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

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.