cIAP1/2 antagonism eliminates MHC class I–negative tumors through T cell–dependent reprogramming of mononuclear phagocytes
Kevin Roehle, Qiang Li, Katherine S. Ventre, Daniel Heid, Lestat R. Ali, Patrick J. Lenehan, Max Heckler, Stephanie J. Crowley, Courtney T. Stump, Gabrielle Ro, Anže Godicelj, M. Aladdin Bhuiyan, Annan Yang, Maria Quiles del Rey, Tamara Biary, Adrienne Luoma, Patrick T. Bruck, Jana F. Tegethoff, Svenja L. Nopper, Jinyang Li, Katelyn T. Byrne, Marc R. Pelletier, Kai W. Wucherpfennig, Ben Z. Stanger, James J. Akin, Joseph D. Mancias, Judith Agudo, Michael Dougan, Stephanie K. Dougan
Abstract
M)-deficient 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, cIAP1/2 antagonism reduces tumor burden by increasing phagocytosis of live tumor cells. Efficacy is augmented by combination with CD47 blockade. Thus, activation of noncanonical NF-κB stimulates a T cell-macrophage axis that curtails growth of tumors that are resistant to checkpoint blockade because of loss of MHC class I or IFN-γ sensing. These findings provide a potential mechanism for controlling checkpoint blockade refractory tumors.