cIAP1/2 Antagonism Induces Antigen-Specific T Cell-Dependent Immunity

• Published in: The Journal of immunology (1950) Vol. 210; no. 7; pp. 991 - 1003
• Main Authors: Ventre, Katherine S, Roehle, Kevin, Bello, Elisa, Bhuiyan, Aladdin M, Biary, Tamara, Crowley, Stephanie J, Bruck, Patrick T, Heckler, Max, Lenehan, Patrick J, Ali, Lestat R, Stump, Courtney T, Lippert, Victoria, Clancy-Thompson, Eleanor, Conce Alberto, Winiffer D, Hoffman, Megan T, Qiang, Li, Pelletier, Marc, Akin, James J, Dougan, Michael, Dougan, Stephanie K
• Format: Journal Article
• Language: English
• Published: United States 01.04.2023
• Subjects: Animals; Apoptosis; Cell Line, Tumor; Immunity; Inhibitor of Apoptosis Proteins; Mice; NF-kappa B - metabolism; Pancreatic Neoplasms; T-Lymphocytes - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.2200646

Checkpoint blockade immunotherapy has failed in pancreatic cancer and other poorly responsive tumor types in part due to inadequate T cell priming. Naive T cells can receive costimulation not only via CD28 but also through TNF superfamily receptors that signal via NF-κB. Antagonists of the ubiquitin ligases cellular inhibitor of apoptosis protein (cIAP)1/2, also called second mitochondria-derived activator of caspases (SMAC) mimetics, induce degradation of cIAP1/2 proteins, allowing for the accumulation of NIK and constitutive, ligand-independent activation of alternate NF-κB signaling that mimics costimulation in T cells. In tumor cells, cIAP1/2 antagonists can increase TNF production and TNF-mediated apoptosis; however, pancreatic cancer cells are resistant to cytokine-mediated apoptosis, even in the presence of cIAP1/2 antagonism. Dendritic cell activation is enhanced by cIAP1/2 antagonism in vitro, and intratumoral dendritic cells show higher expression of MHC class II in tumors from cIAP1/2 antagonism-treated mice. In this study, we use in vivo mouse models of syngeneic pancreatic cancer that generate endogenous T cell responses ranging from moderate to poor. Across multiple models, cIAP1/2 antagonism has pleiotropic beneficial effects on antitumor immunity, including direct effects on tumor-specific T cells leading to overall increased activation, increased control of tumor growth in vivo, synergy with multiple immunotherapy modalities, and immunologic memory. In contrast to checkpoint blockade, cIAP1/2 antagonism does not increase intratumoral T cell frequencies. Furthermore, we confirm our previous findings that even poorly immunogenic tumors with a paucity of T cells can experience T cell-dependent antitumor immunity, and we provide transcriptional clues into how these rare T cells coordinate downstream immune responses.