Dose-Response Association of CD8⁺ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer

Abstract

Importance Cytotoxic CD8+ T lymphocytes (TILs) participate in immune control of ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors. Objective To define the prognostic role of CD8+ TILs in epithelial ovarian cancer. Design Prospective survival cohort. Setting Multi-center observational. Participants Over 5,500 patients, including 3,196 high-grade serous ovarian carcinomas (HGSOCs), followed prospectively for over 24,650 person-years. Exposure(s) Following immunohistochemistry, CD8+ TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+ TILs per high-powered field: negative (none), low (1–2), moderate (3–19), and high (≥20). CD8+ TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines. Main Outcome Measure(s) Overall survival time. Results Among the five major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (p-trend=4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+ TIL counts showed a near linear functional form. Conclusions and Relevance This study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+ TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors which drive infiltration will be key to unravelling outcome heterogeneity in this cancer.

Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study

“…Most of these patients also participated in previous OTTA studies 18, 19, 20, and all studies received ethics board approval for tumor profiling. TMAs were constructed containing 1–6 cores of 0.6–1.0 mm in diameter from formalin‐fixed paraffin embedded tissue representing tumor from each patient.…”

Adoptive cell transfer using autologous tumor infiltrating lymphocytes in gynecologic malignancies

“…Overall survival (OS) was similarly improved in patients with TILs at 50.3 months vs. 18 months in patients without TILs. Other studies confirmed these findings and showed that the presence of CD8+ TILs in high-grade serous ovarian cancer was significantly associated with improved survival [14], with a dose response relationship and a median survival of 2.8 years in patients with low CD8+ TIL infiltration vs. 5.1 years in patients with high CD8+ TIL infiltration [55]. It has also been observed that ovarian cancer patients with a higher mutational burden have an improved treatment response, PFS and OS [56].…”

Immunotherapies based on PD-1/PD-L1 pathway inhibitors in ovarian cancer treatment

“…Some authors have demonstrated that a high ratio of CD8 + /forkhead box protein 3 (FoxP3 + ) regulatory T cells is a positive prognostic factor in OC patients . Others have shown that a higher number of CD8 + TILs predicts prolonged survival of patients with high‐grade ovarian cancer (HGSOC) . Additional studies show that CD8 + T cells co‐expressing the specific marker CD103 localized in OC epithelium are strongly associated with increased survival rates .…”