AUTHOR=Patel Mickey V. , Shen Zheng , Rodriguez-Garcia Marta , Usherwood Edward J. , Tafe Laura J. , Wira Charles R. TITLE=Endometrial Cancer Suppresses CD8+ T Cell-Mediated Cytotoxicity in Postmenopausal Women JOURNAL=Frontiers in Immunology VOLUME=12 YEAR=2021 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.657326 DOI=10.3389/fimmu.2021.657326 ISSN=1664-3224 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.