cIAP1/2 antagonism eliminates MHC class I-negative tumors through T cell-dependent reprogramming of mononuclear phagocytes

Loss of major histocompatibility complex (MHC) class I and interferon-gamma (IFN-gamma) sensing are major causes of primary and acquired resistance to checkpoint blockade immunotherapy. Thus, additional treatment options are needed for tumors that lose expression of MHC class I. The cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1/2) regulate classical and alternative nuclear factor kappa B (NF-kappa B) signaling. Induction of noncanonical NF-kappa B signaling with cIAP1/2 antagonists mimics costimulatory signaling, augmenting antitumor immunity. We show that induction of noncanonical NF-kappa B signaling induces T cell-dependent immune responses, even in beta(2)-microglobulin (beta M-2)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. Efficacy is augmented by combination with CD47 blockade. Thus, activation of noncanonical NF-kappa B stimulates a T cell-macrophage axis that curtails growth of tumors that are resistant to checkpoint blockade because of loss of MHC class I or IFN-gamma sensing. These findings provide a potential mechanism for controlling checkpoint blockade refractory tumors.

Automated summary

The loss of MHC class 1 and IFN-gamma sensing is a major cause of resistance to checkpoint blockade therapy. Inducing noncanonical NF-kappa B signaling promotes antitumor immunity and inhibits tumor growth in resistant tumors by activating a T cell-macrophage axis. This approach may offer an alternative treatment for tumors with checkpoint blockade refractoriness.