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

Na Qiu; Akshaya Srikanth; Medhanie Mulaw; Umesh Tharehalli; Shanthiya Selvachandran; Martin Wagner; Thomas Seufferlein; Katja Stifter; André Lechel; Reinhold Schirmbeck

doi:10.1080/2162402X.2023.2215096

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

Oncoimmunology. 2023 May 26;12(1):2215096. doi: 10.1080/2162402X.2023.2215096. eCollection 2023.

Authors

Affiliations

¹ Department of Internal Medicine I, University Hospital of Ulm, Ulm, Germany.
² Unit for single-cell Genomics, Medical Faculty, Ulm University, Ulm, Germany.
³ Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands.
⁴ The first Clinical College, Xuzhou Medical University, Xuzhou, Jiangsu, China.

Abstract

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.

Keywords: CD8 T cells; ER-stress; HBV surface antigen; immune escape variants; liver carcinoma; tg mice.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD8-Positive T-Lymphocytes
Carcinoma*
Cell Line
Hepatitis B virus / genetics
Hepatitis B, Chronic* / genetics
Liver Neoplasms* / genetics
Mice
Programmed Cell Death 1 Receptor

Substances

Programmed Cell Death 1 Receptor

Grants and funding

This work was supported by a grant from the Deutsche Forschungsgemeinschaft: Graduiertenkolleg (GRK) 2254 ’Heterogeneity and Evolution in Solid Tumors (HEIST)´ to A.L. and R.S and a grant from the Boehringer Ingelheim Ulm University Biocenter (BIU) to MW, KS and TS. N.Q. is an MD candidate at Ulm University. Her work is submitted in partial fulfillment of the requirement for her MD thesis.