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

High macrophage PD-L1 expression not responsible for T cell suppression

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Tumors are often comprised of microenvironments (TMEs) with a high proportion of cells and molecules that regulate immunity. Peritoneal cavity (PerC) cell culture reproduces key features of TMEs as lymphocyte proliferation is suppressed by PerC macrophages (Mvarphis). We monitored the expression of T cell stimulatory (Class II MHC, B7) and inhibitory (PD-L1) molecules by PerC APCs before and after culture and report here that IFNgamma-driven PD-L1 expression increased markedly on PerC Mvarphis after TCR ligation, even more so than seen with direct APC activation by LPS. Considering the high APC composition of and pronounced PD-L1 expression by PerC cells, it was surprising that blocking PD-1/PD-L1 interaction by mAb neutralization or genetic ablation did not relieve suppression. This result parallels TME challenges observed in the clinic and validates the need for further study of this culture model to inform strategies to promote anti-tumor immunity.

Author Info: (1) Department of Biology, Rider University, Lawrenceville, NJ, 08648, USA. (2) Department of Biology, Rider University, Lawrenceville, NJ, 08648, USA. (3) Department of Biology, Rider

Author Info: (1) Department of Biology, Rider University, Lawrenceville, NJ, 08648, USA. (2) Department of Biology, Rider University, Lawrenceville, NJ, 08648, USA. (3) Department of Biology, Rider University, Lawrenceville, NJ, 08648, USA. (4) Department of Biology, Rider University, Lawrenceville, NJ, 08648, USA. (5) Department of Biology, Rider University, Lawrenceville, NJ, 08648, USA. (6) Department of Biology, Rider University, Lawrenceville, NJ, 08648, USA. (7) Department of Biology, Rider University, Lawrenceville, NJ, 08648, USA. Electronic address: riggs@rider.edu.

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Exosomes associated with human ovarian tumors harbor a reversible checkpoint of T cell responses

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Nano-sized membrane-encapsulated extracellular vesicles isolated from the ascites fluids of ovarian cancer patients are identified as exosomes based on their biophysical and compositional characteristics. We report here that T cells pulsed with these tumor-associated exosomes during TCR-dependent activation inhibit various activation endpoints including translocation of NFkB and NFAT into the nucleus, upregulation of CD69 and CD107a, production of cytokines and cell proliferation. Additionally, the activation of virus-specific CD8+ T cells that are stimulated with the cognate viral peptides presented in the context of class I MHC is also suppressed by the exosomes. The inhibition occurs without loss of cell viability, and coincidentally with the binding and internalization of these exosomes. This exosome-mediated inhibition of T cells was transient and reversible: T cells exposed to exosomes can be reactivated once exosomes are removed. We conclude that tumor-associated exosomes are immunosuppressive, and represent a therapeutic target blockade of which would enhance the antitumor response of quiescent tumor-associated T cells and prevent the functional arrest of adoptively transferred tumor-specific T cells or chimeric antigen receptor (CAR) T cells.

Author Info: (1) Microbiology and Immunology, School of Medicine, University at Buffalo. (2) Microbiology and Immunology, School of Medicine, University at Buffalo. (3) Flow and Image Cytometry

Author Info: (1) Microbiology and Immunology, School of Medicine, University at Buffalo. (2) Microbiology and Immunology, School of Medicine, University at Buffalo. (3) Flow and Image Cytometry Shared Resource, Roswell Park Cancer Institute. (4) Pharmaceutical Sciences, University at Buffalo. (5) Microbiology and Immunology, School of Medicine, University at Buffalo. (6) Flow and Image Cytometry Shared Resource, Roswell Park Cancer Institute. (7) Flow Cytometry, Roswell Park Cancer Institute. (8) Gynecologic Oncology, Roswell Park Cancer Institute. (9) Pharmaceutical Sciences, University at Buffalo. (10) Microbiology and Immunology, School of Medicine, University at Buffalo rbankert@buffalo.edu.

