Journal Articles

Tumor micro-environment

Composition, function and interactions of the tumor immune environment and strategies to modulate the tumor immune environment; Immune biomarkers

Whole exome and transcriptome analyses integrated with microenvironmental immune signatures of lung squamous cell carcinoma

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The immune microenvironment in lung squamous cell carcinoma (LUSC) is not well understood, with interactions between the host immune system and the tumor, as well as the molecular pathogenesis of LUSC, awaiting better characterization. To date, no molecularly targeted agents have been developed for LUSC treatment. Identification of predictive and prognostic biomarkers for LUSC could help optimize therapy decisions. We sequenced whole exomes and RNA from 101 tumors and matched noncancer control Korean samples. We used the information to predict subtype-specific interactions within the LUSC microenvironment and to connect genomic alterations with immune signatures. Hierarchical clustering based on gene expression and mutational profiling revealed subtypes that were either immune defective or immune competent. We analyzed infiltrating stromal and immune cells to further characterize the tumor microenvironment. Elevated expression of macrophage 2 signature genes in the immune competent subtype confirmed that tumor-associated macrophages (TAMs) linked inflammation and mutation-driven cancer. A negative correlation was evident between the immune score and the amount of somatic copy-number variation (SCNV) of immune genes (r = -0.58). The SCNVs showed a potential detrimental effect on immunity in the immune-deficient subtype. Knowledge of the genomic alterations in the tumor microenvironment could be used to guide design of immunotherapy options that are appropriate for patients with certain cancer subtypes.

Author Info: (1) Gong Wu Genomic Medicine Institute, Seoul National University Bundang Hospital jeongsun@snu.ac.kr. (2) Department of Biomedical Sciences, Seoul National University College of Medicine. (3) Department

Author Info: (1) Gong Wu Genomic Medicine Institute, Seoul National University Bundang Hospital jeongsun@snu.ac.kr. (2) Department of Biomedical Sciences, Seoul National University College of Medicine. (3) Department of Biomedical Sciences, Seoul National University College of Medicine. (4) GMI, SNU. (5) Cancer Research Institute, Seoul National University College of Medicine. (6) Cancer Research Institute, Seoul National University College of Medicine. (7) Cancer Research Institute, Seoul National University College of Medicine. (8) Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital. (9) Thoracic and Cardiovascular Surgery, None. (10) Thoracic and Cardiovascular Surgery, Seoul National University Hospital. (11) Department of thoracic and cardiovascular surgery, Seoul National University Hospital. (12) Macrogen, Macrogen Inc. (13) Macrogen Inc. (14) Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital.

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Prognosis of ovarian cancer is associated with effector memory CD8(+) T cell accumulation in ascites, CXCL9 levels and activation-triggered signal transduction in T cells

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The accumulation of intratumoral CD8(+) T cells is associated with the survival of high grade serous ovarian carcinoma patients, but it is unclear which CD8(+) T cell subsets contribute to this effect and how they are affected by the peritoneal tumor microenvironment. Here, we provide evidence for a functional link between long relapse-free survival, accumulation of CD8(+) effector memory T (TEM) cells in peritoneal effusion (ascites), and the level of the CD8(+) TEM attracting chemokine CXCL9, produced by macrophages as a major source. We also propose a novel mechanism by which the tumor microenvironment could contribute to T cell dysfunction and shorter survival, i.e., diminished expression levels of essential signaling proteins, including STAT5B, PLCgamma1 and NFATc2. CD8(+) TEM cells in ascites, CXCL9 levels and the expression of crucial signal transduction proteins may therefore be important biomarkers to gauge the efficiency of immune therapies and potentially represent therapeutic targets.

