Programmed cell death 1 ligand 1 and tumor-infiltrating CD8⁺T lymphocytes are prognostic factors of human ovarian cancer

Abstract

The ligands for programmed cell death 1 (PD-1), an immunoinhibitory receptor belonging to CD28/cytotoxic T lymphocyte antigen 4 family, are PD-1 ligand 1 and 2 (PD-Ls). Recent reports suggest that the aberrant expression of PD-Ls on tumor cells impairs antitumor immunity, resulting in the immune evasion of the tumor cells. Although an inverse correlation between the expression level of PD-Ls and patients' prognosis has been reported for several malignant tumors, the follow-up period was limited because of the lack of the antibody (Ab) applicable to paraffin-embedded specimens. Here we generated a new Ab against PD-1 ligand 1 (PD-L1) and analyzed the expression level of PD-Ls in human ovarian cancer using paraffin-embedded specimens. Patients with higher expression of PD-L1 had a significantly poorer prognosis than patients with lower expression. Although patients with higher expression of PD-1 ligand 2 also had a poorer prognosis, the difference was not statistically significant. A significant inverse correlation was observed between PD-L1 expression and the intraepithelial CD8 ؉ T lymphocyte count, suggesting that PD-L1 on tumor cells directly suppresses antitumor CD8 ؉ T cells. Multivariate analysis showed the expression of PD-L1 on tumor cells and intraepithelial CD8 ؉ T lymphocyte count are independent prognostic factors. The PD-1/ PD-L pathway can be a good target for restoring antitumor immunity in ovarian cancer.costimulation ͉ tumor immunity ͉ immunohistochemistry

Intraepithelial T cells and prognosis in ovarian carcinoma: novel associations with stage, tumor type, and BRCA1 loss

“…[16][17][18] Like Zhang et al, 10 we demonstrate (in two separate laboratories using independent testing and analysis) that intraepithelial CD3 þ tumor-infiltrating lymphocytes correlate with disease-specific survival in serous ovarian carcinomas. Likewise, we have confirmed the results of two recent studies 9,11 by demonstrating that intraepithelial CD8 þ tumorinfiltrating lymphocytes correlate with disease-specific survival in the entire study cohort (including all stages and histologies), as well as in the subset of serous ovarian carcinomas. We have demonstrated that the best marker of immune infiltration (from the panel of immune markers chosen for this study) is CD8, as it is the only marker to significantly predict outcome on multivariate analysis.…”

“…The prognostic significance of the host immune response, as defined by the presence of tumor-infiltrating lymphocytes, has been studied in ovarian cancer [8][9][10][11] and other cancers [12][13][14][15][16][17][18] Zhang et al 10 identified intratumoral (later named intraepithelial) CD3 þ T-cell infiltration to be an independent prognostic factor in 186 advanced ovarian cancers. Curiel et al 8 demonstrated that infiltration of CD4 þ CD25 þ regulatory T-cells carried a worse prognosis in ovarian cancer.…”

“…More recently, immunohistochemical evaluation of intraepithelial tumor-infiltrating lymphocytes in two cohorts of epithelial ovarian cancer of all cell types and stages showed that cases having a higher frequency of intraepithelial CD8 þ tumor-infiltrating lymphocytes rather than CD3 þ cells had improved survival compared to patients with lower frequencies. 9,11 Therefore, the immune response to ovarian cancer may serve as a novel prognostic marker. However, it remains unknown whether tumor histotype, stage or molecular pathogenesis affect the presence or the predictive value of intraepithelial tumor-infiltrating lymphocytes.…”

Clinicopathologic analysis of programmed cell death-1 and programmed cell death-ligand 1 and 2 expressions in pulmonary adenocarcinoma: comparison with histology and driver oncogenic alteration status

“…Several groups demonstrated that increased CD8 + tumor-infiltrating lymphocytes and even PD-1 + tumor-infiltrating lymphocytes were a favorable prognostic factor in various types of cancers. [45][46][47][48] These studies suggested that increased PD-1 + tumor-infiltrating lymphocytes may reflect a subset of immune cells previously activated by the antitumor immune response, and thereby correlated with a favorable clinical outcome. 48 However, PD-1 + T cells have been regarded as functionally exhausted rather than activated because of chronic and persistent antigenic exposure from either viral infection or the tumor microenvironment, suggesting that the PD-1 + /CD8 + tumor-infiltrating lymphocyte ratio might reflect attenuated cytotoxicity of CD8 + T cells against tumors.…”

The blood mMDSC to DC ratio is a sensitive and easy to assess independent predictive factor for epithelial ovarian cancer survival

“…4 , 5 However, once an anti-tumor response is activated, this correlates with better survival. 6-9 An important part of the battle between tumor cells and the immune system is fought within, but not confined to, the tumor microenvironment. CD8+ T cell infiltration into EOC has a positive effect on chemotherapy response, 7 , 8 while infiltration with suppressive immune cells such as regulatory T cells (Tregs), myeloid derived suppressor cells (MDSC) and M2 macrophages is associated with a lower response to chemotherapy in EOC.…”