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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 Parrk 
 HEPATOLOGY, Vol.71(3) : 955-971, 2020 
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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)high cells and not PD-1int and PD-1neg cells. Compared to PD-1int and 4-1BBneg PD-1high CD8+ TILs, 4-1BBpos PD-1high 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 4-1BBpos cells among CD8+ TILs and levels of parameters of tumor reactivity and T-cell activation. Among highly exhausted PD-1high CD8+ TILs, 4-1BBpos 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.
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1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Obstetrics and Gynecology (산부인과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Sung Hoon(김성훈) ORCID logo https://orcid.org/0000-0002-1645-7473
Min, Byung Soh(민병소) ORCID logo https://orcid.org/0000-0003-0180-8565
Lee, Jung-Yun(이정윤) ORCID logo https://orcid.org/0000-0001-7948-1350
Chang, Jong Hee(장종희) ORCID logo https://orcid.org/0000-0003-1509-9800
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