Author Info: (1) Institute of Molecular Biology and Tumor Research, Center for Tumor Biology and Immunology, Philipps University Marburg, Marburg, Germany. (2) Clinic for Gynecology, Gynecological Oncology

Author Info: (1) Institute of Molecular Biology and Tumor Research, Center for Tumor Biology and Immunology, Philipps University Marburg, Marburg, Germany. (2) Clinic for Gynecology, Gynecological Oncology and Gynecological Endocrinology, Center for Tumor Biology and Immunology (ZTI), Philipps University Marburg, Marburg, Germany. (3) FACS Core Facility, Biomedical Research Center, Philipps University Marburg, Marburg, Germany. Institute of Medical Microbiology and Hygiene, Biomedical Research Center, Philipps University Marburg, Marburg, Germany. (4) Institute of Molecular Biology and Tumor Research, Center for Tumor Biology and Immunology, Philipps University Marburg, Marburg, Germany. (5) Department of Gynecology and Obstetrics, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. (6) Department of Gynecology and Obstetrics, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. (7) Clinic for Gynecology, Gynecological Oncology and Gynecological Endocrinology, University Hospital of Giessen and Marburg (UKGM), Marburg, Germany. (8) Clinic for Gynecology, Gynecological Oncology and Gynecological Endocrinology, University Hospital of Giessen and Marburg (UKGM), Marburg, Germany. (9) Institute of Pharmacology, Biochemical-Pharmacological Center (BPC), Philipps University Marburg, Marburg, Germany. Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany. (10) Institute of Molecular Biology and Tumor Research, Center for Tumor Biology and Immunology, Philipps University Marburg, Marburg, Germany. (11) Institute of Medical Microbiology and Hygiene, Biomedical Research Center, Philipps University Marburg, Marburg, Germany.

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Animal Models for Studying Tumor Microenvironment (TME) and Resistance to Lymphocytic Infiltration

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In cancer immunotherapy, cytotoxic T or NK cells need to engage cancer cells to initiate the killing. However, in clinical studies and in mouse models, some solid tumors are found with no lymphocytes. It is likely that these tumors will be resistant to all sorts of immunotherapies. Thus, restoring lymphocytic infiltration will be vital to the success of immunotherapies on solid tumors. In order to understand the complex interaction between cancer cells and stromal cells, we propose to establish animal models for studying the tumor microenvironment and to develop and test therapies to restore lymphocytic infiltration of tumors Without lymphocytes infiltrating tumors, all immunotherapies on solid tumors become ineffective.

Author Info: (1) a Anesthesiology, Kansai Medical University , 2-5-1, shinmachi, Hirakata , Osaka , Japan. (2) b National Center for Microscopy and Imaging Research, Biomedical Science

Author Info: (1) a Anesthesiology, Kansai Medical University , 2-5-1, shinmachi, Hirakata , Osaka , Japan. (2) b National Center for Microscopy and Imaging Research, Biomedical Science Building Room 1000, School of Medicine, University of California San Diego , La Jolla , California , United States.

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High levels of CCL2 or CCL4 in the tumor microenvironment predict unfavorable survival in lung adenocarcinoma

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BACKGROUND: Tumor-associated immune factors are heterogeneous and play an important role in determining outcome in cancer patients. In this study, the expression levels of immune factors in tumor tissue-conditioned media from lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) were analyzed. METHODS: LUAD and LUSC tissue specimens were collected immediately after surgery for antibody array analysis and real-time quantitative PCR. RESULTS: Higher levels of chemokines MCP1/CCL2 (21.11-fold increase) and MIP-1beta/CCL4 (19.33-fold increase) were identified in LUAD than in LUSC. Western blot and quantitative real-time PCR analyses showed higher co-expression of CCL2 and CCL4 in LUAD tissues compared to LUSC (P < 0.0001). Immunofluorescent co-staining showed a high percentage of CCL2(+) /CD68(+) and CCL4(+) /CD68(+) tumor-associated macrophages in LUAD compared to LUSC tissues, which might be responsible for the higher expression of CCL2 and CCL4 in LUAD samples. Kaplan-Meier curves showed that CCL2 overexpression in patients with LUSC was associated with beneficial overall survival (OS; P = 0.048) and progression-free survival (PFS; P = 0.012); however, LUAD patients with higher CCL2 expression had unfavorable OS (P = 6.7e-08) and PFS (P = 0.00098). Similarly, CCL4 overexpression predicted favorable PFS (P = 0.021) in patients with LUSC, but patients with high CCL4 levels in LUAD had shorter OS (P = 0.013). CONCLUSION: Our study revealed that CCL2 and CCL4 expression levels could serve as potential prognostic biomarkers and therapeutic targets for NSCLC patients.

