TERT mutations correlate with higher TMB value and unique tumor microenvironment and may be a potential biomarker for anti‐CTLA4 treatment

Abstract

Abstract Immune checkpoint inhibitors (ICIs) have recently changed therapeutic paradigms for patients across multiple cancer types. However, current biomarkers cannot accurately predict responses to ICIs. Telomerase reverse transcriptase (TERT) mutations lead to an aberrant upregulation of TERT expression, and ultimately allow telomere maintenance, thus supporting immortalization of cancer cells. This study aimed to investigate whether the TERT mutation is a potential predictor of ICI treatment across all cancer types. TERT mutations positively correlated with a higher tumor mutational burden (TMB) value, neoantigen load, and tumor purity. Lymphocyte infiltration, macrophage regulation, interferon‐gamma (IFN‐γ) response, and transforming growth factor‐β (TGF‐β) response which was representative immune‐expression signatures, all had higher signature scores in the TERT mutation group. Activated CD4 T cell, naïve B cell, activated dendritic cell, M0 macrophage, M1 macrophage, neutrophil, resting NK cell, and plasma cells all had relatively higher immune scores in the TERT mutation group, whereas Th series cells, memory B cell, resting mast cells, monocytes, and activated NK cells had lower immune scores. Notably, in the subgroup analysis of monotherapy and combination ICI treatment, only in the anti‐cytotoxic‐T‐lymphocyte‐associated antigen 4 (anti‐CTLA4) group, patients with TERT mutations had a better prognosis, especially for melanoma. Therefore, TERT mutations were closely related to a higher TMB value and unique tumor microenvironment, which may be the reason that TERT mutations may be a potential biomarker for anti‐CTLA4 treatment.

Keywords

• anti‐CTLA4 treatment
• immune cells infiltration
• melanoma
• TERT mutation
• TMB