Abstract B202: Defining the role of IL-27 signaling on responses to metastatic melanoma

Abstract

Abstract Checkpoint blockade and cellular therapies for cancer treatment have yielded impressive clinical results. These approaches harness the ability of T-cells, critical mediators of the body’s immune response to infection, to eliminate tumors. Entry of T-cells into the tumor microenvironment exposes them to an array of regulatory signals that impact T-cell differentiation and function. The immunomodulatory cytokine, interleukin 27 (IL-27), produced by tumor cells and immune cells, is a critical regulator of the immune system. A complex literature exists regarding the role of IL-27 in tumor responses and the conflicting conclusions from these studies can be attributed to differences in tumor models and a lack of lineage-specific genetic tools to dissect the impact of IL-27 signaling on particular cell types. We find that IL-27 receptor alpha (WSX1)-deficient mice exhibit reduced tumor burdens following intravenous administration of B16 melanoma in comparison to wildtype mice. Further, the reduced number of macroscopic nodules corresponds with reduced tumor area within the lungs. Analysis of IL-27 reporter mice reveals a population of nonalveolar macrophage/monocytes to be the primary source of IL-27 in the lung as early as day 10 following B16 melanoma challenge. The production of IL-27 in the lung following tumor challenge and the improved resistance to intravenous dissemination of B16 melanoma by WSX1-deficient mice suggests production of IL-27 suppresses immune responses to melanoma within the lung. In line with these data, we find that tumor nodules in the lungs of WSX1-deficient mice have increased infiltration of CD3+ cells observed by histologic analysis in comparison to tumor nodules in wild-type mice. These data support a model where IL-27 suppresses the infiltration or activity of T-cells responding to metastatic melanoma and suggest that novel strategies targeting IL-27 signaling in the tumor microenvironment may synergize with current immunotherapy approaches to improve T-cell responses to tumors. Citation Format: Anthony T. Phan, Christopher A. Hunter. Defining the role of IL-27 signaling on responses to metastatic melanoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B202.