The favorable prognostic effect of intraepithelial CD8 ؉ TILs did not correlate with concurrent expression of NY-ESO-1 or MAGE antigens. We conclude that intraepithelial CD8 ؉ TILs and a high CD8 ؉ ͞Treg ratio are associated with favorable prognosis in epithelial ovarian cancer.cancer testis antigen ͉ CD8 ϩ T cell

NY-ESO-1 is a "cancer-testis" antigen frequently expressed in epithelial ovarian cancer (EOC) and is among the most immunogenic tumor antigens defined to date. In an effort to understand in vivo tolerance mechanisms, we assessed the phenotype and function of NY-ESO-1-specific CD8 + T cells derived from peripheral blood lymphocytes (PBLs), tumor-infiltrating lymphocytes (TILs), and tumorassociated lymphocytes (TALs) of EOC patients with NY-ESO-1-expressing tumors, with or without humoral immunity to NY-ESO-1. Whereas NY-ESO-1-specific CD8 + T cells were readily detectable ex vivo with tetramers in TILs and TALs of seropositive patients, they were only detectable in PBLs following in vitro stimulation. Compared with PBLs, tumor-derived NY-ESO-1-specific CD8 + T cells demonstrated impaired effector function, preferential usage of dominant T-cell receptor, and enriched coexpression of inhibitory molecules LAG-3 and PD-1. Expression of LAG-3 and PD-1 on CD8 + T cells was up-regulated by IL-10, IL-6 (cytokines found in tumor ascites), and tumor-derived antigen-presenting cells. Functionally, CD8 + LAG-3 + PD-1 + T cells were more impaired in IFN-γ/TNF-α production compared with LAG-3 + PD-1 − or LAG-3 − PD-1 − subsets. Dual blockade of LAG-3 and PD-1 during T-cell priming efficiently augmented proliferation and cytokine production by NY-ESO-1-specific CD8 + T cells, indicating that antitumor function of NY-ESO-1-specific CD8 + T cells could potentially be improved by therapeutic targeting of these inhibitory receptors.tumor-infiltrating lymphocytes | IL-6 | IL-10 | T cell receptor T he presence of tumor-infiltrating lymphocytes within the tumor microenvironment is considered to be an indication of the host immune response to tumor antigens and is thought to reflect the dynamic process of "cancer immunoediting" (1). In epithelial ovarian cancer (EOC), support for the role of immune surveillance of tumors comes from observations indicating that the presence of intraepithelial CD8 + -infiltrating T lymphocytes in tumors is associated with improved survival of patients with the disease (2). Although several lines of evidence have shown that spontaneous or vaccine-induced tumor-antigen-specific CD8 + T cells can recognize EOC targets (3), prolongation of survival in patients treated with immunization has only rarely been observed. This is probably a reflection of several in vivo immunosuppressive mechanisms in EOC-bearing hosts (4). Therefore, understanding factors that regulate the function(s) of tumor-antigen-specific CD8 + T cells is critical for effective control of tumor recurrence.The NY-ESO-1 tumor antigen is a major target of CD8 + T cell recognition in EOC, eliciting both cellular and humoral immune responses in a proportion of patients with advanced NY-ESO-1-expressing tumors (5). However, similar to infectious disease models, chronic antigenic stimulation may result in exhaustion of antigen-specific CD8 + T cells (6) and loss of ability to produce key cytokines that are critical for the maintenance of CD8 + T ce...