Metabolism of Histone Deacetylase Proteins Opsonizes Tumor Cells to Checkpoint Inhibitory Immunotherapies

Abstract

LC3-associated phagocytosis, a distinct form of autophagy, plays a key role in antigen presentation. Autophagy itself plays a central role in the regulation of cellular metabolism. Proteins that regulate autophagy include the AMPK which senses high levels of AMP, and mTOR, which integrates amino acid and fatty acid metabolism with autophagy. More recently, autophagy has been demonstrated to regulate tumor cell immunogenicity via the degradation of histone deacetylase proteins. Individual drugs and drug combinations that activate the ATM-AMPK pathway and inactivate mTOR, cause autophagosome formation. The maturation of autophagosomes into autolysosomes causes the autophagic degradation of histone deacetylase proteins who regulate the transcription of PD-L1, Class I MHCA, ODC and IDO1. Indeed, drug combinations that do not contain an HDAC inhibitor can nevertheless act as de facto HDAC inhibitors, via autophagic degradation of HDAC proteins. Such drug combinations simultaneously kill tumor cells via immunogenic autophagy and in parallel opsonize tumor cells to checkpoint inhibitor immunotherapies via reduced expression of PD-L1, ODC and IDO1, and increased expression of Class I MHCA.

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“…We have previously published that autophagosome formation and autophagic flux can reduce the expression of multiple HDAC proteins ( 11 , 12 ). As single agents, axitinib, entinostat, vorinostat and valproate all exhibited to some degree an ability to reduce HDAC levels, however generally, the combination of axitinib with an HDAC inhibitor resulted in a significantly greater reduction in HDAC expression.…”

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