Endometrial Cancer Suppresses CD8+ T Cell-Mediated Cytotoxicity in Postmenopausal Women
Mickey V. Patel, Zheng Shen, Marta Rodríguez‐García, Edward J. Usherwood, Laura J. Tafe, Charles R. Wira
Abstract
Endometrial cancer is the most common gynecological cancer. To investigate how it suppresses host immune function, we isolated CD8+ T cells from endometrial endometroid carcinomas and adjacent non-cancerous endometrium and determined if the tumor environment regulates cytotoxic capacity. Endometrial carcinomas had increased numbers of CD8+ T cells compared to adjacent non-cancerous endometrium. Tumor CD8+ T cells expressed significantly less granzyme A (GZA), B (GZB), and PD-1 than those in adjacent non-cancerous tissues and also had significantly lower cytotoxic killing of allogeneic target cells. CD103-CD8+ T cells, but not CD103+CD8+ T cells, from both adjacent and tumor tissue were primarily responsible for killing of allogeneic target cells. Secretions recovered from endometrial carcinoma tissues suppressed CD8+ cytotoxic killing and lowered perforin, GZB and PD-1 expression relative to non-tumor CD8+ T cells. Furthermore, tumor secretions contained significantly higher levels of immunosuppressive cytokines including TGFβ than non-tumor tissues. Thus, the tumor microenvironment suppresses cytotoxic killing by CD8+ T cells via the secretion of immunosuppressive cytokines leading to decreased expression of intracellular cytolytic molecules. These studies demonstrate the complexity of CD8+ T cell regulation within the endometrial tumor microenvironment and provide a foundation of information essential for the development of therapeutic strategies for gynecological cancers.