• [Journal for ImmunoTherapy of Cancer] Unique immune characteristics and differential anti-PD-1-mediated reinvigoration potentia
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  • 2024-08-05 16:15:01|
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[Title]
Unique immune characteristics and differential anti-PD- 1- mediated reinvigoration potential of CD8+ TILs based on BRCA1/2 mutation status in epithelial ovarian cancers

[Author]

Junsik Park,1,2 Jung Chul Kim,1,2 Yong Jae Lee,1 Sunghoon Kim,1 Sang Wun Kim,1 Eui-Cheol Shin,3 Jung Yun Lee,1 Su-Hyung Park 3

1Department of Obstetrics and Gynecology, Institute of Women’s Life Medical Science, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
2Department of Obstetrics and Gynecology, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea (the Republic of)
3Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea (the Republic of)
Correspondence to Dr Jung Yun Lee; jungyunlee@yuhs.ac; Dr Su-Hyung Park; park3@kaist.ac.kr


[Journal] 

Journal for ImmunoTherapy of Cancer Jul 2024, 12 (7) e009058; DOI: 10.1136/jitc-2024-009058

[Abstract]

Background 
We aimed to investigate the distinct immunological characteristics of the tumor immune microenvironment in epithelial ovarian cancer (EOC) according to BRCA1/2 mutations status and differential PD-1 expression levels.

Methods 
Tumor-infiltrating lymphocytes (TILs) were collected from patients with newly diagnosed advanced-stage EOC (YUHS cohort, n=117). This YUHS cohort was compared with The Cancer Genome Atlas (TCGA) data for ovarian serous cystadenocarcinoma (n=482), in terms of survival outcomes and immune-related gene profiles according to BRCA1/2 status. We used multicolor flow cytometry to characterize the immune phenotypes and heterogeneity of TILs with or without BRCA1/2 mutations. In vitro functional assays were conducted to evaluate the reinvigorating ability of CD8+ TILs on anti-PD-1 treatment.

Results 
We found that EOC patients with BRCA1/2 mutations (BRCA1/2mt) exhibited better survival outcomes and significantly higher tumor mutation burden (TMB), compared with BRCA1/2 non-mutated (BRCA1/2wt) patients. Furthermore, CD8+ TILs within BRCA1/2mt tumors displayed characteristics indicating more severe T-cell exhaustion than their BRCA1/2wt counterparts. Notably, the capacity for anti-PD-1-mediated reinvigoration of CD8+ TILs was significantly greater in BRCA1/2wt tumors compared with BRCA1/2mt tumors. Additionally, within the BRCA1/2wt group, the frequency of PD-1highCD8+ TILs was positively correlated with the reinvigoration capacity of CD8+ TILs after anti-PD-1 treatment.

Conclusion 
Our results highlight unique immune features of CD8+ TILs in EOC and a differential response to anti-PD-1 treatment, contingent on BRCA1/2 mutation status. These findings suggest that immune checkpoint blockade may be a promising frontline therapeutic option for selected BRCA1/2wt EOC patients.

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