Journal Articles

Tumor micro-environment

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

Anti-CTLA-4 immunotherapy does not deplete FOXP3+ regulatory T cells (Tregs) in human cancers

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PURPOSE: CTLA-4 was the first inhibitory immune checkpoint to be identified. Two monoclonal antibodies, ipilimumab (IgG1) and tremelimumab (IgG2), which block the function of CTLA-4, have demonstrated durable clinical activity in a subset of patients with advanced solid malignancies by augmenting effector T cell-mediated immune responses. Studies in mice suggest that anti-CTLA-4 monoclonal antibodies may also selectively deplete intratumoral FOXP3+ regulatory T cells via an Fc-dependent mechanism. However, it is unclear whether the depletion of FOXP3+ cells occurs in cancer patients treated with anti-CTLA-4 therapies. EXPERIMENTAL DESIGN: Quantitative immunohistochemistry was used to evaluate the densities of intratumoral CD4+, CD8+ and FOXP3+ cells in stage-matched melanoma (N=19), prostate cancer (N=17) and bladder cancer (N=9) samples treated with ipilimumab and in paired melanoma tumors (N=18) treated with tremelimumab. These findings were corroborated with multiparametric mass cytometry analysis of tumor infiltrating cells from paired fresh melanoma tumors (N=5) treated with ipilimumab. RESULTS: Both ipilimumab and tremelimumab increase infiltration of intratumoral CD4+ and CD8+ cells without significantly changing or depleting FOXP3+ cells within the tumor microenvironment. CONCLUSIONS: Anti-CTLA-4 immunotherapy does not deplete FOXP3+ cells in human tumors, which suggests that their efficacy could be enhanced by modifying the Fc portions of the monoclonal antibodies to enhance Fc-mediated depletion of intratumoral regulatory T cells.

Author Info: (1) Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center. (2) Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center

Author Info: (1) Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center. (2) Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center. (3) Department of Immunology, MD Anderson Cancer Center. (4) Immunology, MD Anderson Cancer Center. (5) Immunology, University of Texas MD Anderson Cancer Center. (6) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center. (7) Department of Immunology, MD Anderson Cancer Center. (8) Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles. (9) Department of Immunology, MD Anderson Cancer Center PadSharma@mdanderson.org.

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Surgical trauma contributes to progression of colon cancer by downregulating CXCL4 and recruiting MDSCs

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Surgical stress has been shown to facilitate the tumor growth and metastasis of colon cancer. To unravel the mechanisms underlying surgery induced-colon cancer progression, a syngeneic transplantation tumor model was established with murine colon cancer CT26 cells and the effect of laparotomy on tumor progression was investigated. Especially the expression of several CXC chemokines was assayed, and its roles in regulating myeloid-derived suppressor cells (MDSCs) recruitment were analyzed. We found that laparotomy promoted in vivo tumor growth and angiogenesis. CXCL4 expression was significantly downregulated by laparotomy in the tumor tissue and the peritoneal cavity. Functionally, CXCL4 overexpression significantly reduces tumor volume compared to control. Through analysis of CD11b(+)/Gr1(+) MDSCs cell, we found an upregulated proportion of MDSCs in the tumor tissues and peritoneal cavity following laparotomy, and this enhancement was blocked after CXCL4 overexpression. Further, a negative correlation was found between CXCL4 expression and MDSC amounts in clinical samples. Higher CXCL4 expression and lower MDSCs proportion is positively related to overall survival. CONCLUSION: Surgical trauma contributes to colon cancer progression by downregulating CXCL4 and hence promoting MDSC recruitment, which leads to an immunosuppressive environment.

Author Info: (1) (2) (3) (4) (5) (6) (7)

Author Info: (1) (2) (3) (4) (5) (6) (7)

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The Tumor Microenvironment of Epithelial Ovarian Cancer and Its Influence on Response to Immunotherapy

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Immunotherapy as a treatment for cancer is a growing field of endeavor but reports of success have been limited for epithelial ovarian cancer. Overcoming the challenges to developing more effective therapeutic approaches lies in a better understanding of the factors in cancer cells and the surrounding tumor microenvironment that limit response to immunotherapies. This article provides an overview of some ovarian cancer cell features such as tumor-associated antigens, ovarian cancer-derived exosomes, tumor mutational burden and overexpression of immunoinhibitory molecules. Moreover, we describe relevant cell types found in epithelial ovarian tumors including immune cells (T and B lymphocytes, Tregs, NK cells, TAMs, MDSCs) and other components found in the tumor microenvironment including fibroblasts and the adipocytes in the omentum. We focus on how those components may influence responses to standard treatments or immunotherapies.

