Multi-cohort validation of BRAF-PTPRT co-mutation as a predictor of favorable immunotherapy response in melanoma.

Abstract

Background: Immune checkpoint blockade (ICB) has transformed melanoma therapy, but predictive biomarkers remain suboptimal. BRAF is the most common driver mutation, yet its single-gene association with ICB response remains inconsistent. PTPRT loss activates STAT3-driven immunity. We hypothesized that concurrent BRAF and PTPRT mutations (co-mutation) synergistically enhance immunogenicity and predict ICB benefit.

Methods: We analyzed three independent cohorts: Memorial Sloan Kettering Cancer Center (MSK) (n=320, ICB-treated), The Cancer Genome Atlas (TCGA) (n=448, mixed treatments), and a combined ICB cohort (CS, n=436). Patients were categorized into four groups: co-mutation, BRAF+/PTPRT-, BRAF-/PTPRT+, double wild-type (WT). Overall survival (OS), tumor mutational burden (TMB), neo-antigen load, clinical benefit, immune infiltration, and transcriptomic pathways were evaluated. A simplified risk score (0-2) was constructed by assigning 1 point for co-mutation and 1 point for high TMB (above median) to predict clinical benefit.

Results: In ICB-treated cohorts (MSK and CS), only co-mutation consistently predicted superior OS, while single mutations showed no consistent benefit. Co-mutated tumors exhibited significantly higher TMB and neo-antigen loads, an immune-inflamed microenvironment with elevated M1 macrophages, reduced Tregs, and upregulation of programmed death-ligand 1 (PD-L1), CTLA-4, TIM-3, as well as enrichment of IFN-γ and IL6-JAK-STAT3 pathways. The combined risk score (co-mutation + TMB) predicted clinical benefit with an area under the curve (AUC) of 0.659. Patients with high-risk score (2 points) demonstrated significantly higher clinical benefit rates compared to low-risk score (0 points).

Conclusions: BRAF-PTPRT co-mutation is a robust, cross-cohort predictive biomarker for ICB response in melanoma. A simple risk score integrating co-mutation and TMB further improves patient stratification. Routine testing of both genes may guide immunotherapy decisions.