Cancer-Germline Antigen Expression Discriminates Clinical Outcome to CTLA-4 Blockade Academic Article Article uri icon

Overview

MeSH Major

  • Anti-Infective Agents, Local
  • Facial Paralysis
  • Hearing Loss, Sensorineural
  • Silver Nitrate
  • Tympanic Membrane Perforation
  • Tympanoplasty

abstract

  • © 2018 Elsevier Inc. CTLA-4 immune checkpoint blockade is 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 blockade of 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-4 pathway 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 ligase in vitro. We now show that the expression of the key autophagosome component 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 blockade in melanoma, suggesting exploitation of autophagy induction for potential therapeutic synergy with CTLA-4 inhibitors. Increased expression of a subcluster of MAGE-A cancer-germline antigens predicts resistance specific to CTLA-4, but not PD-1, blockade, and its association with autophagy suppression implicates the role of autophagy in regulating primary resistance to anti-CTLA-4 therapy in melanoma patients.

authors

publication date

  • January 2018

Research

keywords

  • Academic Article

Identity

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2018.03.026

PubMed ID

  • 29656892

Additional Document Info