Abstract
High expression of the MAGE-A subcluster III is associated with anti-CTLA4 resistance in melanoma.
Major finding: High expression of the MAGE-A subcluster III is associated with anti-CTLA4 resistance in melanoma.
Approach: Genomic analyses of tumors treated with mono- or dual ICB revealed drivers of anti-CTLA4 resistance.
Impact: Induction of autophagy may enhance response to anti-CTLA4 therapy.
Immune checkpoint blockade (ICB) therapy targeting CTLA4 has been efficacious against a number of cancer types, most prominently melanoma, particularly in combination with other immunotherapies. However, patients with metastatic melanoma frequently exhibit innate resistance to anti-CTLA4 therapy due to unknown molecular mechanisms. To identify the genomic determinants of anti-CTLA4 response in patients with metastatic melanoma, Shukla, Bachireddy, and colleagues analyzed RNA-sequencing (RNA-seq), transcriptomic, and methylation data from melanomas from patients treated with anti–PD-1 antibodies, the anti-CTLA4 antibody ipilimumab, or combined anti–PD-1/CTLA4. RNA-seq analysis showed that expression of the genes that comprise subcluster III of MAGE-A cancer-germline antigens predicted resistance to anti-CTLA4, but not anti–PD-1, blockade; further, high expression of the MAGE-A subcluster III genes was associated with a transcriptomic signature. Analysis of methylation data revealed that resistant tumors exhibited hypomethylation of MAGE-A subcluster III genes compared to responding tumors and that increased MAGE-A subcluster III expression was significantly correlated with a global decrease in methylation; consistent with these findings, high expression of MAGE-A subcluster III genes was predictive of poor patient outcome after anti-CTLA4 therapy. Analysis of protein databases to identify potential targets of MAGE-A proteins, which are known interact with the TRIM28 ubiquitin ligase to negatively regulate cellular processes, showed that a regulator of autophagy was significantly decreased in melanomas that exhibited elevated MAGE-A subcluster III gene expression, and an in vitro screen identified the autophagy- and immunogenic cell death–related HMGB1 as a target of the MAGE-TRIM28 complex. Similarly, mutual exclusivity of the expression of MAGE-A+ with HMGB1+ or the autophagosome component LC3B was observed both in cells from the same tumor and intratumorally. These results identify autophagy repression as a potential anti-CTLA4 resistance mechanism and suggest potential therapeutic strategies to overcome resistance to anti-CTLA4 therapy.
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