CD137+ Tumor Infiltrating Lymphocytes Correlate With OS in Ovarian Cancer, Study Finds

A higher percentage of CD3+ CD137+ tumor infiltrating lymphocytes (TILs) was associated with improved overall survival (OS) among patients with ovarian cancer, according to a study published in Gynecologic Oncology.

Biomarkers for outcomes are limited for ovarian cancer, which is the leading cause of death from gynecologic malignancy in the US, and data using immunohistochemical (IHC) analysis have been mixed on whether TILs affect survival. However, IHC does not sufficiently quantify rare cell populations such as CD137+ tumor-reactive TILs, the authors noted. In past research, CD137 been identified as a marker of tumor-specific effector T cells found in ovarian cancer specimens, and it correlated with better outcomes after treatment with immune checkpoint blockades in other malignancies.

“IHC studies staining for [CD3+ and CD8+ TILs] do not distinguish between activated and exhausted TILs, which may contribute to the disparate outcomes in previous studies,” the authors wrote. “More so, the presence of TILs alone, detected by IHC, does not indicate the quality of TILs present in the tumor, such as the proportion of active, tumor-reactive TILs.”

AI image of microscope looking at ovarian cancer cells | Image credit: Justlight - stock.adobe.com

The new study aimed to determine whether a higher percentage of CD3+ CD137+ TILs is indicative of improved OS in ovarian cancer by performing flow cytometry on deidentified samples from the Penn Ovarian Cancer Research Center's Tumor BioTrust Collection. Viably frozen ovarian cancer tumor samples collected from patients who underwent cytoreductive surgeries at the Hospital of University of Pennsylvania and Pennsylvania Hospital were used in the analysis, with tissue samples collected between June 2008 and February 2018. Then, chart review and statistical analyses were conducted to determine associations between CD137+ TILs and OS.

Samples from 47 patients with pathologically confirmed ovarian cancer were included in the study, 40 of whom had high-grade serous ovarian carcinoma (HGSOC), papillary serous carcinoma, or undifferentiated histology. Subjects were 18 to 93 years of age, with a median age of 60 years at diagnosis, and 83% self-reported White race, 10.6% Black, and 6.4% “other.” Most tumors were HGSOC (72.2%), 12.8% were moderately/poorly differentiated, 4.3% were low-grade serous, and 4.3% were clear cell carcinoma. The majority (85.1%) of patients were diagnosed with stage III or IV disease, and most samples were collected at tumor resection prior to chemotherapy.

In those with high-grade ovarian cancer (n = 40), an increased proportion of CD3+ CD137+ TILs correlated with favorable OS outcomes (r = 0.48; P = .0016). However, the proportions of CD3+ or CD3+ CD8+ TILs did not show significant associations with OS.

“Patients diagnosed with OC usually have HGSOC, whereas other histologies, including low-grade serous, clear cell, malignant Brenner tumor, and small cell carcinoma are considered by the National Comprehensive Cancer Network to be less common and have different clinical outcomes and treatment strategies,” the authors explained. “For this reason, we initially evaluated the clinically comparable papillary serous, high-grade serous, and undifferentiated OC subject group, referred to as the high-grade cohort, to determine if TILs and CD137+ TIL subsets were predictive of clinical response.”

When stratified into CD3+ CD137+ TIL high and low groups based on median, those with tumors showing high CD3+ CD137+ TIL levels (defined as > 9.6%) experienced longer OS vs those with lower proportions of CD3+ CD137+ TILs (Wilcoxon rank-sum test; P = .0032), as well as improved OS (log rank test; P = .007). Among those with high CD3+ CD137+ TILs, median OS was significantly longer compared with patients whose tumors had low CD3+ CD137+ TILs (49.2 vs 28.9 months; P = .0032).

Further, the researchers found that CD3+ CD137+ TILs were predictive of OS irrespective of germline mutation or debulking status. High CD3+ CD137+ TILs remained correlated with improved survival in those carrying germline mutations, and the association was statistically significant in the group that was negative for mutations (r = 0.56; P = .02). An increased proportion of CD3+ CD137+ TILs was also correlated with survival whether debulking was optimal or suboptimal, although only statistically significantly associated when debulking was optimal (r = 0.56; P = .0029).

The study was limited by a small population, although the authors used the Kaplan-Meier Plotter to validate the findings in a cohort of 1207 subjects from The Cancer Genome Atlas program and other large data sets. Further studies with increased participant diversity are also warranted, the authors noted.

“Overall, this is the first study correlating CD137+ TILs and improved survival in ovarian cancer. Subjects with high CD137+ TILs had increased OS regardless of tumor histology, mutational status, age of diagnosis, and in those with high-grade disease diagnosed at late-stage, regardless of treatment with PARP [inhibitors],” the authors concluded. “…Next steps for clinical application of these findings include validation in a larger dataset and exploration of how CD137+ TILs impact response to cancer treatment including immunotherapy in ovarian cancer.”

Reference

Tubridy EA, Eiva MA, Liu F, et al. CD137+ tumor infiltrating lymphocytes predicts ovarian cancer survival. Gynecol Oncol. Published online January 29, 2024. doi:10.1016/j.ygyno.2024.01.029