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.