Author Info: (1) Cancer Therapeutics Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada. garodriguez@toh.ca. Department of Cellular and Molecular Medicine, University of

Author Info: (1) Cancer Therapeutics Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada. garodriguez@toh.ca. Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada. garodriguez@toh.ca. (2) Cancer Therapeutics Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada. kgalpin@ohri.ca. Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada. kgalpin@ohri.ca. (3) Cancer Therapeutics Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada. cmccloskey@ohri.ca. Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada. cmccloskey@ohri.ca. (4) Cancer Therapeutics Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada. bvanderhyden@ohri.ca. Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada. bvanderhyden@ohri.ca.

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Interaction of cancer cell-derived Foxp3 and tumor microenvironment in human tongue squamous cell carcinoma

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The forkhead transcription factor, Foxp3, has been proved essential for differentiation and activation of regulatory T cells (Tregs). Recently, Foxp3 expression in tumor cells (cancer cell-derived Foxp3) has gained increasing interest, but the function has yet to be confirmed. In the current investigation, we identified the interaction of cancer cell-derived Foxp3 and tumor microenvironment in human tongue squamous cell carcinoma(TSCC) by various in vitro methods. We detected cancer cell-derived Foxp3 was closely associated with the infiltration of Foxp3+ lymphocytes in TSCC lesions using immunohistochemical staining. The cytokines secretion (IFN-gamma, TGFbeta, IL-2, IL-6, IL-1beta, IL-10, IL-8, IL-17, IL-23) of PBMC and differentiation of CD4+T cells were modulated by the expression of Foxp3 in TSCC, shown by ELISA and flow cytometry. As feedback, increasing TGFbeta and decreasing IL-17 further up-regulated cancer cell-derived Foxp3. Furthermore, CHIP on chip assay showed that both TGFbeta and IL-17 decreased the number of Foxp3-binding genes in TSCC. GO and pathway analysis suggested that, treated with TGFbeta or Th17, Foxp3-binding genes were inclined to the negative regulation of TGFbeta signal pathway. Taken together, this study showed cancer cell-derived Foxp3 contributed to Tregs expansion in TSCC microenvironment with positive and negative feedbacks.

Author Info: (1) Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University56th Lingyuanxi Road, Guangzhou, Guangdong, 510055, China; Guangdong Province

Author Info: (1) Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University56th Lingyuanxi Road, Guangzhou, Guangdong, 510055, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou 510080, Guangdong, China. (2) Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University56th Lingyuanxi Road, Guangzhou, Guangdong, 510055, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou 510080, Guangdong, China. (3) Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University56th Lingyuanxi Road, Guangzhou, Guangdong, 510055, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou 510080, Guangdong, China. (4) Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University56th Lingyuanxi Road, Guangzhou, Guangdong, 510055, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou 510080, Guangdong, China. (5) Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University56th Lingyuanxi Road, Guangzhou, Guangdong, 510055, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou 510080, Guangdong, China. Electronic address: drliaoguiqing@hotmail.com. (6) Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University56th Lingyuanxi Road, Guangzhou, Guangdong, 510055, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou 510080, Guangdong, China. Electronic address: yujie0350@126.com.

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Recombinant Listeria promotes tumor rejection by CD8+ T cell-dependent remodeling of the tumor microenvironment

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Deng et al. demonstrate that live-attenuated Listeria monocytogenes lacking two virulence genes and expressing an endogenous retroviral antigen induced KLRG1+PD1loCD62- effector CD8+ T cells, which localized to the spleen, were functional and not exhausted, produced IFNγ, infiltrated the tumor, and converted the tumor microenvironment from immunosuppressive to inflamed by repolarizing the tumor-associated macrophages from M2 to M1, decreasing Tregs, and increasing proinflammatory cytokines. The treatment led to durable tumor rejection and formation of immunological memory in mice.

