Roehle, Kevin, Qiang, Li, Ventre, Katherine, Heid , Daniel, Ali, Lestat, Lenehan, Patrick, Heckler, Max, Crowley, Stephanie, Stump, Courtney, Ro, Gabrielle, Godicelj, Anze, Bhuiyan, Aladdin, Yang, Annan, Quiles del Rey, Maria, Biary, Tamara, Luoma, Adrienne, Bruck, Patrick, Tegethoff, Jana, Nopper, Svenja, Li, Jinyang, Byrne, Katelyn, Pelletier, Marc, Wucherpfennig , Kai, Stanger , Ben, Akin, James, Mancias, Joe, Agudo, Judith, Dougan, Michael and Dougan, Stephanie (2021) cIAP1/2 antagonism eliminates MHC class I-negative tumors through T cell-dependent reprogramming of mononuclear phagocytes. Science translational medicine, 13. ISSN 1946-6242

Abstract

Loss of MHC class I and IFNγ sensing are major causes of primary and acquired resistance to checkpoint blockade immunotherapy. The cellular (c)-IAPs regulate classical and alternative NF-κB signaling. Induction of non-canonical NF-κB signaling with IAP antagonists mimics costimulatory signaling, augmenting anti-tumor immunity. We now show that induction of non-canonical NF-κB signaling induces T cell-dependent immune responses even in β2m-/- tumors, demonstrating that direct CD8 T cell recognition of tumor cell expressed MHC class I is not required. Instead, T cell-produced lymphotoxin reprograms both mouse and human macrophages to be tumoricidal. In wild type mice, but not mice incapable of antigen-specific T cell responses, IAP antagonism reduces tumor burden by increasing phagocytosis of live tumor cells. Efficacy is augmented by combination with CD47 blockade. Activation of non-canonical NF-κB stimulates a T cell-macrophage axis that curtails growth of tumors that are resistant to checkpoint blockade due to loss of MHC class I or IFNγ sensing.

Item Type:	Article
Date Deposited:	13 Jul 2021 00:45
Last Modified:	13 Jul 2021 00:45
URI:	https://oak.novartis.com/id/eprint/44550