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Notch1 signaling in melanoma cells promoted tumor-induced immunosuppression via upregulation of TGF-beta1

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BACKGROUND: The receptors of Notch family play an important role in controlling the development, differentiation, and function of multiple cell types. The aim of this study is to investigate the role of Notch1 signaling upon immune suppression induced by melanoma cells. METHODS: Melanoma cell line B16 cells were transfected by lentivirus containing mouse Notch1 gene or Notch1 shRNA to generate B16 cell line that highly or lowly expressed Notch1. Notch1 in anti-tumor immune response was comprehensively appraised in murine B16 melanoma tumor model in immunocompetent and immunodeficient mice. The ratios of CD3(+)CD8(+) cytotoxic T cells, CD49b(+)NK cells, CD4(+)CD25(+)FoxP3(+) Tregs and Gr1(+)CD11b(+) MDSCs in tumor-DLN or spleen were examined by flow cytometry. After the co-culture of B16 cells and CD8(+) T cells, the effects of Notch1 on the proliferation and activation of T cells were assessed by CCK8 assay, CFSE dilution and Chromium-release test. The mRNA expression and supernatant secretion of immunosuppressive cytokines, TGF-beta1, VEGF, IL-10 and IFN-gamma were measured by RT-PCR and ELISA, respectively. RESULTS: Downregulation or overexpression of Notch1 in B16 melanoma cells inhibited or promoted tumor growth in immunocompetent mice, respectively. Notch1 expression in B16 melanoma cells inhibited the infiltration of CD8+ cytotoxic T lymphocytes and NK cells and reduced IFN-gamma release in tumor tissue. It could also enhance B16 cell-mediated inhibition of T cell proliferation and activation, and upregulate PD-1 expression on CD4(+) and CD8(+) T cells. The percentage of CD4(+)CD25(+)FoxP3(+) Tregs and Gr1(+)CD11b(+)MDSCs were significantly increased in tumor microenvironment, and all these were attributed to the upregulation of TGF-beta1. CONCLUSION: These findings suggested that Notch1 signaling in B16 melanoma cells might inhibit antitumor immunity by upregulation of TGF-beta1.

Author Info: (1) Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, No.13, Shiliugang Road, Haizhu District, Guangzhou, 510315, Guangdong Province, People's Republic of China

Author Info: (1) Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, No.13, Shiliugang Road, Haizhu District, Guangzhou, 510315, Guangdong Province, People's Republic of China. (2) Cancer Center, The First People's Hospital of Huaihua City, Huaihua, 418000, Hunan Province, People's Republic of China. (3) Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, No.13, Shiliugang Road, Haizhu District, Guangzhou, 510315, Guangdong Province, People's Republic of China. (4) Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, No.13, Shiliugang Road, Haizhu District, Guangzhou, 510315, Guangdong Province, People's Republic of China. (5) Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, No.13, Shiliugang Road, Haizhu District, Guangzhou, 510315, Guangdong Province, People's Republic of China. (6) Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, No.13, Shiliugang Road, Haizhu District, Guangzhou, 510315, Guangdong Province, People's Republic of China. (7) Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, No.13, Shiliugang Road, Haizhu District, Guangzhou, 510315, Guangdong Province, People's Republic of China. (8) Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, No.13, Shiliugang Road, Haizhu District, Guangzhou, 510315, Guangdong Province, People's Republic of China. luorc02@vip.163.com. (9) Oncology Department, Nanfang Hospital, Southern Medical University, No.1838, North of Guangzhou Avenue, Baiyun District, Guangzhou, Guangdong Province, 510515, People's Republic of China. kangshijunlb@163.com.

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Immune Evasion in Pancreatic Cancer: From Mechanisms to Therapy