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Deng et al. demonstrate that live-attenuated Listeria monocytogenes lacking two virulence genes and expressing an endogenous retroviral antigen induced KLRG1+PD1loCD62- effector CD8+ T cells, which localized to the spleen, were functional and not exhausted, produced IFNγ, infiltrated the tumor, and converted the tumor microenvironment from immunosuppressive to inflamed by repolarizing the tumor-associated macrophages from M2 to M1, decreasing Tregs, and increasing proinflammatory cytokines. The treatment led to durable tumor rejection and formation of immunological memory in mice.

Agents that remodel the tumor microenvironment (TME), prime functional tumor-specific T cells, and block inhibitory signaling pathways are essential components of effective immunotherapy. We are evaluating live-attenuated, double-deleted Listeria monocytogenes expressing tumor antigens (LADD-Ag) in the clinic. Here we show in numerous mouse models that while treatment with nonrecombinant LADD induced some changes in the TME, no antitumor efficacy was observed, even when combined with immune checkpoint blockade. In contrast, LADD-Ag promoted tumor rejection by priming tumor-specific KLRG1(+)PD1(lo)CD62L(-) CD8(+) T cells. These IFNgamma-producing effector CD8(+) T cells infiltrated the tumor and converted the tumor from an immunosuppressive to an inflamed microenvironment that was characterized by a decrease in regulatory T cells (Treg) levels, a proinflammatory cytokine milieu, and the shift of M2 macrophages to an inducible nitric oxide synthase (iNOS)(+)CD206(-) M1 phenotype. Remarkably, these LADD-Ag-induced tumor-specific T cells persisted for more than 2 months after primary tumor challenge and rapidly controlled secondary tumor challenge. Our results indicate that the striking antitumor efficacy observed in mice with LADD-based immunotherapy stems from TME remodeling which is a direct consequence of eliciting potent, systemic tumor-specific CD8(+) T cells.

Author Info: (1) Aduro Biotech, Inc., Berkeley, CA 94710; wdeng@aduro.com tdubensky@tempesttx.com. (2) Aduro Biotech, Inc., Berkeley, CA 94710. (3) Aduro Biotech, Inc., Berkeley, CA 94710. (4) Aduro

Author Info: (1) Aduro Biotech, Inc., Berkeley, CA 94710; wdeng@aduro.com tdubensky@tempesttx.com. (2) Aduro Biotech, Inc., Berkeley, CA 94710. (3) Aduro Biotech, Inc., Berkeley, CA 94710. (4) Aduro Biotech, Inc., Berkeley, CA 94710. (5) Aduro Biotech, Inc., Berkeley, CA 94710. (6) Aduro Biotech, Inc., Berkeley, CA 94710. (7) Aduro Biotech, Inc., Berkeley, CA 94710. (8) Aduro Biotech, Inc., Berkeley, CA 94710. (9) Aduro Biotech, Inc., Berkeley, CA 94710. (10) Aduro Biotech, Inc., Berkeley, CA 94710. (11) Aduro Biotech, Inc., Berkeley, CA 94710. (12) Department of Molecular and Cell Biology, University of California, Berkeley, CA The School of Public Health, University of California, Berkeley, CA 94720. (13) Aduro Biotech, Inc., Berkeley, CA 94710; wdeng@aduro.com tdubensky@tempesttx.com.

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HDACi Delivery Reprograms Tumor-Infiltrating Myeloid Cells to Eliminate Antigen-Loss Variants

