Effects of different immune microenvironment characteristics on effect of immune checkpoint inhibitors in solid tumors with TGFBR2 mutation.

Abstract

e21027 Background: TGFBR2 is a member of the TGF-β receptor family, the protein encoded by it was involved in the regulation of cell proliferation, apoptosis, differentiation and other biological processes. TGFBR2 mutation can affect the occurrence of tumors. previous research showed that the TGF-β signaling pathway suppresses the tumor immune response, so TGFBR2 mutations may lead to tumor resistance to immunotherapy. However, effect of TGFBR2 mutations on ICIs and its correlation with immune microenvironment are rarely explored. Methods: NGS data from an independent cohort (the MSKCC study cohort) of 1661 patients and Chinese clinical dataset (panel on 733-gene) of 35337 patients with pan-cancer to explore the association between PTCH1 mutations and immune biomarkers. TMB was defined as total number of somatic non-synonymous mutations in coding region. MSI was evaluated by NGS of 500 known MSI loci. PD-L1 expression was evaluated using immunohistochemistry (Dako 22C3). Patients from three independent cohorts (OAK, POPLAR and MSKCC study cohort) and were used to analyze the correlation between PTCH1 mutations and the efficacy of immune checkpoint blockade immunotherapies (ICIs). Estimation of immune filtration cells scores were conducted via TIMER2.0 (http://timer.cistrome.org/). Results: In Chinese cohort, there were 831 (4.32%) patients harboured TGFBR2 mutation ( TGFBR2mut), in which the most number patients with TGFBR2mut were gastric carcinoma (10.53%), followed by colorectal (8.63%) and NSCLC (2.98%). Same as the MSKCC cohort (2.77%). For the TMB, both Chinese (median, 28.64 Muts/Mb vs 8.39 Muts/Mb, P ＜0.001) and MSKCC (median, 28.53 Muts/Mb vs 6.89 Muts/Mb, P = 0.030) cohort were associated with higher TMB than the wild-type. Supplemental analysis of MSI in the Chinese cohort showed significant differences between the TGFBR2mut and TGFBR2wt groups (P ＜0.001), but not on PD-L1 levels (P = 0.50). In terms of prognostic effect with ICIs therapy, TGFBR2mut were significantly associated with the overall survival (OS) of NSCLC (median, 2 months vs 11 months; HR = 3.46; 95% CI, 1.63-7.35; P ＜0.001) in OAK and POPLAR cohort, same as MSKCC cohort (median, 3 months vs 10 months; HR = 2.21; 95% CI, 1.04-4.71; P = 0.034). Interestingly, In the MSKCC cohort, opposite with NSCLC, majority tumors with TGFBR2mut had a longer survival value, showing a trend toward longer survival. Exploring the correlation between TGFBR2 and immune microenvironment. The results showed NK cell (P = 0.042) and CD4+ T cell (P = 0.036) infiltration were significantly negatively correlated in NSCLC. However, other solid tumors such as colorectal and melanoma are opposite. Conclusions: The results showed that the TGFBR2 had a high correlation in solid tumors with TMB and MSI. The TGFBR2 might a potential biomarker for ICIs therapy in NSCLC, and the immune microenvironment may be a factor affecting of it.