Loss of major histocompatibility complex (MHC) class I and interferon (IFN)g sensing are major causes of primary and acquired resistance to checkpoint blockade immunotherapy. Additional treatment options are needed for tumors that lose expression of MHC class I. IAP antagonism can be used to skew cytokine production by T cells and has pleiotropic effects across other immune cell types by mimicking signaling through TNF superfamily receptors. We tested the effect of IAP antagonists in multiple models of highly refractory pancreatic cancer. Induction of non-canonical NF-kB signaling induces T cell-dependent immune responses, even in beta-2-microglobulin (b2M)-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. Knowing the mechanism of action inspired combination therapy with CD47 blockade, which resulted in beneficial responses in multiple models of pancreatic cancer where checkpoint blockade fails. Thus, activation of non-canonical NF-kB stimulates a T cell-macrophage axis that curtails growth of tumors that are resistant to checkpoint blockade due to loss of MHC class I or IFNg sensing. 

See manuscripts in Science Translational Medicine.