Investigating the PD-L1:NLRP3 signaling axis as a tumor intrinsic mechanism of adaptive resistance to anti-PD-1 antibody immunotherapy

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Despite the positive impact that checkpoint inhibitor immunotherapy has had on the field of oncology, the majority of our cancer patients do not respond to this treatment strategy. It is clear that a more complete understanding of these mechanisms driving resistance to checkpoint inhibitor immunotherapy will lead to the development of more effective immunotherapy regimens and to improved patient selection for specific therapies. However, our understanding of active tumor- mediated resistance mechanisms that are more responsive to pharmacologic targeting remains poor. Myeloid-derived suppressor cells (MDSCs) are an immunosuppressive cell population that have been correlated with inferior responses to checkpoint inhibitor therapy. Using pre-clinical models of different tumor types as well as clinical specimens harvested from melanoma patients, we have found that resistance to anti-PD-1 antibody (ab) immunotherapy is associated with the recruitment of granulocytic MDSCs (PMN-MDSCs) into the tumor bed. Subsequent mechanistic studies were conducted to understand the molecular underpinnings for this accumulation of PMN- MDSCs in tumors undergoing checkpoint inhibitor immunotherapy which noted that CXCR2- dependent chemokines are upregulated in response to a Wnt5a-YAP1 signaling axis and that this pathway is triggered by the release of heat shock protein-70 (HSP70) by tumors in response to CD8+ T cell activation. Using a genome-wide CRISPR screen, we have determined that the tumor NLRP3 inflammasome is essential for the induction of this signaling cascade and the ultimate recruitment of PMN-MDSCs to the tumor bed. Based on this cumulative data, we hypothesize that the adaptive recruitment of PMN-MDSCs and its subsequent suppression of effector T cell activity in response to anti-PD-1 ab immunotherapy is mediated by activation of the tumor NLRP3 inflammasome via tumor intrinsic PD-L1 signaling. We further propose that the pharmacologic inhibition of the NLRP3 inflammasome will enhance the efficacy of anti-PD-1 ab immunotherapy in an autochthonous model of BRAFV600E melanoma and that genetic mutations impacting this pathway can lead to differential responses to checkpoint inhibitor immunotherapy. In addition to modeling specific gain-of-function NLRP3 mutations in pre-clinical melanoma models, we will also leverage an ongoing clinical protocol designed to harvest tissue specimens from melanoma patients, enabling the association of NLRP3 genetic mutations and expression levels, PMN-MDSC tumor infiltration, and clinical response to checkpoint inhibitor immunotherapy. Overall, this study promises to contribute significantly to our understanding of adaptive resistance to anti-PD- 1 ab immunotherapy in cancer.