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4-1BB co-stimulation further enhances anti-PD-1-mediated reinvigoration of exhausted CD39 + CD8 T cells from primary and metastatic sites of epithelial ovarian cancers

 Galam Leem  ;  Junsik Park  ;  Minwoo Jeon  ;  Eui-Soon Kim  ;  Sang Wun Kim  ;  Yong Jae Lee  ;  Seong Jin Choi  ;  Baekgyu Choi  ;  Seongyeol Park  ;  Young Seok Ju  ;  Inkyung Jung  ;  Sunghoon Kim  ;  Eui-Cheol Shin  ;  Jung Yun Lee  ;  Su-Hyung Park 
 JOURNAL FOR IMMUNOTHERAPY OF CANCER, Vol.8(2) : e001650, 2020-12 
Journal Title
Issue Date
CD8-positive T-lymphocytes ; adaptive immunity ; immunity ; lymphocytes ; tumor-infiltrating
Background: Responses to immunotherapy vary between different cancer types and sites. Here, we aimed to investigate features of exhaustion and activation in tumor-infiltrating CD8 T cells at both the primary and metastatic sites in epithelial ovarian cancer. Methods: Tumor tissues and peripheral blood were obtained from 65 patients with ovarian cancer. From these samples, we isolated tumor-infiltrating lymphocytes (TILs) and peripheral blood mononuclear cells. These cells were used for immunophenotype using multicolor flow cytometry, gene expression profile using RNA sequencing and ex vivo functional restoration assays. Results: We found that CD39+ CD8 TILs were enriched with tumor-specific CD8 TILs, and that the activation status of these cells was determined by the differential programmed cell death protein 1 (PD-1) expression level. CD39+ CD8 TILs with high PD-1 expression (PD-1high) exhibited features of highly tumor-reactive and terminally exhausted phenotypes. Notably, PD-1high CD39+ CD8 TILs showed similar characteristics in terms of T-cell exhaustion and activation between the primary and metastatic sites. Among co-stimulatory receptors, 4-1BB was exclusively overexpressed in CD39+ CD8 TILs, especially on PD-1high cells, and 4-1BB-expressing cells displayed immunophenotypes indicating higher degrees of T-cell activation and proliferation, and less exhaustion, compared with cells not expressing 4-1BB. Importantly, 4-1BB agonistic antibodies further enhanced the anti-PD-1-mediated reinvigoration of exhausted CD8 TILs from both primary and metastatic sites. Conclusion: Severely exhausted PD-1high CD39+ CD8 TILs displayed a distinctly heterogeneous exhaustion and activation status determined by differential 4-1BB expression levels, providing rationale and evidence for immunotherapies targeting co-stimulatory receptor 4-1BB in ovarian cancers.
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1. College of Medicine (의과대학) > Dept. of Obstetrics and Gynecology (산부인과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Sang Wun(김상운) ORCID logo https://orcid.org/0000-0002-8342-8701
Kim, Sung Hoon(김성훈) ORCID logo https://orcid.org/0000-0002-1645-7473
Park, Junsik(박준식)
Lee, Yong Jae(이용재) ORCID logo https://orcid.org/0000-0003-0297-3116
Lee, Jung-Yun(이정윤) ORCID logo https://orcid.org/0000-0001-7948-1350
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