Author Info: (1) State Key Laboratory of Oncology, South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. (2) Department of

Author Info: (1) State Key Laboratory of Oncology, South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. (2) Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. (3) State Key Laboratory of Oncology, South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. (4) State Key Laboratory of Oncology, South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. (5) State Key Laboratory of Oncology, South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. (6) State Key Laboratory of Oncology, South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. (7) State Key Laboratory of Oncology, South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China.

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THE LINK BETWEEN BONE MICROENVIRONMENT AND IMMUNE CELLS IN MULTIPLE MYELOMA: EMERGING ROLE OF CD38

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The relationship between bone and immune cells is well established both in physiological and pathological conditions. Multiple myeloma (MM) is a plasma cell malignancy characterized by an increase of number and activity of osteoclasts (OCLs) and a decrease of osteoblasts (OBs). These events are responsible for bone lesions of MM patients. OCLs support MM cells survival in vitro and in vivo. Recently, the possible role of OCLs as immunosuppressive cells in the MM BM microenvironment has been underlined. OCLs protect MM cells against T cell-mediated cytotoxicity through the expression of several molecules including programmed death-ligand (PD-L) 1, galectin (Gal) 9, CD200, and indoleamine-2,3-dioxygenase (IDO). Among the molecules that could be involved in the link between immune-microenvironment and osteoclastogenesis the role of CD38 has been hypothesized. CD38 is a well-known adhesion molecule and an ectoenzyme highly expressed by MM cells. Moreover, CD38 is expressed by OCLs and at the surface level on OCL precursors. Targeting CD38 with monoclonal antibodies showed inhibition of both osteoclastogenesis and OCL-mediated suppression of T cell function. This review elucidates this evidence indicating that osteoclastogenesis affect MM immune-microenvironment being a potential target to improve anti-MM immunity and to ameliorate bone disease.

Author Info: (1) Department Medicine and Surgery, University of Parma, 43126 Parma, Italy. (2) Department Medicine and Surgery, University of Parma, 43126 Parma, Italy. (3) Department Medicine

Author Info: (1) Department Medicine and Surgery, University of Parma, 43126 Parma, Italy. (2) Department Medicine and Surgery, University of Parma, 43126 Parma, Italy. (3) Department Medicine and Surgery, University of Parma, 43126 Parma, Italy. (4) Department Medicine and Surgery, University of Parma, 43126 Parma, Italy; Biopathology and Medical Biotechnologies, Biology and Genetic Section, University of Palermo, 90133 Palermo, Italy. (5) Department Medicine and Surgery, University of Parma, 43126 Parma, Italy; Hematology and BMT Center, "Azienda Ospedaliero-Universitaria di Parma", 43126 Parma, Italy. (6) Department Medicine and Surgery, University of Parma, 43126 Parma, Italy; Hematology and BMT Center, "Azienda Ospedaliero-Universitaria di Parma", 43126 Parma, Italy. Electronic address: nicola.giuliani@unipr.it.

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Immunomodulatory effects of CD38-targeting antibodies

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The fist in class CD38-targeting antibody, daratumumab, is currently approved as single agent and in combination with standards of care for the treatment of relapsed and refractory multiple myeloma. Based on the high activity and favorable toxicity profile of daratumumab, other CD38 antibodies, such as isatuximab, MOR202, and TAK-079, are being evaluated in MM and other malignancies. The CD38-targeting antibodies have classic Fc-dependent immune effector mechanisms, including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC). These mechanisms of action are dependent on CD38 expression on the tumor cells. There is increasing evidence that CD38 antibodies also improve host-anti-tumor immune response by eliminating CD38-positive immune suppressor cells, including regulatory T cells, regulatory B cells, and myeloid-derived suppressor cells. Indeed, daratumumab treatment results in a marked increase in T cell numbers and activity. CD38-targeting antibodies probably also reduce adenosine production in the bone marrow microenvironment, which may contribute to improved T cell activity. Preclinical and clinical studies have demonstrated that CD38-targeting antibodies have synergistic activity with several other anti-cancer drugs, including various agents with immune stimulating activity, such as lenalidomide and pomalidomide, as well as PD1/PD-L1 inhibitors.

