The protective role of γδ T cells in endometrial cancer

Γδ T cells are non-conventional T cells that are not MHC restricted and have T cell receptors (TCRs) that are stimulated by phosphoantigens, stress-induced proteins, lipids, and other antigens. These cells are prognostic across cancer types in The Cancer Genome Atlas (TCGA) but have not been well studied in endometrial cancer, which has a rising incidence and mortality rate. Endometrial cancer patients have variable responses to checkpoint inhibitors which are related to the molecular subtype of their cancer. As such, there is a pressing need to understand the immune microenvironment in endometrial cancer. This study addresses this gap in knowledge by investigating γδ T cell repertoires and transcriptomes in this disease site. γδ T cell repertoires were obtained for 543 endometrial cancer patients within the TCGA and from 5 endometrial cancer patients in the single cell dataset SRP349751 using TRUST4. GLIPH2 was used to identify TCRs predicted to bind the same antigen. Transcriptomes were investigated in the single cell dataset. DNA Polymerase Epsilon Exonuclease (POLE) and Microsatellite Instability High (MSI-H) endometrial cancer subtypes had the most γδ T cell infiltration. Vδ1 and Vδ3 γδ T cell infiltration was prognostic independent of stage and molecular subtype. GLIPH2 analysis revealed TCRδ motifs for TDK, YTD, and GEL were public across all four molecular subtypes and were present in the single cell data set. Vδ1 γδ T cell transcriptomes were associated with cytotoxicity and recent TCR stimulation. These data support further investigation of immunotherapies targeting γδ T cells in endometrial cancer.