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

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 -KB. 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, ligandindependent activation of alternate NF -KB 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. The Journal of Immunology, 2023, 210: 991-1003.

Automated summary

Checkpoint blockade immunotherapy has failed in pancreatic cancer and other poorly responsive tumor types due to inadequate T cell priming. cIAP1/2 antagonists have pleiotropic beneficial effects on antitumor immunity, including increased activation and control of tumor growth, synergy with multiple immunotherapy modalities, and immunologic memory. This study confirms the importance of T cell-dependent antitumor immunity and provides insights into how rare T cells coordinate downstream immune responses.