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Pancreatic ductal adenocarcinoma (PDA), the most frequent type of pancreatic cancer, remains one of the most challenging problems for the biomedical and clinical fields, with abysmal survival rates and poor therapy efficiency. Desmoplasia, which is abundant in PDA, can be blamed for much of the mechanisms behind poor drug performance, as it is the main source of the cytokines and chemokines that orchestrate rapid and silent tumor progression to allow tumor cells to be isolated into an extensive fibrotic reaction, which results in inefficient drug delivery. However, since immunotherapy was proclaimed as the breakthrough of the year in 2013, the focus on the stroma of pancreatic cancer has interestingly moved from activated fibroblasts to the immune compartment, trying to understand the immunosuppressive factors that play a part in the strong immune evasion that characterizes PDA. The PDA microenvironment is highly immunosuppressive and is basically composed of T regulatory cells (Tregs), tumor-associated macrophages (TAMs), and myeloid-derived suppressive cells (MDSCs), which block CD8(+) T-cell duties in tumor recognition and clearance. Interestingly, preclinical data have highlighted the importance of this immune evasion as the source of resistance to single checkpoint immunotherapies and cancer vaccines and point at pathways that inhibit the immune attack as a key to solve the therapy puzzle. Here, we will discuss the molecular mechanisms involved in PDA immune escape as well as the state of the art of the PDA immunotherapy.

Author Info: (1) Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona 08003, Spain. nmartinez@imim.es. (2) Cancer Research Program, Hospital del Mar Medical Research Institute

Author Info: (1) Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona 08003, Spain. nmartinez@imim.es. (2) Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona 08003, Spain. jvinaixa@imim.es. (3) Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona 08003, Spain. pnavarro@imim.es. Institute of Biomedical Research of Barcelona (IIBB-CSIC), Barcelona 08036, Spain. pnavarro@imim.es.

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Antigen-specific antitumor responses induced by OX40 agonist are enhanced by IDO inhibitor indoximod

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Although an immune response to tumors may be generated using vaccines, so far, this approach has only shown minimal clinical success. This is attributed to the tendency of cancer to escape immune surveillance via multiple immune suppressive mechanisms. Successful cancer immunotherapy requires targeting these inhibitory mechanisms along with enhancement of antigen-specific immune responses to promote sustained tumor-specific immunity. Here we evaluated the effect of indoximod, an inhibitor of the immunosuppressive indoleamine-(2,3)-dioxygenase (IDO) pathway, on antitumor efficacy of anti-OX40 agonist in the context of vaccine in the IDO- TC-1 tumor model. We demonstrate that although the addition of anti-OX40 to the vaccine moderately enhances therapeutic efficacy, incorporation of indoximod into this treatment leads to enhanced tumor regression and cure of established tumors in 60% of treated mice. We show that the mechanisms by which the IDO inhibitor leads to this therapeutic potency include (i) an increment of vaccine-induced tumor-infiltrating effector T cells that is facilitated by anti-OX40, and (ii) a decrease of IDO enzyme activity produced by non-tumor cells within the tumor microenvironment that results in enhancement of the specificity and the functionality of vaccine-induced effector T cells. Our findings suggest a translatable strategy to enhance the overall efficacy of cancer immunotherapy.

Author Info: (1) Georgia Cancer Center, Augusta University. (2) Georgia Cancer Center, Augusta University. (3) Georgia Cancer Center, Augusta University. (4) Georgia Cancer Center, Augusta University. (5)

Author Info: (1) Georgia Cancer Center, Augusta University. (2) Georgia Cancer Center, Augusta University. (3) Georgia Cancer Center, Augusta University. (4) Georgia Cancer Center, Augusta University. (5) Georgia Cancer Center, Augusta University. (6) Georgia Cancer Center, Augusta University. (7) Georgia Cancer Center, Augusta University. (8) Georgia Cancer Center, Augusta University. (9) The University of Aberdeen Dental School & Hospital, The Institute of Medicine, Medical Sciences & Nutrition, The University of Aberdeen. (10) Medimmune Inc. (11) Georgia Cancer Center, Augusta University. (12) Georgia Cancer Center, Augusta University skhleif@augusta.edu.

