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Cancer-Germline Antigen Expression Discriminates Clinical Outcome to CTLA-4 Blockade

Sachet A Shukla1, Pavan Bachireddy2, Bastian Schilling3

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA.

Cell
|April 17, 2018
PubMed

Insights

A specific MAGE-A gene signature predicts resistance to CTLA-4 blockade in melanoma. This resistance is linked to suppressed autophagy, suggesting autophagy induction as a potential therapy.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immune checkpoint blockade shows clinical efficacy in a subset of metastatic melanoma patients.
  • Cancer-germline antigens, specifically MAGE-A, are implicated in immune responses.
  • Autophagy is crucial for anti-cancer immunity and can be regulated by MAGE-TRIM28.

Purpose of the Study:

  • To identify biomarkers predicting resistance to CTLA-4 blockade in melanoma.
  • To investigate the role of MAGE-A antigens and autophagy in CTLA-4 resistance.
  • To explore therapeutic strategies for overcoming CTLA-4 resistance.

Main Methods:

  • Gene expression profiling to identify MAGE-A antigen subcluster on chromosome Xq28.
  • Validation of the gene expression signature in independent patient cohorts treated with anti-CTLA-4 and anti-PD-1 therapies.
  • Assessment of the association between MAGE-A protein levels, autophagy markers (LC3B), and patient response.

Main Results:

  • A MAGE-A antigen subcluster on chromosome Xq28 predicts resistance specifically to CTLA-4 blockade, not PD-1 blockade.
  • This resistance signature was validated in independent patient cohorts.
  • MAGE-A protein levels negatively correlate with autophagy activators like LC3B in melanoma, including in samples from patients resistant to CTLA-4 blockade.

Conclusions:

  • Autophagy suppression is implicated in melanoma resistance to CTLA-4 blockade.
  • Targeting MAGE-A antigens may overcome resistance to CTLA-4 therapy.
  • Inducing autophagy could offer a potential therapeutic synergy with CTLA-4 inhibitors in melanoma treatment.
Keywords:
CTLA-4MAGE-APD-1autophagycancer-germline antigencheckpoint blockadeimmunogenomicsimmunotherapyipilimumabmelanoma

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