Patterns of cytotoxic T-cell densities in immunogenic endometrial cancers reveal a potential mechanism for differences in immunotherapy efficacy

Ryan, Neil and Glaire, Mark and Walker, Thomas and Haar, Natalja ter and Ijsselsteijn, Marieke and Bolton, James and Miranda, Noel de and Evans, Gareth and Church, David N and Bosse, Tjalling and Crosbie, Emma (2024) Patterns of cytotoxic T-cell densities in immunogenic endometrial cancers reveal a potential mechanism for differences in immunotherapy efficacy. BMJ Oncology, 3 (1): e000320. ISSN 2752-7948

Abstract

Objective To explore the impact of molecular subtype in endometrial cancer (EC) on CD8+T cell densities. Furthermore, this work will test the assumption that all mismatch repair deficient (MMRd) tumours are immunologically similar which would enable current trial data to be generalised to all MMRd ECs. Methods and analysis All tumours were characterised into the four clinical molecular subtypes. For analysis, theTP53mutant and no-specific molecular profile tumours were grouped together and described as the low mutational burden (LMB) cohort. CD8+T cell counts were taken from four regions of interest which sampled the tumour-stromal interface and the tumour core. CD8+T cell counts were analysed as mean averages. Results In total, 607 ECs contributed to the analysis. CD8+T cell counts in confirmed Lynch syndrome (LS) ECs were significantly higher thanMLH1-methylated ECs in all tumour locations excluding the tumour stroma. Confirmed LS and path_POLEECs had significantly higher CD8+T cell counts across all tumour locations when compared with LMB ECs. There were limited significant differences in CD8+T cell counts between path_POLEversus confirmed LS ECs. There was no significant difference in the CD8+T cells counts and gene (MLH1,MSH2,MSH6,PMS2) in which the LS pathogenic variant was found; however, this analysis was limited by small numbers. Conclusion These data indicate that CD8+T cell numbers and distribution is not equal betweenMLH1-methylated and confirmed LS ECs. This is relevant when interpreting current trial data looking to the application of checkpoint inhibition treatments in MMRd cancers.