Research ArticleCancer

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

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Science Translational Medicine  19 May 2021:
Vol. 13, Issue 594, eabf5058
DOI: 10.1126/scitranslmed.abf5058

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Macrophages eat up MHC-negative tumors

A common mechanism of tumor immune evasion is loss of major histocompatibility complex (MHC) class I molecules on tumor cells. This renders tumor cells invisible to CD8 T cells; however, MHC class I recognition is not the only antitumor function of CD8 T cells. In this study, Roehle et al. demonstrated that treatment with an inhibitor of cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1/2) induced CD8 T cells to produce lymphotoxin, which, in turn, activated macrophages to phagocytose tumor cells, promoting clearance of MHC class I–deficient tumors in vivo. Thus, cIAP1/2 antagonism may be a therapeutic option for tumors that lose MHC class I expression.

Abstract

Loss of major histocompatibility complex (MHC) class I and interferon-γ (IFN-γ) 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 κB (NF-κB) signaling. Induction of noncanonical NF-κB signaling with cIAP1/2 antagonists mimics costimulatory signaling, augmenting antitumor immunity. We show that induction of noncanonical NF-κB signaling induces T cell–dependent immune responses, even in β2-microglobulin (β2M)–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-κB 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-γ sensing. These findings provide a potential mechanism for controlling checkpoint blockade refractory tumors.

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