Interleukin 6 Drives Durable T Cell-Mediated Immunity to Pancreatic Cancer

Tumor immune resistance is recognized as a contributor to low survivorship in pancreatic ductal adenocarcinoma (PDAC). The inflammatory cytokine interleukin-6 (IL-6) promotes polarization of CD4 T cell populations away from immune tolerance, and induces differentiation of cytotoxic CD8 T cells. This work aims to test whether IL-6 could stimulate an anti-tumor response in PDAC METHODS: We overexpressed IL-6 in multiple Kras^G12D/+, Tp53^R172H/+, Pdx1-Cre (KPC) cell lines, which were orthotopically implanted in mice (OT-PDAC^IL6). We followed mouse survival and measured tumor growth, tumor histology, and plasma IL-6 at 5 and 10 days after tumor implantation. We measured tumor immune cell infiltration via flow cytometry and histology. We used antibody-based T cell depletion and secondary tumor implantation rechallenge to test the dependency of the durable immune reaction on T cells. We use lipid nanoparticle (LNP)-based delivery of IL-6 mRNA to the pancreas as an orthogonal approach for testing the effect of elevated IL-6 in the tumor microenvironment on anti-tumor T cell invasion.

Improved survival occurred in all instances of OT-PDAC^IL6, with one cell line (KxPxCx) reproducibly resulting in long-term recurrence-free survival. With KxPxCx cells, circulating IL-6 was 100-fold higher in OT-KxPxCx^IL6 than in OT-KxPxCx^parental mice. Flow cytometry revealed increased T cells and natural killer cells and decreased T regulatory cells, and we observed significantly increased lymphoid aggregates in OT-KxPxXCx^IL6 as compared with OT--KxPxCx^parental tumors. Antibody-based CD4⁺ and CD8⁺ T cell depletion prevented tumor clearance and completely abolished the survival advantage in OT-KxPxCx^IL6 mice. The anti-tumor immune response to OT-KxPxCx^IL6 rendered mice immune to re-challenge with OT-KxPxCx^parental tumors. LNP delivery of IL-6 to the pancreas elevated systemic IL-6 levels ∼50 fold, lowered tumor burden, and increased anti-tumor T cell phenotypes.

Locally high IL-6 concentrations potently enhance the T cell-mediated anti-tumor response to PDAC.