Adipocyte PDL1 suppresses immune checkpoint blockade (ICB) therapy through promoting MDSC-mediated IFNγ suppression 2226486

Abstract

Abstract Introduction Adipocytes are a key component of the tumor microenvironment (TME), but their contributions to ICB response remain relatively understudied. Methods Using an adipocyte rich, PDL1+ mouse melanoma model (NCH1), we found that while αPDL1 treated NCH1 tumors in wild-type (WT) mice, αPDL1 response in adipocyte-PDL1KO mice was significantly improved. αPDL1 in adipocyte-PDL1KO mice, versus WT mice, enhanced IFNγ production in CD4+ T and CD8+ T cells, while decreasing MDSC prevalence in the TME. Results Mechanistically, MDSC depletion in WT mice improved αPDL1 response and restored IFNγ production to levels similar to adipocyte-PDL1KO. In a complementary approach, we pharmacologically inhibited adipocyte PDL1 expression with the PPARγ inhibitor GW9662, as PDL1+ adipocytes differentiate from PDL1- pre-adipocytes through PPARγ. GW9662+αPDL1 phenocopied adipocyte-PDL1KO in controlling NCH1 growth and induced immune memory that protected against secondary melanoma rechallenge, with an establishment of polyfunctional CD69+CD103+ tissue resident memory T-cells. For rapid clinical translation, we tested imatinib, an orally bioavailable FDA-approved drug that inhibits PPARγ. It improved improve αPDL1 response in the AT3 breast cancer model. Surprisingly, though, imatinib inhibited adipocyte differentiation in vitro but did not suppress their PDL1 expression, suggesting unknown complexity in adipocyte differentiation. Conclusion Taken together, these results support the role of adipocyte PDL1 in promoting MDSCs in the TME that suppress IFNγ production and support the development of clinical strategies that deplete adipocyte PDL1 to improve ICB responses. Funding Source R01CA279566 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)