CD137+ tumor infiltrating lymphocytes predicts ovarian cancer survival

• Published in: Gynecologic oncology 2024-05, Vol.184, p.74-82
• Main Authors: Tubridy, Elizabeth A., Eiva, Monika A., Liu, Fang, Omran, Dalia K., Gysler, Stefan, Brown, Erica G., Roy, Allison G., Zeng, Yuyan, Oh, Jinhee, Cao, Quy, Gitto, Sarah B., Powell, Daniel J.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; CD137; CD3 Complex - analysis; Cystadenocarcinoma, Serous - immunology; Cystadenocarcinoma, Serous - mortality; Cystadenocarcinoma, Serous - pathology; Female; Humans; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - pathology; Middle Aged; Ovarian cancer; Ovarian Neoplasms - immunology; Ovarian Neoplasms - mortality; Ovarian Neoplasms - pathology; TILs; Tumor infiltrating lymphocytes; Tumor Necrosis Factor Receptor Superfamily, Member 9 - analysis; Tumor Necrosis Factor Receptor Superfamily, Member 9 - immunology; Tumor Necrosis Factor Receptor Superfamily, Member 9 - metabolism
• ISSN: 0090-8258; 1095-6859; 1095-6859
• DOI: 10.1016/j.ygyno.2024.01.029

Ovarian cancer (OC) is the leading cause of death from gynecologic malignancy in the United States, and biomarkers of patient outcomes are limited. Data using immunohistochemical (IHC) analysis are mixed regarding whether and which tumor infiltrating lymphocytes (TILs) impact survival, and IHC does not adequately quantify rare cell populations, including CD137+ (4-1BB) tumor-reactive TILs. Our study investigates if a higher percentage of CD3+ CD137+ TILs is associated with improved overall survival (OS) in OC. Flow cytometry was performed on viably banked OC digests. Chart review and statistical analysis were performed. Forty-seven patients were included, 40 of whom were diagnosed with high-grade serous ovarian carcinoma (HGSOC), papillary serous carcinoma, or undifferentiated histology. A high percentage of CD3+ CD137+ TILs correlated with improved OS (n = 40, r = 0.48, P = 0.0016). Subjects were divided into CD3+ CD137+ TIL high and low groups by the median. Subjects with high CD3+CD137+ TIL frequencies (>9.6%) had longer OS (Wilcoxon rank-sum test; P = 0.0032) and improved OS (logrank test; P = 0.007). Differences in CD3+ or CD3+ CD8+ TILs did not impact survival. CD3+ CD137+ TILs were predictive of OS regardless of germline mutation or debulking status. Analysis of subgroups including late stage HGSOC and late stage HGSOC with primary optimal cytoreduction indicated CD3+ CD137+ TILs correlated with improved OS after adjusting for age and PARP inhibitor use (P = 0.034 and P = 0.016, respectively). Prevalence of CD3+ CD137+ TILs in digested OC specimens is associated with improved OS, while general TIL markers are not. CD137 has the potential to be a novel biomarker for survival in OC. •Subjects with a higher proportion of CD3+ CD137+ TILs present in their ovarian tumor samples had increased overall survival.•In subjects with stage IIIC+ HGSOC, CD3+ CD137+ TILs and survival were correlated regardless of age or PARP inhibitor use.•CD3+ TILs and CD3+ CD8+ TILs were not associated with overall survival.