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

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.