MYC Overexpression Drives Immune Evasion in Hepatocellular Carcinoma That Is Reversible through Restoration of Proinflammatory Macrophages

Cancers evade immune surveillance, which can be reversed through immune-checkpoint therapy in a small subset of cases. Here, we report that the MYC oncogene suppresses innate immune surveillance and drives resistance to immunotherapy. In 33 different human cancers, MYC genomic amplification and overexpression increased immune-checkpoint expression, predicted nonrespon-siveness to immune-checkpoint blockade, and was associated with both Th2-like immune profile and reduced CD8 T-cell infiltration. MYC transcriptionally suppressed innate immunity and MHCI-mediated antigen presentation, which in turn impeded T-cell response. Combined, but not individual, blockade of PDL1 and CTLA4 could reverse MYC-driven immune suppression by leading to the recruitment of proinflammatory antigen-presenting macro-phages with increased CD40 and MHCII expression. Depletion of macrophages abrogated the antineoplastic effects of PDL1 and CTLA4 blockade in MYC-driven hepatocellular carcinoma (HCC). Hence, MYC is a predictor of immune-checkpoint responsiveness and a key driver of immune evasion through the suppression of proin-flammatory macrophages. The immune evasion induced by MYC in HCC can be overcome by combined PDL1 and CTLA4 blockade.Significance: Macrophage-mediated immune evasion is a ther-apeutic vulnerability of MYC-driven cancers, which has implica-tions for prioritizing MYC-driven hepatocellular carcinoma for combination immunotherapy.

Automated summary

MYC oncogene suppresses innate immune surveillance and drives resistance to immunotherapy. Overexpression of MYC increases immune-checkpoint expression, predicts nonresponsiveness to immune-checkpoint blockade, and is associated with Th2-like immune profile and reduced CD8 T-cell infiltration. MYC transcriptionally suppresses innate immunity and MHCI-mediated antigen presentation, impeding T-cell response. Combined blockade of PDL1 and CTLA4 can reverse MYC-driven immune suppression by recruiting proinflammatory antigen-presenting macrophages. Depletion of macrophages abrogates the antineoplastic effects of PDL1 and CTLA4 blockade in MYC-driven hepatocellular carcinoma.