Cancer-Germline Antigen Expression Discriminates Clinical Outcome to CTLA-4 Blockade
2018
Summary
CTLA-4
immune checkpoint
blockadeis clinically effective in a subset of patients with metastatic melanoma. We identify a subcluster of MAGE-A cancer-germline antigens, located within a narrow 75 kb region of chromosome
Xq28, that predicts resistance uniquely to
blockadeof
CTLA-4, but not PD-1. We validate this gene expression signature in an independent anti-
CTLA-4-treated cohort and show its specificity to the
CTLA-4pathway with two independent anti-PD-1-treated cohorts. Autophagy, a process critical for optimal anti-cancer immunity, has previously been shown to be suppressed by the MAGE-
TRIM28
ubiquitin ligasein vitro . We now show that the expression of the key
autophagosomecomponent LC3B and other activators of autophagy are negatively associated with MAGE-A protein levels in human melanomas, including samples from patients with resistance to
CTLA-4
blockade. Our findings implicate autophagy suppression in resistance to
CTLA-4
blockadein melanoma, suggesting exploitation of autophagy induction for potential therapeutic synergy with
CTLA-4inhibitors.
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