Combined MEK and STAT3 inhibition reprograms the tumor microenvironment to overcome immunotherapy resistance in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by immune exclusion, stromal desmoplasia, and resistance to immune checkpoint inhibition (ICI). We have previously demonstrated that reciprocally activated RAS/RAF/MEK/ERK and JAK/STAT3 pathways mediate therapeutic resistance, while combined MEK and STAT3 inhibition (MEKi/STAT3i) overcomes this resistance in PDAC. Herein, we show that combined MEKi/STAT3i alters stromal architecture and remodels the tumor-infiltrating innate and adaptive immune compartments by downregulating immunosuppressive myeloid populations and promoting T-cell enrichment and activation in Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) mice. MEKi/STAT3i-mediated reprogramming of the PDAC tumor microenvironment primes tumor-infiltrating CD8+ T-cells for PD-1 blockade to augment their activation and functional cytotoxicity. As such, the addition of MEKi/STAT3i to PD-1 blockade dramatically inhibits tumor growth and prolongs survival, overcoming resistance to ICI, in PKT mice. Importantly, treatment of a patient with chemotherapy-refractory metastatic PDAC with MEKi (Trametinib), STAT3i (Ruxolitinib), and PD-1 inhibitor (Nivolumab) was not only well-tolerated but also yielded significant clinical benefit. Significance These data uncover a novel paradigm in which combined MEKi/STAT3i reprograms the stromal and immune microenvironment to overcome immunotherapy resistance in PDAC. The clinical efficacy of combined MEKi, STAT3i, and anti-PD1 treatment in chemotherapy-refractory PDAC provides encouraging signals for its translatability, and is being currently pursued in a clinical trial.