Author Info: (1) Department of Hematology, VU University Medical Center, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands. Electronic address: n.vandedonk@vumc.nl.

Author Info: (1) Department of Hematology, VU University Medical Center, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands. Electronic address: n.vandedonk@vumc.nl.

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Immune Escape Mechanisms and Future Prospects for Immunotherapy in Neuroblastoma

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Neuroblastoma (NB) is the most common extracranial solid tumor in childhood with 5-year survival rate of 40% in high-risk patients despite intensive therapies. Recently, adoptive cell therapy, particularly chimeric antigen receptor (CAR) T cell therapy, represents a revolutionary treatment for hematological malignancies. However, there are challenges for this therapeutic strategy with solid tumors, as a result of the immunosuppressive nature of the tumor microenvironment (TME). Cancer cells have evolved multiple mechanisms to escape immune recognition or to modulate immune cell function. Several subtypes of immune cells that infiltrate tumors can foster tumor development, harbor immunosuppressive activity, and decrease an efficacy of adoptive cell therapies. Therefore, an understanding of the dual role of the immune system under the influences of the TME has been crucial for the development of effective therapeutic strategies against solid cancers. This review aims to depict key immune players and cellular pathways involved in the dynamic interplay between the TME and the immune system and also to address challenges and prospective development of adoptive T cell transfer for neuroblastoma.

Author Info: (1) Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Ratchathewi, Bangkok 10400, Thailand. (2) Pediatric Translational Research Unit

Author Info: (1) Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Ratchathewi, Bangkok 10400, Thailand. (2) Pediatric Translational Research Unit, Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Ratchathewi, Bangkok 10400, Thailand. Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. (3) Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Ratchathewi, Bangkok 10400, Thailand. (4) Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Ratchathewi, Bangkok 10400, Thailand.

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Tumor inherent interferons: Impact on immune reactivity and immunotherapy

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Immunotherapy has revolutionized cancer treatment, with sustained responses to immune checkpoint inhibitors reported in a number of malignancies. Such therapeutics are now being trialed in aggressive or advanced cancers that are heavily reliant on untargeted therapies, such as triple negative breast cancer. However, responses have been underwhelming to date and are very difficult to predict, leading to an inability to accurately weigh up the benefit-to-risk ratio for their implementation. The tumor immune microenvironment has been closely linked to immunotherapeutic response, with superior responses observed in patients with T cell-inflamed or 'hot' tumors. One class of cytokines, the type I interferons, are a major dictator of tumor immune infiltration and activation. Tumor cell inherent interferon signaling dramatically influences the immune microenvironment and the expression of immune checkpoint proteins, hence regulators and targets of this pathway are candidate biomarkers of immunotherapeutic response. In support of a link between IFN signaling and immunotherapeutic response, the combination of type I interferon inducers with checkpoint immunotherapy has recently been demonstrated critical for a sustained anti-tumor response in aggressive breast cancer models. Here we review evidence that links type I interferons with a hot tumor immune microenvironment, response to checkpoint inhibitors and reduced risk of metastasis that supports their use as biomarkers and therapeutics in oncology.

Author Info: (1) Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia. (2) Department of Biochemistry and Genetics, La

Author Info: (1) Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia. (2) Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia. Electronic address: Belinda.Parker@latrobe.edu.au.

