Interleukin 6 drives durable T cell-mediated immunity to pancreatic cancer

ABSTRACT Background & Aims: 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. Results: 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 NK cells, and decreased T regulatory cells, and we observed significantly increased lymphoid aggregates in OT-KXPXCX IL6 as compared to 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. Conclusions: Locally high IL-6 concentrations potently enhance the T cell-mediated anti-tumor response to PDAC. SYNOPSIS: Interleukin-6 induces rapid and durable T cell-driven immune clearance of pancreatic ductal adenocarcinoma. The anti-tumor immune microenvironment is hallmarked by increased lymphoid aggregate formation, increased CD4 T cell abundance, and decreased Treg abundance.