Based on prior clinical observations, Ware et al. investigated if the combination of IL-6 inhibition with anti-CTLA-4 would improve antitumor responses in pancreatic ductal adenocarcinoma (PDAC). In both subcutaneous and orthotopic mouse PDAC models, dual IL-6 and CTLA-4 blockade significantly slowed tumor growth in a CD4+ and CD8+ T cell-dependent manner. In vitro mechanistic studies found that the anti-IL-6/CTLA-4 combination increased CD4+ T cell IFNγ production, which stimulated high levels of tumor cell-derived CXCR3 ligands, CXCL10 and 11. An in vivo study showed CXCR3 inhibition prevented tumor regression by the combination.
Contributed by Katherine Turner
ABSTRACT: This study aimed to enhance anti-tumor immune responses to pancreatic cancer via antibody-based blockade of IL-6 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Mice bearing subcutaneous or orthotopic pancreatic tumors were treated with blocking antibodies to IL 6 and/or CTLA-4. In both tumor models, dual IL-6 and CTLA-4 blockade significantly inhibited tumor growth. Additional investigations revealed that dual therapy induced an overwhelming infiltration of T cells into the tumor as well as changes in CD4+ T cell subsets. Dual blockade therapy elicited CD4+ T cells to secrete increased IFN-_ in vitro. Likewise, in vitro stimulation of pancreatic tumor cells with IFN-_ profoundly increased tumor cell production of CXCR3 specific chemokines, even in the presence of IL-6. In vivo blockade of CXCR3 prevented orthotopic tumor regression in the presence of the combination treatment, demonstrating a dependence on the CXCR3 axis for anti-tumor efficacy. Both CD4+ and CD8+ T cells were required for the anti-tumor activity of this combination therapy, as their in vivo depletion via antibodies impaired outcomes. These data represent the first report of IL-6 and CTLA 4 blockade as a means to regress pancreatic tumors with defined operative mechanisms of efficacy. Given these results, this therapeutic combination has potential for immediate clinical translation.
Author Info: (1) Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, United States of America. (2) Department of Hematology and Medical Oncolog
Author Info: (1) Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, United States of America. (2) Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, United States of America. (3) Department of Internal Medicine, The Ohio State University, Columbus, United States of America. (4) Department of Surgery, Winship Cancer Institute of Emory University, Atlanta, United States of America. (5) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, United States of America. (6) Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, United States of America. (7) Department of Pathology, Winship Cancer Institute of Emory University, Atlanta, United States of America. (8) Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, United States of America. (9) Department of Internal Medicine, The Ohio State University, Columbus, United States of America. (10) Department of Biostatistics and Bioinformatics, Winship Cancer Institute of Emory University, Atlanta, United States of America. (11) Department of Biostatistics and Bioinformatics, Winship Cancer Institute of Emory University, Atlanta, United States of America. (12) Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, United States of America. (13) Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, United States of America. (14) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, United States of America. (15) Medicine, The Ohio State University, Columbus, United States of America. (16) Department of Pathology, Winship Cancer Institute of Emory University, Atlanta, United States of America. (17) Center for Biostatistics, The Ohio State University, Columbus, United States of America. (18) Department of Internal Medicine, The Ohio State University, Columbus, United States of America. (19) Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, United States of America. (20) Department of Surgery, Winship Cancer Institute of Emory University, Atlanta, United States of America. (21) Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, United States of America.
