4-1BB Delineates Distinct Activation Status of Exhausted Tumor-Infiltrating CD8 T Cells in Hepatocellular Carcinoma.
Hyung-Don Kim, Seongyeol Park, Seongju Jeong, Yong Joon Lee, Hoyoung Lee, Chang Gon Kim, Kyung Hwan Kim, Seung-Mo Hong, Jung-Yun Lee, Sunghoon Kim, Hong Kwan Kim, Byung Soh Min, Jong Hee Chang, Young Seok Ju, Eui-Cheol Shin, Gi-Won Song, Shin Hwang, Su-Hyung Park
Author Information
Hyung-Don Kim: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
Seongyeol Park: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
Seongju Jeong: Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
Yong Joon Lee: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
Hoyoung Lee: Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
Chang Gon Kim: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
Kyung Hwan Kim: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
Seung-Mo Hong: Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Jung-Yun Lee: Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Sunghoon Kim: Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Hong Kwan Kim: Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Byung Soh Min: Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Jong Hee Chang: Department of Neurosurgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Young Seok Ju: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
Eui-Cheol Shin: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
Gi-Won Song: Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Shin Hwang: Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Su-Hyung Park: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea. ORCID
BACKGROUND AND AIMS: Targeting costimulatory receptors with agonistic antibodies is a promising cancer immunotherapy option. We aimed to investigate costimulatory receptor expression, particularly 4-1BB (CD137 or tumor necrosis factor receptor superfamily member 9), on tumor-infiltrating CD8 T cells (CD8 tumor-infiltrating lymphocytes [TILs]) and its association with distinct T-cell activation features among exhausted CD8 TILs in hepatocellular carcinoma (HCC). APPROACH AND RESULTS: Tumor tissues, adjacent nontumor tissues, and peripheral blood were collected from HCC patients undergoing surgical resection (n = 79). Lymphocytes were isolated and used for multicolor flow cytometry, RNA-sequencing, and in vitro functional restoration assays. Among the examined costimulatory receptors, 4-1BB was most prominently expressed on CD8 TILs. 4-1BB expression was almost exclusively detected on CD8 T cells in the tumor-especially on programmed death 1 (PD-1) cells and not PD-1 and PD-1 cells. Compared to PD-1 and 4-1BB PD-1 CD8 TILs, 4-1BB PD-1 CD8 TILs exhibited higher levels of tumor reactivity and T-cell activation markers and significant enrichment for T-cell activation gene signatures. Per-patient analysis revealed positive correlations between percentages of 4-1BB cells among CD8 TILs and levels of parameters of tumor reactivity and T-cell activation. Among highly exhausted PD-1 CD8 TILs, 4-1BB cells harbored higher proportions of cells with proliferative and reinvigoration potential. Our 4-1BB-related gene signature predicted survival outcomes of HCC patients in the The Cancer Genome Atlas cohort. 4-1BB agonistic antibodies enhanced the function of CD8 TILs and further enhanced the anti-PD-1-mediated reinvigoration of CD8 TILs, especially in cases showing high levels of T-cell activation. CONCLUSION: 4-1BB expression on CD8 TILs represents a distinct activation state among highly exhausted CD8 T cells in HCC. 4-1BB costimulation with agonistic antibodies may be a promising strategy for treating HCCs exhibiting prominent T-cell activation.
