CD8 T cell-mediated depletion of HBV surface-antigen-expressing, bilineal-differentiated liver carcinoma cells generates highly aggressive escape variants

The expression of viral antigens in chronic hepatitis B virus (HBV) infection drives continuous liver inflammation, one of the main risk factors to develop liver cancer. HBV developed immune-suppressive functions to escape from the host immune system, but their link to liver tumor development is not well understood. Here, we analyzed if and how HBV surface antigen (HBs) expression in combined hepatocellular-cholangiocarcinoma (cHCC/iCCA) cells influences their antigenicity for CD8 T cells. We randomly isolated liver tumor tissues from AlfpCre(+)-Trp53(fl/fl)/Alb-HBs(+) tg mice and established primary carcinoma cell lines (pCCL) that showed a bilineal (CK7(+)/HNF4α(+)) cHCC/iCCA phenotype. These pCCL uniformly expressed HBs (HBs(hi)), and low levels of MHC-I (MHC-I(lo)), and were transiently convertible to a high antigenicity (MHC-I(hi)) phenotype by IFN-γ treatment. HBs(hi)/pCCL induced HBs/(K(b)/S(190–197))-specific CD8 T cells and developed slow-growing tumors in subcutaneously transplanted C57Bl/6J (B6) mice. Interestingly, pCCL-ex cells, established from HBs(hi)/pCCL-induced and re-explanted tumors in B6 but not those in immune-deficient Rag1(−/−) mice showed major alterations, like an MHC-I(hi) phenotype, a prominent growth-biased gene expression signature, a significantly decreased HBs expression (HBs(lo)) and a switch to fast-growing tumors in re-transplanted B6 or PD-1(−/−) hosts with an unlocked PD-1/PD-L1 control system. CD8 T cell-mediated elimination of HBs(hi)/pCCL, together with the attenuation of the negative restraints of HBs in the tumor cells, like ER-stress, reveals a novel mechanism to unleash highly aggressive HBs(lo)/pCCL-ex immune-escape variants. Under certain conditions, HBs-specific CD8 T-cell responses thus potentiate tumor growth, an aspect that should be considered for therapeutic vaccination strategies against chronic HBV infection and liver tumors.