PD-L2 blockade elicits IL-17-induced IFNγ to treat melanoma in the aged host through CD8+ T and gd T cell effects 4160

Abstract Description Overall, immune checkpoint blockade (ICB) response remains low at ∼15%, indicating better treatment options are needed. Aging alters immunity, and most cancer patients are older. However, most ICB studies are done in young hosts. The PD-L2 immune checkpoint remains poorly understood, yet it binds PD-1 with 3.3-fold affinity > PDL1. We use aged (18-28 mos.) and young (2-6 mos.) mice to study why αPD-L2 treats B16 melanoma in aged but not young mice. We found the aged tumor microenvironment (TME) has elevated IFNγ and IL-17 expression. We found that αPDL2 efficacy is through IL17-driven IFNγ using IL17KO and IFNγKO mice. We showed γδ T cells promoted CD8+ T cell effector functions but not prevalence for efficacy, using aged δTCRKO mice and CD8+ depletion. Adoptive transfer of WT aged CD4+ T cells into aged IL-17KO mice rescued αPD-L2 efficacy, which was abrogated with IL-17 receptor blockade, defining CD4+ T cell IL17 as a mechanism. Strikingly, giving young WT mice exogenous rIL-17 elicited αPD-L2 therapy in these otherwise refractory hosts. We mined scRNA-seq data to find that PDL2 expression increases with age. These and other data implicated cDC1 as initial αPDL2 targets. These data show novel ICB efficacy and age-dependent mechanisms. αPDL2 also treated heterotopic MB49 better in aged versus young. These studies show PDL2 is a good ICB target and could combine with other ICB as well to help overcome ICB resistance. Funding Sources NIH T32GM113896 (STX MSTP) Award (C.O. and C.M.) and the NCI F31CA281345 (C.O.). NCI (CA252057, CA268641, CA246707, CA292467), Gmelich chair and Guyre funds supported Curiel. Work was supported by the Dartmouth Cancer Center and DartLab, the Immune Monitoring and Flow Cytometry Shared Resource at the Dartmouth Cancer Center, with NCI Cancer Center Support Grant 5P30 CA023108-41. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)