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

Abstract

Importance: Cytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial 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, setting, and participants: This was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24 650 person-years.

Exposures: Following immunohistochemical analysis, 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 outcomes and measures: Overall survival time.

Results: The final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 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 value for trend = 4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with 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-log-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 that drive infiltration will be the key to unraveling outcome heterogeneity in this cancer.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Bowtell receives funding from Astra Zeneca and Genentech Roche for the conduct of research studies and clinical trials unrelated to the work described in this article. Dr Huntsman is a founder and Chief Medical Officer of Contextual Genomics, a somatic mutation testing laboratory; the company’s work and interests do not overlap with the subject of and methodologies used in this manuscript. No other disclosures were reported.

Figures

Figure. Kaplan-Meier Overall Survival Plots by CD8+ Tumor-Infiltrating Lymphocyte (TIL) Levels for the High-Grade Serous, Endometrioid, and Mucinous Ovarian Cancer

Negative, no CD8+ TILs; low, 1–2 CD8+ TILs; moderate, 3–19 CD8+ TILs; high, 20 or more CD8+ TILs per high-powered field. The numbers just above the x-axis represent the number of women at risk in two year time intervals. Number at risk on date of diagnosis may be smaller than number at risk later due to left truncation of follow-up resulting from delayed study enrollment.