Tumor-specific indicators, such as tumor mutation burden (TMB) have been shown to affect overall survival (OS) in melanoma. Recently, pan-cancer analyses from The Cancer Genome Atlas (TCGA) discovered specific tumor immune signatures predictive of overall survival (OS), yet it is unclear how these interact with other prognostic markers, independently of immunotherapy (IT). We aimed to combine the immune landscape signatures with TMB and other prognostic markers to improve melanoma OS prediction in patients, independent of IT.
We examined the whole-exome data in conjunction with the molecular, clinical and immune features from 278 metastatic melanomas from TCGA, not treated by IT, to develop an improved prognostic model of melanoma OS. Using the discovery (N = 139) and validation (N = 139) design we performed multivariate Cox proportional hazards (Cox HR) models, adjusted for age and tumor stage at primary diagnosis, to identify interaction between TMB and melanoma immune features (n = 59), refining the prediction of melanoma OS.
We identified 4 immune features that were significantly associated with OS in both the discovery and validation cohorts. The multivariate Cox HR models revealed that IFN-γ response (IFN-γ R) and macrophage regulation (MR) signatures in combination with TMB were the most significantly associated with OS (p = 8.80E-14). After further refinement, we observed that patients with high TMB, high IFN-γ R and high MR had significantly better OS compared to high TMB, low IFN-y R and low MR (HR = 2.8, p = 3.55E-08). This association was not observed in low TMB patients.
We show, for the first time, that TMB and tumor immune features are significantly associated with improved OS, independent of IT. Further analysis of patients revealed that high TMB associates with improved OS in patients with high IFN- γ R and MR but not in low IFN- γ R and MR. Hence, this data provides first evidence that patients with high TMB have distinct OS outcome depending on other tumor immune features. Beside biological link between TMB and IFN-y and MR, our data suggest that these associations may significantly improve the current melanoma prognostic models.
Clinical trial identification
Legal entity responsible for the study
Has not received any funding.
J.S. Weber: Advisory / Consultancy: Merck; Advisory / Consultancy: BMS; Advisory / Consultancy: Novartis; Licensing / Royalties, Biomarker Patient: Biodesix. All other authors have declared no conflicts of interest.