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.
Highlights
It is well-recognized that LC3-associated phagocytosis (LAP), a specialized form of autophagy, causes the ingestion of non-self extracellular proteins whose breakdown product peptides are used for antigen presentation on the cell surface [1,2,3,4,5]
We demonstrated that GI tumor cells were killed by the multi-kinase inhibitor sorafenib combined with the histone deacetylase (HDAC) inhibitors vorinostat or sodium valproate, in part, via CD95 death receptor signalling and autophagosome formation; this data was translated into two clinical trials (NCT02349867; NCT01075113)
Magnification we discovered that vehicle control tumors stained for RAS proteins that were localized at the periphery of the cell, but in tumors previously exposed to [neratinib + valproate] the much feebler staining for RAS presented as being evenly distributed all over the cell. [Neratinib + valproate] treatment significantly lowered the expression of IDO-1 and ODC which was not modified in tumors that were exposed to the antiPD1 antibody as a single agent. [Neratinib + valproate] treatment elevated the expression of Class I MHCA and lowered the expression of PD-L1
Summary
It is well-recognized that LC3-associated phagocytosis (LAP), a specialized form of autophagy, causes the ingestion of non-self extracellular proteins whose breakdown product peptides are used for antigen presentation on the cell surface [1,2,3,4,5]. Because of the efficacy of checkpoint inhibitory immunotherapy antibodies in this disease, we determined whether our drug combination had the potential to opsonize tumor cells to the novel immunotherapy [22,23] With both [neratinib + HDAC inhibitors] and [pemetrexed + sildenafil], as well as with other regimens which strongly induced autophagosome formation, we observed that drug-treated cells rapidly reduced their expression of PD-L1, ODC and IDO-1, and increased their expression of Class I MHCA [24,25]. In Lewis Lung Carcinoma tumours [22,23] pemetrexed and sildenafil interacted to further supress tumor growth, which was enhanced by administration of either anti-PD1 or anti-CTLA4 checkpoint inhibitory antibodies These findings validate the in vitro experience of observing autophagy-dependent reduced PD-L1 and enhanced MHCA expression. The actions of [pemetrexed + sildenafil] had re-programed the surviving LLC cells to have a maintained higher immunogenicity for checkpoint inhibitory antibodies
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
