of Hematology, First Affiliated Hospital, Institute of Hematology, School of Medicine, Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, China. (6) Department of Hematology, First Affiliated Hospital, Institute of Hematology, School of Medicine, Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, China. (7) Department of Hematology, First Affiliated Hospital, Institute of Hematology, School of Medicine, Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, China. (8) Department of Hematology, First Affiliated Hospital, Institute of Hematology, School of Medicine, Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, China. (9) Department of Oncology, First Affiliated Hospital, Jinan University, Guangzhou, China. (10) Department of Hematology, First Affiliated Hospital, Institute of Hematology, School of Medicine, Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, China. (11) Department of Hematology, First Affiliated Hospital, Institute of Hematology, School of Medicine, Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, China. Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan University, Guangzhou, China.

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LSD1 Ablation Stimulates Anti-tumor Immunity and Enables Checkpoint Blockade

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Chromatin regulators play a broad role in regulating gene expression and, when gone awry, can lead to cancer. Here, we demonstrate that ablation of the histone demethylase LSD1 in cancer cells increases repetitive element expression, including endogenous retroviral elements (ERVs), and decreases expression of RNA-induced silencing complex (RISC) components. Significantly, this leads to double-stranded RNA (dsRNA) stress and activation of type 1 interferon, which stimulates anti-tumor T cell immunity and restrains tumor growth. Furthermore, LSD1 depletion enhances tumor immunogenicity and T cell infiltration in poorly immunogenic tumors and elicits significant responses of checkpoint blockade-refractory mouse melanoma to anti-PD-1 therapy. Consistently, TCGA data analysis shows an inverse correlation between LSD1 expression and CD8(+) T cell infiltration in various human cancers. Our study identifies LSD1 as a potent inhibitor of anti-tumor immunity and responsiveness to immunotherapy and suggests LSD1 inhibition combined with PD-(L)1 blockade as a novel cancer treatment strategy.

Author Info: (1) Division of Newborn Medicine and Epigenetics Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115

Author Info: (1) Division of Newborn Medicine and Epigenetics Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. (2) Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (3) Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA. (4) Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2M9, Canada. (5) Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2M9, Canada. (6) Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA. (7) Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599. (8) Division of Newborn Medicine and Epigenetics Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. (9) Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599. (10) Department of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung City 202, Taiwan. (11) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (12) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (13) Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2M9, Canada. (14) Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2M9, Canada. (15) Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address: arlene_sharpe@hms.harvard.edu. (16) Division of Newborn Medicine and Epigenetics Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: yang_shi@hms.harvard.edu.

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Immune Suppression and Reversal of the Suppressive Tumor Microenvironment

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Most tumors employ multiple strategies to attenuate T cell-mediated immune response. In particular, immune suppression surrounding the tumor is achieved by interfering with antigen-presenting cells and effector T cells. Controlling both the tumor and the tumor microenvironment (TME) is critical for cancer treatment. Checkpoint blockade therapy can overcome tumor-induced immune suppression, but more than half of the patients fail to respond to this treatment; therefore, more effective cancer immunotherapies are needed. Generation of an antitumor immune response is a multi-step process of immune activation against the tumor that requires effector T cells to recognize and exert toxic effects against tumor cells, for which two strategies are employed-inhibition of various types of immune suppressor cells, such as myeloid cells and regulatory T cells; and establishment of antitumor immune surveillance including, activation of natural killer cells and cytotoxic T cells. It was recently shown that anti-cancer drugs not only directly kill tumor cells, but also influence the immune response to cancer by promoting immunogenic cell death, enhancing antigen presentation, or depleting immunosuppressive cells. Herein, we reviewed the mechanisms by which tumors exert immune suppression as well as their regulation. We then discuss how the complex reciprocal interactions between immunosuppressive and immunostimulatory cells influence immune cell dynamics in the TME. Finally, we highlight the new therapies that can reverse immune suppression in the TME and promote antitumor immunity.

Author Info: (1) Laboratory for Immunotherapy, RIKEN Center for Integrative Medical Sciences, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, Japan. (2) Laboratory for Immunotherapy, RIKEN Center for Integrative Medical Sciences

Author Info: (1) Laboratory for Immunotherapy, RIKEN Center for Integrative Medical Sciences, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, Japan. (2) Laboratory for Immunotherapy, RIKEN Center for Integrative Medical Sciences, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, Japan. (3) Laboratory for Immunotherapy, RIKEN Center for Integrative Medical Sciences, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, Japan. (4) Laboratory for Immunotherapy, RIKEN Center for Integrative Medical Sciences, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, Japan. (5) Laboratory for Immunotherapy, RIKEN Center for Integrative Medical Sciences, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, Japan.

