title: Follicular helper T cell exhaustion induced by PD-L1 expression in hepatocellular carcinoma results in impaired cytokine expression and B cell help, and is associated with advanced tumor stages.
abstract: Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is one of the most common cancers in HBV-endemic regions, with irreversible progression and poor prognosis. HBV-related HCC patients lack effective antiviral/antitumor B cell antibody responses. We hypothesize that dysregulation of PD-1-expressing follicular helper T (Tfh) cell, induced by intrahepatic/intratumoral PD-L1 expression in HCC, could contribute to the defects in B cell immunity. The Tfh responses in healthy control (HC) subjects, chronic hepatitis B (HepB) patients, and HBV-related HCC patients were examined. Compared to HC and HepB individuals, HCC patients showed reduced ICOS expression, IL-10 and IL-21 secretion, and proliferation in Tfh cells. Tfh cells from stage III patients demonstrated increased impairment than those from stage I and stage II patients. Compared to Tfh cells from HC and HepB subjects, those from stage III HCC patients were significantly less effective at inducing the differentiation of naive B cells toward plasmablasts. HCC is known to upregulate hepatic PD-L1 expression, which could suppress Tfh responses. Blocking PD-1 partially rescued the Tfh functions in stage I and stage II HCC subjects but not in stage III HCC patients, while treatment with recombinant PD-L1 strongly suppressed Tfh functions in all HCC stages. Moreover, the level of IL-10 and IL-21 expression by Tfh cells was inversely correlated with the intensity of PD-L1 expression in resected tumors. Together, our results demonstrated an HCC-specific Tfh exhaustion, which might have resulted from elevated PD-1 and PD-L1 signaling.
authors: Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital Shanghai, China.
authors: Zun-Qiang
authors: ZQ
authors: Zhou
authors: Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital Shanghai, China.
authors: Da-Nian
authors: DN
authors: Tong
authors: Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital Shanghai, China.
authors: Jiao
authors: J
authors: Guan
authors: Beijing General Hospital Bejing, China.
authors: Hung-Wu
authors: HW
authors: Tan
authors: Beijing General Hospital Bejing, China.
authors: Lu-Don
authors: LD
authors: Zhao
authors: Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital Shanghai, China.
authors: Ying
authors: Y
authors: Zhu
authors: Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital Shanghai, China.
authors: Jing
authors: J
authors: Yao
authors: Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital Shanghai, China.
authors: Jun
authors: J
authors: Yang
authors: Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital Shanghai, China.
authors: Zheng-Yun
authors: ZY
authors: Zhang
keywords: Follicular helper T cells; PD-L1; hepatocellular carcinoma