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Immune recognition of tumor-expressed antigens by cytotoxic CD8(+) T cells is the foundation of adoptive T cell therapy (ACT) and has been shown to elicit significant tumor regression. However, therapy-induced selective pressure can sculpt the antigenicity of tumors, resulting in outgrowth of variants that lose the target antigen. We demonstrate that tumor relapse from ACT and subsequent oncolytic viral vaccination can be prevented using class I HDACi, MS-275. Drug delivery subverted the phenotype of tumor-infiltrating CD11b(+) Ly6C(hi) Ly6G(-) myeloid cells, favoring NOS2/ROS secretion and pro-inflammatory genes characteristic of M1 polarization. Simultaneously, MS-275 abrogated the immunosuppressive function of tumor-infiltrating myeloid cells and reprogrammed them to eliminate antigen-negative tumor cells in a caspase-dependent manner. Elevated IFN-gamma within the tumor microenvironment suggests that MS-275 modulates the local cytokine landscape to favor antitumor myeloid polarization through the IFN-gammaR/STAT1 signaling axis. Exploiting tumor-infiltrating myeloid cell plasticity thus complements T cell therapy in targeting tumor heterogeneity and immune escape.

Author Info: (1) Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8N 3Z5, Canada. (2) Department of Pathology and Molecular Medicine

Author Info: (1) Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8N 3Z5, Canada. (2) Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8N 3Z5, Canada. (3) Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8N 3Z5, Canada. (4) Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8N 3Z5, Canada. (5) Advanced Cell Diagnostics, Toronto, ON, Canada. (6) Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8N 3Z5, Canada. (7) Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8N 3Z5, Canada. (8) Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8N 3Z5, Canada. (9) Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8N 3Z5, Canada. Electronic address: wanyong@mcmaster.ca.

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Chronic Sleep Restriction Impairs the Antitumor Immune Response in Mice

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OBJECTIVES: Sleep regulates immune function reciprocally and can affect the parameters that are directly involved in the immune response. Sleep deprivation is considered to be a stress-causing factor and is associated with impaired immune activity. It causes increased glucocorticoid concentrations by activating the hypothalamic-pituitary-adrenal axis; this can lead to a series of disorders that are associated with the prolonged or increased secretion of these hormones. The aim of this study was to evaluate the effects of sleep restriction (SR) on the development of pulmonary experimental metastasis and the modulation of the tumor immune response. METHODS: The SR protocol was accomplished by depriving C57BL/6 male mice of sleep for 18 h/day for 2, 7, 14, and 21 days. The modified multiple-platforms method was used for SR. RESULTS: The results showed that cytotoxic cells (i.e., natural killer [NK] and CD8+ T cells) were reduced in number and regulatory T cells were predominant in the tumor microenvironment. Sleep-restricted mice also exhibited a reduced number of dendritic cells in their lymph nodes, which may have contributed to the ineffective activation of tumor-specific T cells. Peripheral CD4+ and CD8+ T cells were also reduced in the sleep-restricted mice, thus indicating an immunosuppressive status. CONCLUSIONS: Sleep dep-rivation induces failure in the activity of cells that are im-portant to the tumor immune response, both in the tumor microenvironment and on the periphery. This leads to the early onset and increased growth rate of lung metastasis.

Author Info: (1) Centro Universitario Sao Camilo, Sao Paulo, Brazil. (2) Centro Universitario Sao Camilo, Sao Paulo, Brazil. (3) Centro Universitario Sao Camilo, Sao Paulo, Brazil. (4)

Author Info: (1) Centro Universitario Sao Camilo, Sao Paulo, Brazil. (2) Centro Universitario Sao Camilo, Sao Paulo, Brazil. (3) Centro Universitario Sao Camilo, Sao Paulo, Brazil. (4) Centro Universitario Sao Camilo, Sao Paulo, Brazil. (5) Centro Universitario Sao Camilo, Sao Paulo, Brazil. (6) Centro Universitario Sao Camilo, Sao Paulo, Brazil. (7) Instituto de Ciencias da Saude, Pos Graduacao em Patologia Ambiental e Experimental, Universidade Paulista, Sao Paulo, Brazil. (8) Instituto de Ciencias da Saude, Pos Graduacao em Patologia Ambiental e Experimental, Universidade Paulista, Sao Paulo, Brazil. (9) Centro Universitario Sao Camilo, Sao Paulo, Brazil.

