演題

Reprograming the Tumor Microenvironment to Enhance Immunotherapy in Pancreatic Cancer

[演者] Nipun Merchant:1
1:University of Miami Miller School of Medicine

Pancreatic cancer (PDAC) remains a major therapeutic challenge due to its innate and acquired chemoresistance. Three major contributors to therapeutic resistance that have been difficult to overcome in PDAC are mutations in the KRAS oncogene, the presence of a dense desmoplastic stroma that acts as a barrier to drug delivery and effector immune cell infiltration, and the immunosuppressive tumor microenvironment (TME) that renders the tumor ineffective to immunotherapy. Our efforts at targeting downstream effectors of oncogenic RAS, have shown that MEK inhibition (MEKi) results in reciprocal activation of STAT3 signaling, which confers therapeutic resistance and continued PDAC cell growth. Combined inhibition of JAK/STAT3 (STAT3i) and MEKi overcomes therapeutic resistance following RAS inhibition that is mediated through parallel feedback loop activation. We have now identified a novel mechanism showing that combined MEKi and STAT3i also inhibits tumor fibrosis and enhances CD8+ cytotoxic T-cell (CTL) infiltration to the tumor while downregulating immunosuppressive regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSCs) in the TME, resulting in reduced tumor burden and improved survival in genetically engineered mouse models of PDAC. In addition, we have shown that the tumor suppressive effects of MEKi and STAT3i are T cell dependent. This change in the TME, however, is accompanied by sustained PD-L1/PD-1 expression. We further show that combined MEKi and STAT3i with PD-1 inhibition can harness the effects of immune checkpoint inhibitors for an enhanced anti-tumor response. Therapeutic strategies that reprogram the tumor stroma to activate T-cell anti-tumor immunity and reverse immune tolerance are of paramount importance as they have the potential to revolutionize treatment for pancreatic cancer and improve clinical outcomes.
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