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Contribution to Tumor Angiogenesis From Innate Immune Cells Within the Tumor Microenvironment: Implications for Immunotherapy

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The critical role of angiogenesis in promoting tumor growth and metastasis is strongly established. However, tumors show considerable variation in angiogenic characteristics and in their sensitivity to antiangiogenic therapy. Tumor angiogenesis involves not only cancer cells but also various tumor-associated leukocytes (TALs) and stromal cells. TALs produce chemokines, cytokines, proteases, structural proteins, and microvescicles. Vascular endothelial growth factor (VEGF) and inflammatory chemokines are not only major proangiogenic factors but are also immune modulators, which increase angiogenesis and lead to immune suppression. In our review, we discuss the regulation of angiogenesis by innate immune cells in the tumor microenvironment, specific features, and roles of major players: macrophages, neutrophils, myeloid-derived suppressor and dendritic cells, mast cells, gammadeltaT cells, innate lymphoid cells, and natural killer cells. Anti-VEGF or anti-inflammatory drugs could balance an immunosuppressive microenvironment to an immune permissive one. Anti-VEGF as well as anti-inflammatory drugs could therefore represent partners for combinations with immune checkpoint inhibitors, enhancing the effects of immune therapy.

Author Info: (1) Scientific and Technology Pole, IRCCS MultiMedica, Milano, Italy. Department of Medicine and Surgery, University Milano-Bicocca, Monza, Italy. (2) Scientific and Technology Pole, IRCCS MultiMedica

Author Info: (1) Scientific and Technology Pole, IRCCS MultiMedica, Milano, Italy. Department of Medicine and Surgery, University Milano-Bicocca, Monza, Italy. (2) Scientific and Technology Pole, IRCCS MultiMedica, Milano, Italy. (3) Scientific and Technology Pole, IRCCS MultiMedica, Milano, Italy. Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy. (4) Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy.

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Dying to Be Noticed: Epigenetic Regulation of Immunogenic Cell Death for Cancer Immunotherapy

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Immunogenic cell death (ICD) activates both innate and adaptive arms of the immune system during apoptotic cancer cell death. With respect to cancer immunotherapy, the process of ICD elicits enhanced adjuvanticity and antigenicity from dying cancer cells and consequently, promotes the development of clinically desired antitumor immunity. Cancer ICD requires the presentation of various "hallmarks" of immunomodulation, which include the cell-surface translocation of calreticulin, production of type I interferons, and release of high-mobility group box-1 and ATP, which through their compatible actions induce an immune response against cancer cells. Interestingly, recent reports investigating the use of epigenetic modifying drugs as anticancer therapeutics have identified several connections to ICD hallmarks. Epigenetic modifiers have a direct effect on cell viability and appear to fundamentally change the immunogenic properties of cancer cells, by actively subverting tumor microenvironment-associated immunoevasion and aiding in the development of an antitumor immune response. In this review, we critically discuss the current evidence that identifies direct links between epigenetic modifications and ICD hallmarks, and put forward an otherwise poorly understood role for epigenetic drugs as ICD inducers. We further discuss potential therapeutic innovations that aim to induce ICD during epigenetic drug therapy, generating highly efficacious cancer immunotherapies.

Author Info: (1) Department of Pathology, Dalhousie University, Halifax, NS, Canada. (2) Department of Pathology, Dalhousie University, Halifax, NS, Canada. (3) Department of Pathology, Dalhousie University, Halifax

Author Info: (1) Department of Pathology, Dalhousie University, Halifax, NS, Canada. (2) Department of Pathology, Dalhousie University, Halifax, NS, Canada. (3) Department of Pathology, Dalhousie University, Halifax, NS, Canada. Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada. (4) Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, Greensboro, NC, United States. Department of Chemistry, Acadia University, Wolfville, NS, Canada. (5) Gustave Roussy Comprehensive Cancer Institute, Villejuif, France. INSERM, U1138, Paris, France. Equipe 11 labellisee par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. Universite Paris Descartes, Universite Sorbonne Paris Cite, Paris, France. Universite Pierre et Marie Curie, Paris, France. (6) Department of Pathology, Dalhousie University, Halifax, NS, Canada. Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada. Department of Biology, Dalhousie University, Halifax, NS, Canada. Centre for Innovative and Collaborative Health Services Research, IWK Health Centre, Halifax, NS, Canada.

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