CTLA4 methylation predicts response to anti–PD-1 and anti–CTLA-4 immunotherapy in melanoma patients

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Abstract

Recent years have witnessed the groundbreaking success of immune checkpoint blockage (ICB) in metastasized malignant melanoma. However, biomarkers predicting the response to ICB are still urgently needed. In the present study, we investigated CTLA4 promoter methylation (mCTLA4) in 470 malignant melanoma patients from The Cancer Genome Atlas (non-ICB cohort) and in 50 individuals with metastasized malignant melanomas under PD-1/CTLA-4–targeted immunotherapy (ICB cohort). mCTLA4 levels were quantified using the Infinium HumanMethylation450 BeadChip (non-ICB cohort) and methylation-specific quantitative real-time PCR in DNA formalin-fixed and paraffin-embedded tissues (ICB cohort). Methylation levels were associated with molecular and clinicopathological variables and analyzed with respect to response (irRECIST) and overall survival. CTLA-4 mRNA and mCTLA4 showed a significant inverse correlation (non-ICB cohort: Spearman’s ρ = –0.416, P < 0.001). In ICB-treated melanoma patients, low mCTLA4 was further strongly correlated with response to therapy (P = 0.009, ANOVA) and overall survival (hazard ratio = 2.06 [95% CI: 1.29–3.29], P = 0.003). Our data strongly support the assumption that mCTLA4 predicts response to both anti–PD-1 and anti–CTLA-4 targeted ICB in melanoma and provides paramount information for the selection of patients likely to respond to ICB.

Authors

Diane Goltz, Heidrun Gevensleben, Timo J. Vogt, Joern Dietrich, Carsten Golletz, Friedrich Bootz, Glen Kristiansen, Jennifer Landsberg, Dimo Dietrich