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The expression of PD-1 ligands and IDO1 by macrophage/microglia in primary central nervous system lymphoma

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Recent progress in anti-tumor immunotherapy has focused on the significance of the tumor microenvironment in tumor progression and resistance to chemo/radio-therapy. Myeloid cells such as macrophages are predominant stromal components in hematological malignancies. In the present study, we investigated the regulation of programmed death-1 (PD-1) ligand expression in primary central nervous system lymphoma (PCNSL) using PCNSL cell lines and human monocyte-derived macrophages. TK PCNSL cell line-derived soluble factors induced overexpression of PD-1 ligands, indoleamine 2,3-dioxygenase (IDO1), and several other cytokines in macrophages. The expression of PD-1 ligands was dependent on the activation of signal transducer and activator of transcription 3. PD-L1 and IDO1 were overexpressed by macrophage/microglia in PCNSL tissues, and gene expression profiling indicated that IDO1 expression was positively correlated with the expression of macrophage and lymphocyte markers. Macrophage-derived factors did not influence the proliferation or chemo-sensitivity of cell lines. These data suggest that the expression of immunosuppressive molecules, including PD-1 ligands and IDO1, by macrophage/microglia may be involved in immune evasion of lymphoma cells.

Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10)

Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10)

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Phenotype molding of stromal cells in the lung tumor microenvironment

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Cancer cells are embedded in the tumor microenvironment (TME), a complex ecosystem of stromal cells. Here, we present a 52,698-cell catalog of the TME transcriptome in human lung tumors at single-cell resolution, validated in independent samples where 40,250 additional cells were sequenced. By comparing with matching non-malignant lung samples, we reveal a highly complex TME that profoundly molds stromal cells. We identify 52 stromal cell subtypes, including novel subpopulations in cell types hitherto considered to be homogeneous, as well as transcription factors underlying their heterogeneity. For instance, we discover fibroblasts expressing different collagen sets, endothelial cells downregulating immune cell homing and genes coregulated with established immune checkpoint transcripts and correlating with T-cell activity. By assessing marker genes for these cell subtypes in bulk RNA-sequencing data from 1,572 patients, we illustrate how these correlate with survival, while immunohistochemistry for selected markers validates them as separate cellular entities in an independent series of lung tumors. Hence, in providing a comprehensive catalog of stromal cells types and by characterizing their phenotype and co-optive behavior, this resource provides deeper insights into lung cancer biology that will be helpful in advancing lung cancer diagnosis and therapy.

Author Info: (1) VIB Center for Cancer Biology, Leuven, Belgium. diether.lambrechts@kuleuven.vib.be. Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium. diether.lambrechts@kuleuven.vib.be. (2) Respiratory Oncology

Author Info: (1) VIB Center for Cancer Biology, Leuven, Belgium. diether.lambrechts@kuleuven.vib.be. Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium. diether.lambrechts@kuleuven.vib.be. (2) Respiratory Oncology Unit (Pneumology) and Leuven Lung Cancer Group, University Hospitals KU Leuven, Leuven, Belgium. Laboratory of Pneumology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium. (3) VIB Center for Cancer Biology, Leuven, Belgium. Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium. (4) Laboratory for Computational Biology, Department of Human Genetics, KU Leuven, Leuven, Belgium. VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium. (5) Histopathology Expertise Center, VIB Leuven Center for Cancer Biology, VIB, Leuven, Belgium. Department of Oncology, KU Leuven, Leuven, Belgium. (6) VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium. Laboratory of Genetics of Autoimmunity, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium. (7) VIB Center for Cancer Biology, Leuven, Belgium. Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium. (8) Department of Thoracic Surgery, University Hospitals KU Leuven, Leuven, Belgium. Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium. (9) VIB Center for Cancer Biology, Leuven, Belgium. Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, Belgium. (10) Translational Cell & Tissue Research, Department of Imaging & Pathology, KU Leuven, Leuven, Belgium. (11) Translational Cell & Tissue Research, Department of Imaging & Pathology, KU Leuven, Leuven, Belgium. (12) Translational Cell & Tissue Research, Department of Imaging & Pathology, KU Leuven, Leuven, Belgium. (13) Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium. (14) VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium. Laboratory of Genetics of Autoimmunity, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium. (15) Respiratory Oncology Unit (Pneumology) and Leuven Lung Cancer Group, University Hospitals KU Leuven, Leuven, Belgium. Laboratory of Pneumology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium. (16) VIB Center for Cancer Biology, Leuven, Belgium. Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, Belgium. State Key Laboratory of Ophthalmology, Zhongsan Ophthalmic Center, SunYat-Sen University, Guangzhou, China. (17) Laboratory for Computational Biology, Department of Human Genetics, KU Leuven, Leuven, Belgium. VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium. (18) VIB Center for Cancer Biology, Leuven, Belgium. bernard.thienpont@kuleuven.be. Laboratory for Functional Epigenetics, Department of Human Genetics, KU Leuven, Leuven, Belgium. bernard.thienpont@kuleuven.be.

