COMBINED MEK AND STAT3 INHIBITION REPROGRAMS TUMOR MICROENVIRONMENT TO ENHANCE IMMUNOTHERAPY IN PANCREATIC CANCER

OBJECTIVE: Pancreas cancer (PDAC) is an immunologically “cold” tumor due to its immunosuppressive tumor-microenvironment (TME) and the lack of T-cell infiltration is a major barrier to immune-checkpoint inhibitor... [ view full abstract ]

OBJECTIVE: Pancreas cancer (PDAC) is an immunologically “cold” tumor due to its immunosuppressive tumor-microenvironment (TME) and the lack of T-cell infiltration is a major barrier to immune-checkpoint inhibitor therapies. We have shown that combined MEK and STAT3 inhibition (MEKi and STAT3i) remodels the tumor stroma to enhance drug delivery to the tumor. We now sought to determine the effects of  MEKi/STAT3i on the immunosuppressive PDAC TME.

METHODS: PKT (Ptf1aCre/+;LSL-KrasG12D/+;Tgfbr2flox/flox) mice were treated with MEKi and/or STAT3i. At endpoint, pancreas weight was measured and histological analysis of tumor area was used to determine tumor burden. T_regs, MDSCs, and CD8⁺ cells in the tumor were quantified by flow cytometry and immunofluorescence. Tumor lysates were assayed for pERK and pSTAT3 by western blot to determine target inhibition.

RESULTS: Combined MEKi/STAT3i significantly downregulated immunosuppressive T_regs and MDSCs in TME and decreased tumor fibrosis. Compared to vehicle treatment, infiltration of CD8⁺ T-cells was significantly increased in pancreas of MEKi/STAT3i treated mice. Depletion of T-cells abrogated the efficacy of MEKi/STAT3i. Despite target inhibition, levels of PD-1 and PD-L1 in TME remained unchanged. MEKi/STAT3i with PD-1 blockade further decreased tumor burden in PKT mice.

CONCLUSION: We have identified a novel mechanism showing that combined MEKi/STAT3i inhibits tumor fibrosis and enhances CD8⁺ cytotoxic T-cell infiltration while downregulating immunosuppressive T_regs and MDSCs in the TME, resulting in reduced tumor burden and improved survival in genetically engineered mouse models of PDAC. In addition, combined MEKi/STAT3i with PD-1 inhibition can harness the effects of immune-checkpoint inhibitors for enhanced anti-tumor response.