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SIRT1 and HIF1alpha signaling in metabolism and immune responses

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SIRT1 and HIF1alpha are regarded as two key metabolic sensors in cellular metabolism pathways and play vital roles in influencing immune responses. SIRT1 and HIF1alpha regulate immune responses in metabolism-dependent and -independent ways. Here, we summarized the recent knowledge of SIRT1 and HIF1alpha signaling in metabolism and immune responses. HIF1alpha is a direct target of SIRT1. Sometimes, SIRT1 and HIF1alpha cooperate or act separately to mediate immune responses. In innate immune responses, SIRT1 can regulate the glycolytic activity of myeloid-derived suppressor cells (MDSCs) and influence MDSC functional differentiation. SIRT1 can regulate monocyte function through NF-kappaB and PGC-1, accompanying an increased NAD(+) level. The SIRT1-HIF1alpha axis bridges the innate immune signal to an adaptive immune response by directing cytokine production of dendritic cells in a metabolism-independent manner, promoting the differentiation of CD4(+) T cells. For adaptive immune cells, SIRT1 can mediate the differentiation of inflammatory T cell subsets in a NAD(+)-dependent manner. HIF1alpha can stimulate some glycolysis-associated genes and regulate the ATP and ROS generations. In addition, SIRT1-and HIF1alpha-associated metabolism inhibits the activity of mTOR, thus negatively regulating the differentiation and function of Th9 cells. As immune cells are crucial in controlling immune-associated diseases, SIRT1-and HIF1alpha associated-metabolism is closely linked to immune-associated diseases, including infection, tumors, allergic airway inflammation, and autoimmune diseases.

Author Info: (1) Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing

Author Info: (1) Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875 China. (2) Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875 China. (3) Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875 China. (4) Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875 China. Electronic address: liugw@bnu.edu.cn.

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Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma

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Immune checkpoint inhibitors targeting the programmed cell death-1 receptor (PD-1) improve survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). To identify genomic alterations in ccRCC that correlate with response to anti-PD-1 monotherapy, we performed whole exome sequencing of metastatic ccRCC from 35 patients. We found that clinical benefit was associated with loss-of-function mutations in the PBRM1 gene (p=0.012), which encodes a subunit of a SWI/SNF chromatin remodeling complex (the PBAF subtype). We confirmed this finding in an independent validation cohort of 63 ccRCC patients treated with PD-(L)1 blockade therapy alone or in combination with anti-CTLA-4 therapies (p=0.0071). Gene expression analysis of PBAF-deficient ccRCC cell lines and PBRM1-deficient tumors revealed altered transcriptional output in JAK/STAT, hypoxia, and immune signaling pathways. PBRM1 loss in ccRCC may alter global tumor cell expression profiles to influence responsiveness to immune checkpoint therapy.

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. (3) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (4) Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA. (5) Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (6) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (7) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (8) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (9) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. (10) Bristol-Myers Squibb, New York, NY 10154, USA. (11) Bristol-Myers Squibb, New York, NY 10154, USA. (12) Bristol-Myers Squibb, New York, NY 10154, USA. (13) Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. (14) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. (15) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (16) Columbia University Medical Center, New York, NY 10032, USA. (17) James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (18) James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (19) Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (20) Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA. (21) Mayo Clinic, Scottsdale, AZ 85259, USA. (22) Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA. (23) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (24) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (25) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. eliezerm_vanallen@dfci.harvard.edu toni_choueiri@dfci.harvard.edu. (26) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. eliezerm_vanallen@dfci.harvard.edu toni_choueiri@dfci.harvard.edu. Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA.

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A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing

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Many human cancers are resistant to immunotherapy for reasons that are poorly understood. We used a genome-scale CRISPR/Cas9 screen to identify mechanisms of tumor cell resistance to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. Inactivation of >100 genes sensitized mouse B16F10 melanoma cells to killing by T cells, including Pbrm1, Arid2 and Brd7, which encode components of the PBAF form of the SWI/SNF chromatin remodeling complex. Loss of PBAF function increased tumor cell sensitivity to interferon-gamma, resulting in enhanced secretion of chemokines that recruit effector T cells. Treatment-resistant tumors became responsive to immunotherapy when Pbrm1 was inactivated. In many human cancers, expression of PBRM1 and ARID2 inversely correlated with expression of T cell cytotoxicity genes, and Pbrm1-deficient murine melanomas were more strongly infiltrated by cytotoxic T cells.

Author Info: (1) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (2) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston

Author Info: (1) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (2) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (3) Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (4) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (5) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (6) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (7) Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (8) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (9) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (10) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (11) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (12) Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (13) Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (14) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (15) Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. kai_wucherpfennig@dfci.harvard.edu xsliu@jimmy.harvard.edu. (16) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. kai_wucherpfennig@dfci.harvard.edu xsliu@jimmy.harvard.edu. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.

