Sex-based differences of the tumor mutational burden and T-cell inflammation of the tumor microenvironment
Authors: F. Conforti, L. Pala, V. Bagnardi, G. Viale, T. De Pas, E. Pagan, R.D. Gelber, A. Goldhirsch
Journal: Annals of Oncology (2019)

It has been recently reported the validation of a new biomarker, with strong predictive value for response to pembrolizumab, based on the tumor mutational burden (TMB) and a gene expression signature of 18 genes (T-cell-inflamed GEP) [1.Cristescu R. Mogg R. Ayers M. et al.Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy.Science. 2018; 362: eaar3593Crossref PubMed Scopus (1101) Google Scholar]. TMB is an indirect measure of tumor antigenicity generated by somatic tumor mutations [2.Gubin M.M. Artyomov M.N. Mardis E.R. Schreiber R.D. Tumor neoantigens: building a framework for personalized cancer immunotherapy.J Clin Invest. 2015; 125: 3413-3421Crossref PubMed Scopus (408) Google Scholar]. T-cell-inflamed GEP signature includes genes indicative of an ongoing Th1 and cytotoxic CD8+ T-cell-driven immune response, including IFN-γ signaling, cytolytic activity, antigen presentation, and T-cell trafficking, as well as adaptive inhibitory molecules such as programmed cell death protein 1 (PD-1)/programmed death-ligand 1 and indoleamine 2,3-dioxygenase 1, that are co-regulated within tumor microenvironment [3.Ayers M. Lunceford J. Nebozhyn M. et al.IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade.J Clin Invest. 2017; 127: 2930-2940Crossref PubMed Scopus (1784) Google Scholar]. Both tumor antigenicity and a T-cell-driven inflammation of the tumor microenvironment are necessary elements to obtain a response to immune-checkpoint inhibitors [4.Chen D. Mellman I. Elements of cancer immunity and the cancer–immune set point.Nature. 2017; 541: 321-330Crossref PubMed Scopus (2616) Google Scholar]. Jointly analyzing these two variables, the new biomarker categorizes tumors in four different groups [(i) GEP low and TMB low, (ii) GEP low and TMB high, (iii) GEP high and TMB low, (iv) GEP high and TMB high], characterized by a different degree of responsiveness to pembrolizumab, regardless of tumor histotype. The predictive value of this new biomarker has been validated in three independent cohorts of patients with 22 different tumor histotypes, treated with pembrolizumab. We previously described that the modality through which women and men with cancer respond to immunotherapies is different, with men obtaining a significantly larger benefit than women from anti-CTLA4 or anti-PD-1 monotherapy compared with chemotherapy, regardless of tumor type [5.Conforti F. Pala L. Bagnardi V. et al.Cancer immunotherapy efficacy and patients' sex: a systematic review and meta-analysis.Lancet Oncol. 2018; 19: 737-746Abstract Full Text Full Text PDF PubMed Scopus (459) Google Scholar]. We therefore re-analyzed available patient-level data, used to validate the new biomarker [1.Cristescu R. Mogg R. Ayers M. et al.Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy.Science. 2018; 362: eaar3593Crossref PubMed Scopus (1101) Google Scholar], according with patients' sex. We found that tumors of male and female patients were differently distributed among the four biomarker-defined groups (Figure 1A). In the whole patient population, the percentage of tumors with low levels of either TMB and GEP score—a condition that strongly predicts for absence of response to pembrolizumab—was nearly double in women as compared with men (GEPlo TMBlo 29% in women versus 15% in men, prevalence ratio 1.9, 95% confidence interval 1.22–2.96). By contrast, the percentage of tumors characterized by high TMB and GEP score—that is associated with a high probability of response to pembrolizumab—was almost halved in women compared with men (GEPhi TMBhi 26% in women versus 42% in male, prevalence ratio 0.61, 95% confidence interval 0.43–0.88). These differences were observed in all the three independent cohorts of patients analyzed to validate the biomarker [1.Cristescu R. Mogg R. Ayers M. et al.Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy.Science. 2018; 362: eaar3593Crossref PubMed Scopus (1101) Google Scholar] (i.e. melanoma, head and neck squamous cell carcinoma and the pan-cancer cohort, that includes 20 different cancer types; P-heterogeneity: 0.47), with the largest difference observed in the cohort of patients with melanoma (Figure 1B). Sex retained a significant association with the biomarker-defined groups after controlling for age and tumor histotype in a logistic multivariable model (P = 0.032). Such large sex-based differences in both TMB and T-cell inflammation of the tumor microenviroment, which are key elements of the anticancer immune-response and are strongly associated with responsiveness to pembrolizumab, further confirm the relevance of sex-dimorphism in spontaneous as well as drug-enhanced anticancer immune responses. Confirmation of the predictive value for response to pembrolizumab of the new biomarker separately in male and female patients would be warranted. None declared.