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IL-6 mediates cross-talk between activated fibroblasts and tumor cells in the tumor microenvironment

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The tumor microenvironment (TME) plays a major role in the pathogenesis of multiple cancer types, including upper-gastrointestinal (GI) cancers that currently lack effective therapeutic options. Cancer-associated fibroblasts (CAF) are an essential component of the TME, contributing to tumorigenesis by secreting growth factors, modifying the extracellular matrix, supporting angiogenesis, and suppressing anti-tumor immune responses. Through an unbiased approach, we have established that IL-6 mediates crosstalk between tumor cells and CAF not only by supporting tumor cell growth, but also by promoting fibroblast activation. As a result, IL-6 receptor (IL-6Ralpha) and downstream effectors offer opportunities for targeted therapy in upper-GI cancers. IL-6 loss suppressed tumorigenesis in physiologically relevant 3D organotypic and 3D tumoroid models and murine models of esophageal cancer. Tocilizumab, an anti-IL-6Ralpha antibody, suppressed tumor growth in vivo in part via inhibition of STAT3 and MEK/ERK signaling. Analysis of a pan-cancer TCGA dataset revealed an inverse correlation between IL-6 and IL-6Ralpha overexpression and patient survival. Therefore, we expanded evaluation of tocilizumab to head-and-neck squamous cell carcinoma patient-derived xenografts and gastric adenocarcinoma xenografts, demonstrating suppression of tumor growth and altered STAT3 and ERK1/2 gene signatures. We used small molecule inhibitors of STAT3 and MEK1/2 signaling to suppress tumorigenesis in the 3D organotypic model of esophageal cancer. We demonstrate that IL-6 is a major contributor to the dynamic crosstalk between tumor cells and CAF in the TME. Our findings provide a translational rationale for inhibition of IL-6Ralpha and downstream signaling pathways as a novel targeted therapy in oral-upper-GI cancers.

Author Info: (1) Division of Gastroenterology, Departments of Medicine and Genetics, Pancreatic Cancer Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine

Author Info: (1) Division of Gastroenterology, Departments of Medicine and Genetics, Pancreatic Cancer Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine. (2) Division of Gastroenterology; Department of Medicine, University of Pennsylvania. (3) Division of Gastroenterology; Department of Medicine, University of Pennsylvania. (4) Division of Gastroenterology; Department of Medicine, University of Pennsylvania. (5) Division of Gastroenterology; Department of Medicine, University of Pennsylvania. (6) Division of Gastroenterology; Department of Medicine, University of Pennsylvania. (7) Cancer Biology Program, Fox Chase Cancer Center. (8) Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania. (9) Department of Otorhinolaryngology - Head and Neck Surgery, University of Pennsylvania. (10) Therapeutic Oncology, Graduate School of Medicine, Kyoto University. (11) Kyoto University. (12) Dept of Medical Oncology, Dana-Farber Cancer Institute. (13) Dept of Medical Oncology, Dana-Farber Cancer Institute. (14) Dept of Medical Oncology, Dana-Farber Cancer Institute. (15) Biostatistics, Epidemiology, and Informatics, University of Pennsylvania. (16) Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania. (17) Bioengineering, University of Pennsylvania. (18) Department of Bioengineering, University of Pennsylvania. (19) Department of Biochemistry and Molecular Biology, Medical University of South Carolina. (20) Perlmutter Cancer Center, New York University Langone Medical Center. (21) Department of Medical Oncology, Dana-Farber Cancer Institute. (22) Division of Gastroenterology, Departments of Medicine and Genetics, Pancreatic Cancer Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine anil2@pennmedicine.upenn.edu.

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