Pancreatic cancer cells overexpressing interleukin 6 induce T-cell-mediated tumor clearance and durable anti-tumor immune response

Abstract

Tumor immune resistance is recognized as a contributor to low survivorship in pancreatic ductal adenocarcinoma (PDAC). We developed a novel murine model of spontaneous PDAC clearance, generated by overexpressing interleukin-6 (IL-6) in orthotopically implanted PDAC cancer cells (OT-PDAC^IL6). Circulating IL-6 was 100-fold higher in OT-PDAC^IL6 than in OT-PDAC^parental mice. OT-PDAC^IL6 tumors were present at 5 days post-implantation, and undetectable by 10 days post implantation. Flow cytometry revealed increased T cells and NK cells, and decreased T regulatory cells in OT-PDAC^IL6 as compared to OT-PDAC^parental tumors. Increased lymphoid aggregates were apparent by histological assessment and may account for elevated T cell content. Antibody-based depletion of CD4⁺ and CD8⁺ T cells prevented tumor clearance and significantly reduced survival of OT-PDAC^IL6 mice. The anti-tumor immune response to OT-PDAC^IL6 rendered mice immune to re-challenge with OT-PDAC^parental tumors. In high concentrations, IL-6 acts in opposition to previously described pro-tumorigenic effects by enhancing the T cell-mediated anti-tumor response to PDAC.

Keywords: Interleukin 6; Pancreatic Ductal Adenocarcinoma; T-cell response.