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Blockade of CCR5-mediated myeloid derived suppressor cell accumulation enhances anti-PD1 efficacy in gastric cancer

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PURPOSE: Myeloid derived suppressor cells (MDSC) play an important role in tumor immune evasion and its level significantly increased in patients with gastric cancer. Studies confirmed the associations between MDSC and various cytokines in the peripheral blood. However, little is known about the mechanism drawing MDSC into tumor parenchyma. This study was to analyze the correlation between MDSC subsets and CCR5 level in gastric cancer. MATERIALS AND METHODS: G-MDSC and M-MDSC from the peripheral blood and tumor parenchyma were analyzed by flow cytometry. CCR5 ligand CCL5 was detected by ELISA. CCR5 was detected by real-time PCR, western blot and flow cytometry. Furthermore, the therapeutic effects of CCR5 blockade was assessed by the tumor model. RESULTS: CCR5 ligand, gene and protein expression of CCR5, and surface expression of CCR5 significantly increased in blood and tumor of tumor-bearing mice, suggesting MDSC may be attracted into the parenchyma by CCL5/CCR5. Anti-CCR5 treatment decreased G-MDSC and M-MDSC in the periphery and tumor. In addition, combination treatment enhanced CD4+ and CD8+ T cell infiltration and decreased the tumor burden of tumor-bearing mice. CONCLUSIONS: This study elucidated a possible association between MDSC subsets and CCR5, in addition to provide a new potential target to enhance the efficacy of immunotherapy in patients with gastric cancer.

Author Info: (1) a Department of Gastroenterology, Shanghai Ninth People's Hospital, School of Medicine , Shanghai Jiaotong University , Shanghai , P.R. China. (2) b Department of

Author Info: (1) a Department of Gastroenterology, Shanghai Ninth People's Hospital, School of Medicine , Shanghai Jiaotong University , Shanghai , P.R. China. (2) b Department of Surgery, Shanghai Ninth People's Hospital, School of Medicine , Shanghai Jiaotong University , Shanghai , P.R. China. (3) b Department of Surgery, Shanghai Ninth People's Hospital, School of Medicine , Shanghai Jiaotong University , Shanghai , P.R. China. (4) c Department of Pathology, Shanghai Ninth People's Hospital, School of Medicine , Shanghai Jiaotong University , Shanghai , P.R. China. (5) d Division of Gastroenterology and Department of Internal Medicine, Veterans Affairs Medical Center, Karmanos Cancer Institute, School of Medicine , Wayne State University , Detroit , MI , USA. (6) e Department of Surgery , Jingan Branch of Huashan Hospital, Fudan University , Shanghai , P.R. China.

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Modulating Tumor Immunology by Inhibiting Indoleamine 2,3-Dioxygenase (IDO): Recent Developments and First Clinical Experiences

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Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) catalyze the first rate-limiting step in the oxidative metabolism of compounds containing indole rings, including the transformation of the essential amino acid L-tryptophan to N-formyl-L-kynurenine. Through direct and indirect means, IDO exerts both tolerogenic and pro-inflammatory effects and has a profound immunoregulatory role in the tumor microenvironment. Although the role of IDO in mediating peripheral acquired immunologic tolerance has been known for some time, its role in tumorigenesis and the subversion of anti-tumor immunity have only recently been appreciated. Small-molecule inhibitors of IDO1 and TDO are being evaluated as single agents and in combination with immune checkpoint blockade in a host of advanced cancers. In this review, we delineate the tolerogenic and pro-inflammatory effects of IDO as it relates to immune escape and discuss current clinical progress in this area.

Author Info: (1) Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh Medical Center, 5117 Centre Avenue, Pittsburgh, PA, 15232, USA. (2) Department of Medicine, Division of

Author Info: (1) Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh Medical Center, 5117 Centre Avenue, Pittsburgh, PA, 15232, USA. (2) Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh Medical Center, 5117 Centre Avenue, Pittsburgh, PA, 15232, USA. baharyn@upmc.edu.

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