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Expression patterns of programmed death ligand 1 correlate with different microenvironments and patient prognosis in hepatocellular carcinoma

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BACKGROUND: Recent clinical studies have suggested that programmed death ligand 1 (PD-L1) expression in a tumour could be a potential biomarker for PD-L1/PD-1 blockade therapies. METHODS: To better characterise PD-L1 expression in hepatocellular carcinoma (HCC), we analysed its expression patterns in 453 HCC patients by double staining for CD68 and PD-L1 using the Tyramide Signal Amplification Systems combined with immunohistochemistry. We also investigated its correlation with clinical features, prognosis and immune status. RESULTS: The results showed that PD-L1 expression on tumour cells (TCs) was negatively associated with patients' overall survival (OS; P = 0.001) and relapse-free survival (RFS; P = 0.006); however, PD-L1 expression on macrophages (Mphis) was positively correlated with OS (P = 0.017). Multivariate analysis revealed that PD-L1 expression on TCs and Mphis were both independent prognostic factors for OS (hazard ratio (HR) = 1.168, P = 0.004 for TC-PD-L1; HR = 0.708, P = 0.003 for Mphi-PD-L1). Further studies showed that Mphi-PD-L1(+) tumours exhibited an activated immune microenvironment, with high levels of CD8(+) T-cell infiltration and immune-related gene expression. CONCLUSION: Our study provided a novel methodology to evaluate PD-L1 expression in the tumour microenvironment, which might help to select patients who would benefit from anti-PD-1/PD-L1 immunotherapies.

Author Info: (1) Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China

Author Info: (1) Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China. (2) Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China. (3) Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, 510060, Guangzhou, P. R. China. (4) Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, P. R. China. (5) Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China. (6) Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China. (7) Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, P. R. China. (8) Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, P. R. China. (9) Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, 510060, Guangzhou, P. R. China. zhangyuj@sysucc.org.cn. (10) Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China. zhenglm@mail.sysu.edu.cn. Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, P. R. China. zhenglm@mail.sysu.edu.cn.

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STAT3 in Tumor-Associated Myeloid Cells: Multitasking to Disrupt Immunity

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Myeloid immune cells, such as dendritic cells, monocytes, and macrophages, play a central role in the generation of immune responses and thus are often either disabled or even hijacked by tumors. These new tolerogenic activities of tumor-associated myeloid cells are controlled by an oncogenic transcription factor, signal transducer and activator of transcription 3 (STAT3). STAT3 multitasks to ensure tumors escape immune detection by impairing antigen presentation and reducing production of immunostimulatory molecules while augmenting the release of tolerogenic mediators, thereby reducing innate and adaptive antitumor immunity. Tumor-associated myeloid cells and STAT3 signaling in this compartment are now commonly recognized as an attractive cellular target for improving efficacy of standard therapies and immunotherapies. Hereby, we review the importance and functional complexity of STAT3 signaling in this immune cell compartment as well as potential strategies for cancer therapy.

Author Info: (1) Department of Immuno-Oncology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, 91010 CA, USA. yulsu@coh.org. (2) Department of Immuno-Oncology, Beckman Research

Author Info: (1) Department of Immuno-Oncology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, 91010 CA, USA. yulsu@coh.org. (2) Department of Immuno-Oncology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, 91010 CA, USA. shbanerjee@coh.org. (3) Department of Immuno-Oncology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, 91010 CA, USA. sewhite@coh.org. (4) Department of Immuno-Oncology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, 91010 CA, USA. mkortylewski@coh.org.

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Cancer-Associated Fibroblasts Affect Intratumoral CD8(+) and FoxP3(+) T Cells via Interleukin 6 in the Tumor Microenvironment

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PURPOSE: Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) play a central role in tumor progression. We investigated whether CAFs can regulate tumor-infiltrating lymphocytes (TILs) and their role in tumor immunosuppression. EXPERIMENTAL DESIGN: 140 cases of esophageal cancer were analyzed for CAFs and CD8(+)or forkhead box protein 3 (FoxP3(+)) TILs by immunohistochemistry. We analyzed cytokines using murine or human fibroblasts and cancer cells. Murine-derived fibroblasts and cancer cells were also inoculated into BALB/c or BALB/c-nu/numice, and the tumors treated with recombinant interleukin 6 (IL-6) or anti-IL-6 antibody. RESULTS: CD8(+)TILs and CAFs were negatively correlated in intra-tumoral tissues (P< 0.001), while FoxP3(+)TILs were positively correlated (P< 0.001) in esophageal cancers. Co-cultured Colon26 cancer cells and fibroblasts resulted in accelerated tumor growth in BALB/c mice, along with decreased CD8(+)and increased FoxP3(+)TILs, compared with cancer cells alone. In vitro, IL-6 was highly secreted in both murine and human cancer cell/fibroblast co-cultures. IL-6 significantly increased Colon26 tumor growth in immune-competent BALB/c (P< 0.001) with fewer CD8(+)TILs than untreated tumors (P< 0.001), whereas no difference in BALB/c-nu/numice. In contrast, FoxP3(+)TILs increased in IL-6-treated tumors (P< 0.001). IL-6 antibody blockade of tumors co-cultured with fibroblasts resulted not only in regression of tumor growth but also in the accumulation of CD8(+)TILs in intra-tumoral tissues. CONCLUSIONS: CAFs regulate immunosuppressive TIL populations in the TME via IL-6. IL-6 blockade, or targeting CAFs, may improve pre-existing tumor immunity and enhance the efficacy of conventional immunotherapies.

Author Info: (1) Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences. (2) Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical

Author Info: (1) Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences. (2) Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences knoma@md.okayama-u.ac.jp. (3) Pathology & Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences. (4) Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences. (5) Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences. (6) Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences. (7) Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences. (8) Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences. (9) Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences. (10) Center for Innovative Clinical Medicine, Okayama University Hospital. (11) Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine. (12) Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences.

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