Dual IL-6 and CTLA-4 blockade regresses pancreatic tumors in a T cell- and CXCR3-dependent manner

• Type of Material: Article
• Authors: Michael Brandon Ware, Emory University; Maggie Phillips, Emory University; Christopher McQuinn, Ohio State University; Mohammad Y. Zaidi, Emory University; Hannah M. Knochelmann, Medical University of South Carolina; Emily Greene, Emory University; Brian Robinson, Emory University; Cameron J. Herting, Emory University; Thomas A. Mace, Ohio State University; Zhengjia Chen, Emory University; Chao Zhang, Emory University; Matthew R. Farren, Emory University; Amanda N. Ruggieri, Emory University; Jacob S. Bowers, Medical University of South Carolina; Reena Shakya, Ohio State University; Alton Farris III, Emory University; Gregory Young, Ohio State University; William E. Carson III, Ohio State University; Bassel El-Rayes, Emory University; Chrystal Paulos, Emory University; Gregory Lesinski, Emory University
• Language: English
• Date: 2023-03-07
• Publisher: AMER SOC CLINICAL INVESTIGATION INC
• Publication Version: Final Published Version
• Copyright Statement: © 2023 Ware et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1172/jci.insight.155006
• Title of Journal or Parent Work: JCI INSIGHT
• Volume: 8
• Issue: 8
• Grant/Funding Information: This research was supported by NIH grants R01CA208253, R01CA228406, and P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. We would like to acknowledge the cores at Winship Cancer Institute and Emory University that made this research possible, including the Pediatric/Winship Flow Cytometry Core, the Winship Cancer Tissue and Pathology Shared Resource, the Winship Biostatistics and Bioinformatics Core, the Winship Cancer Animal Models Shared Resource, the Winship Integrated Cellular Imaging Core, and the Emory Integrated Genomics Core (EIGC), under NIH/NCI award P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
• Keywords: Life Sciences & Biomedicine; RESISTANCE; IMMUNOTHERAPY; Medicine, Research & Experimental; INFILTRATION; Research & Experimental Medicine; FIBROBLASTS; CHEMOKINE; PATHWAY; ANTI-CTLA-4; Science & Technology; EXPRESSION; DIFFERENTIATION; IFN-GAMMA
• Research Categories: Health Sciences, Immunology; Biology, Cell

Abstract

This study aimed to enhance antitumor immune responses to pancreatic cancer via Ab-based blockade of IL-6 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Mice bearing s.c. or orthotopic pancreatic tumors were treated with blocking Abs 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-γ in vitro. Likewise, in vitro stimulation of pancreatic tumor cells with IFN-γ 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 antitumor efficacy. Both CD4+ and CD8+ T cells were required for the antitumor activity of this combination therapy, as their in vivo depletion via Abs impaired outcomes. These data represent the first report to our knowledge of IL-6 and CTLA‑4 blockade as a means to regress pancreatic tumors with defined operative mechanisms of efficacy.