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. Naïve T cells can receive co-stimulation not only via CD28 but also through TNF superfamily receptors that signal via NF-κB. 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-κB 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 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. TCRα-/- mice were implanted orthotopically with M8 live passage organoids and treated with vehicle or LCL-161 (75mg/kg) by oral gavage every 3 days starting on day 4. Tumors and spleens were harvested on day 12 after 3 doses of LCL-161 and single cell suspensions prepared. CD4 and CD8 T cells were isolated by FACS and subjected to limited bulk transcriptional profiling. N=3 per group.