Ventre, Katherine, Roehle, Kevin, Bello, Elisa, Bhuiyan, Aladdin, Biary, Tamara, Crowley, Stephanie, Bruck, Patrick, Heckler, Max, Lenehan, Patrick, Ali, Lestat, Stump, Courtney, Lippert, Victoria, Clancy-Thompson, Eleanor, Conce Alberto, Winiffer D., Hoffman, Megan, Qiang, Li, Pelletier, Marc, Akin, James, Dougan, Michael and Dougan, Stephanie (2023) cIAP1/2 antagonism induces antigen-specific T cell dependent immunity. The journal of immunology, 210. pp. 991-1003. ISSN 1550-6606

Abstract

Checkpoint blockade immunotherapy has failed in pancreatic cancer and other poorly responsive tumor types in part due to inadequate T cell priming. Naïve T cells can receive co-stimulation not only via CD28 but also through TNF superfamily receptors that signal via NF-B. Antagonists of the ubiquitin ligases cIAP1/2, also called SMAC mimetics, induce degradation of cIAP1/2 proteins, allowing for the accumulation of NIK and constitutive, ligand-independent activation of alternate NF-B signaling that mimics co-stimulation 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. Here, we use in vivo 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 anti-tumor immunity, including increased activation of dendritic cells and 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 anti-tumor immunity, and we provide transcriptional clues into how these rare T cells coordinate downstream immune responses.

Item Type:	Article
Date Deposited:	05 Jul 2023 00:45
Last Modified:	05 Jul 2023 00:45
URI:	https://oak.novartis.com/id/eprint/49484