T cell-inflamed phenotype and increased Foxp3 expression in infiltrating T-cells of mismatch-repair deficient endometrial cancers

Mismatch repair-deficient endometrial cancers have a high somatic mutation burden, suggesting that patients with these tumors may benefit from immunotherapy. Elucidating the immune suppressive mechanisms of mismatch repair-deficient endometrial cancers is fundamental to developing future immune-based interventions. This study aimed to determine the immune cell populations associated with mismatch repair-deficient endometrial cancers, especially focusing on targetable regulatory pathways of the immune response. A total of 76 endometrial cancer hysterectomy specimens were evaluated for tumor-infiltrating immune cells by immunohistochemistry. Immune specific markers were used to evaluate each specimen for the number of CD8？+？cytotoxic T lymphocytes, forkhead-box P3 (FoxP3)？+？regulatory T cells, CD68？+？tumor-associated macrophages, as well as programmed death-1 (PD-1)？+？immune cells, and the percentage of programmed death ligand-1 (PD-L1)？+？immune cells. Mismatch repair-deficient tumors exhibited a significantly higher number of CD8？+？cytotoxic T lymphocytes (p？=？0.0006), FoxP3？+？regulatory T cells (p？=？0.0003), PD-1？+？immune cells (p？=？0.0069), and a higher percentage of PD-L1？+？immune cells (p？=？0.0007) occupying the tumor compared to mismatch repair-proficient endometrial cancers. There was no significant difference in CD68？+？tumor-associated macrophages infiltration between the two groups. Endometrial cancers with tumor PD-L1 expression also showed significantly increased infiltration of CD8？+？cytotoxic T lymphocytes (p？=？0.0002), FoxP3？+？regulatory T cells (p？=？0.0003), PD-1？+？immune cells (p？<？0.0001), and PD-L1？+？immune cells (p？<？0.0001). Endometrial cancers showing mismatch repair-deficiency and PD-L1 expression in tumor cells exhibit a prominent T cell-inflamed phenotype. More importantly, the increased number of FoxP3？+？regulatory T cells in mismatch repair-deficient endometrial cancers suggests that combination therapy by targeting both regulatory T cells and immune checkpoints may be warranted to improve clinical efficacy