Tert Mutations Correlate With Higher Tmb Value And Unique Tumor Microenvironment And May Be A Potential Biomarker For Anti-Ctla4 Treatment

Immune checkpoint inhibitors (ICIs) have recently changed therapeutic paradigms for patients across multiple cancer types. However, current biomarkers cannot accurately predict responses toICIs. Telomerase reverse transcriptase (TERT) mutations lead to an aberrant upregulation ofTERTexpression, and ultimately allow telomere maintenance, thus supporting immortalization of cancer cells. This study aimed to investigate whether theTERTmutation is a potential predictor ofICItreatment across all cancer types.TERTmutations positively correlated with a higher tumor mutational burden (TMB) value, neoantigen load, and tumor purity. Lymphocyte infiltration, macrophage regulation, interferon-gamma (IFN-gamma) response, and transforming growth factor-beta (TGF-beta) response which was representative immune-expression signatures, all had higher signature scores in theTERTmutation group. ActivatedCD4 Tcell, naiveBcell, activated dendritic cell,M0macrophage,M1macrophage, neutrophil, restingNKcell, and plasma cells all had relatively higher immune scores in theTERTmutation group, whereasThseries cells, memoryBcell, resting mast cells, monocytes, and activatedNKcells had lower immune scores. Notably, in the subgroup analysis of monotherapy and combinationICItreatment, only in the anti-cytotoxic-T-lymphocyte-associated antigen 4 (anti-CTLA4) group, patients withTERTmutations had a better prognosis, especially for melanoma. Therefore,TERTmutations were closely related to a higherTMBvalue and unique tumor microenvironment, which may be the reason thatTERTmutations may be a potential biomarker for anti-CTLA4treatment.