CD137+ tumor infiltrating lymphocytes predicts ovarian cancer survival

Elizabeth A Tubridy; Monika A Eiva; Fang Liu; Dalia K Omran; Stefan Gysler; Erica G Brown; Allison G Roy; Yuyan Zeng; Jinhee Oh; Quy Cao; Sarah B Gitto; Daniel J Powell Jr

doi:10.1016/j.ygyno.2024.01.029

CD137+ tumor infiltrating lymphocytes predicts ovarian cancer survival

Gynecol Oncol. 2024 Jan 29:184:74-82. doi: 10.1016/j.ygyno.2024.01.029. Online ahead of print.

Authors

Affiliations

¹ Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
² Department of Pathology and Laboratory Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Ovarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
³ Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁴ Ovarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁵ Department of Pathology and Laboratory Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Gynecology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, China.
⁶ Department of Obstetrics and Gynecology, Pennsylvania Hospital, 800 Spruce Street, Philadelphia, PA 19107, USA.
⁷ Department of Pathology and Laboratory Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁸ Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Ovarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: poda@pennmedicine.upenn.edu.

PMID: 38290413
DOI: 10.1016/j.ygyno.2024.01.029

Abstract

Objective: 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.

Methods: 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.

Results: 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).

Conclusions: 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.

Keywords: CD137; Ovarian cancer; TILs; Tumor infiltrating lymphocytes.