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

Abstract

Intraepithelial tumor-infiltrating T cells have been correlated with improved outcomes in ovarian carcinoma, however, it is not known whether there is an association with disease stage, histological subtype, or BRCA mutation/expression. Two case series of ovarian carcinomas were included in the study; a retrospective series of 500 patients, and 40 prospectively collected cases fully characterized for BRCA1 mutation status and expression. Intraepithelial immune cells were assessed as present or absent by immunohistochemical staining of tissue microarrays. In the retrospective case series, the presence of intraepithelial CD8 þ T-cells correlated with improved disease-specific survival (P ¼ 0.027), whereas intraepithelial CD3 þ T cells did not (P ¼ 0.49). For serous ovarian carcinomas, the presence of intraepithelial CD3 þ and CD8 þ T-cells correlated with improved disease-specific survival (P ¼ 0.0016 and Pr0.0001, respectively). The presence of intraepithelial CD8 þ T cells was not associated with improved survival in endometrioid or clear cell carcinomas. On multivariate analysis, disease stage and CD8 þ T cells were found to be independently predictive of improved disease-specific survival, whereas grade, age at surgery, and type of adjuvant treatment were not. In the prospective patient cohort, intraepithelial CD8 þ T-cells correlated with the presence of mutation or loss of expression of BRCA1 through promoter methylation (P ¼ 0.019). Intraepithelial CD8 þ tumor-infiltrating T-cells correlate with improved clinical outcomes for all stages of ovarian cancer; this association is restricted to the serous ovarian cancer subtype, and is an independent prognostic factor on multivariate analysis. The presence of intraepithelial CD8 þ T cells also significantly correlates with loss of BRCA1. rates to chemotherapy and the demonstrated improvements in median overall survival, fewer than 40% of patients with advanced disease survive to 5 years. 3 Many potential molecular prognostic factors in ovarian cancer have been investigated (eg HER2, TP53). 4 Most factors were identified in small studies and have not been reproduced or independently validated, precluding clinical utility. In addition, mutations of the BRCA1 and 2 tumor suppressor genes have been associated with improved clinical outcomes 5-7 but the biologic mechanisms underlying these findings are not well understood to date.The prognostic significance of the host immune response, as defined by the presence of tumor-infiltrating lymphocytes, has been studied in ovarian

BRCA1 and BRCA2 mutations correlate with TP53 abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma

“…These markers were not associated with improved outcomes in our relatively small cohort of highgrade serous carcinomas but other series with greater case numbers have consistently demonstrated immune cell infiltrates to be a favorable prognostic factor. 18,19,22,24,59 TP53 abnormalities (loss of expression, which correlates with nonsense mutations or deletions, or overexpression, which correlates with missense mutations) were essentially ubiquitous in high-grade serous cancers with BRCA1 or BRCA2 abnormalities and also were associated with favorable outcome. Thus BRCA mutations, immune cell infiltrates, and TP53 abnormalities co-vary in high-grade serous carcinomas.…”

“…16,17 Tumors from women with high-grade serous cancers frequently show a host immune response, and the presence of cytotoxic T lymphocytes, and T-regulatory cells is consistently associated with favorable prognosis. [18][19][20][21][22][23][24] Germline mutations in BRCA1 and BRCA2 are present in B18% of ovarian cancer patients with high-grade serous carcinoma. [25][26][27] When combined with BRCA deficiencies that result from somatic mutations or epigenetic silencing, it appears that up to half of all high-grade serous ovarian cancers (hereditary and sporadic) have BRCA dysfunction.…”

PD-1 and CD103 Are Widely Coexpressed on Prognostically Favorable Intraepithelial CD8 T Cells in Human Ovarian Cancer

“…Moreover, TIL are often abundant in late-stage tumors yet have obviously failed to prevent tumor progression (15)(16)(17)(18)(19). Together, these features suggest that TIL in ovarian cancer may have experienced prolonged exposure to their cognate antigen and, as a consequence, may be functionally exhausted.…”

The clinicopathological significance of Bax and Bcl-2 protein expression with tumor infiltrating lymphocytes in ovarian carcinoma

“…Tumor-infiltrating lymphocytes (TILs) occur as a host response to several types of human carcinomas [7]. Several studies have evaluated the impact of T-lymphocyte infiltration on prognosis in ovarian cancer [8][9][10][11][12][13]. The presence of TILs (especially CD8+ subtype) appear to confer a survival advantage in some of these studies [8,[11][12][13].…”

“…Several studies have evaluated the impact of T-lymphocyte infiltration on prognosis in ovarian cancer [8][9][10][11][12][13]. The presence of TILs (especially CD8+ subtype) appear to confer a survival advantage in some of these studies [8,[11][12][13]. The aim of presented study was to investigate the effects of Bax and Bcl-2 protein expression and the presence of TILs on survival and response to chemotherapy and to determine their correlation with clinicopathological features in primary epithelial ovarian carcinoma. )]…”