IL-15 complex with agonistic anti-CD40 + anti-PDL1 overcomes T cell exhaustion and drives a T-bet+ effector program for pancreatic ductal adenocarcinoma eradication 3573

Abstract Description New approaches are needed to improve immunotherapy outcomes in the lethal malignancy, pancreatic ductal adenocarcinoma (PDA). As such, we performed scRNA-seq combined with scV(D)J-seq of tumor-infiltrating and peripheral CD8 T cells isolated from mice bearing orthotopic neoantigen+ KPC2a pancreatic tumors and treated with agonistic aCD40, aPD-L1, or the combination. aCD40 promoted the intratumoral expansion of CD8+Tcf1+Slamf6+ stem (TSTEM) cells and CD4 T helper cells. In contrast, aPD-L1 induced intratumoral clonal expansion of tumor-specific CD8+Gzmk+ progenitor exhausted (TPEX) T cells. aCD40 + aPD-L1 drove clonal expansion and dysfunction of CD8+ TPEX in the spleen. Dysfunctional, or exhausted T cells infiltrating spleen and tumor expressed IL-2Rb. Provision of IL-15 complex (IL-15C) prevented aCD40 + aPD-L1 -driven systemic T cell exhaustion and promoted T-bet upregulation in all subsets of tumor-infiltrating CD8 T cells, with highest levels in TSTEM and Klrg1+ TEFF. Addition of IL-15C to aCD40 + aPD-L1 therapy significantly extended mouse survival and cured 100% of mice. Orthotopic tumor rechallenge in IL-15C cured animals revealed complete protection in response to the original KPC2a cells, as well as significant antitumor effects against the parental KPC2 cells. Thus, loss of critical cytokine support interferes with the efficacy of combination immunotherapy, and provision of IL-15C safely improves immunotherapy activity. Funding Sources ZCS is supported by a NIH T32 AG029796 followed by NIH F31CA275289. IMS is supported by NIH R01CA255039, R01CA249393, U54CA268069, P01CA254849, DOD W81XWH2110525, an AACR Pancreatic Cancer Action Network Catalyst Award (19-35- STRO), American Cancer Society RSG-21-102-01-IBCD, and Randy Shaver Research grant. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)