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

IF 7.2 2区医学 Oncoimmunology Pub Date : 2023-01-01 DOI:10.1080/2162402X.2023.2215096

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

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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.

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CD8 T细胞介导的表达HBV表面抗原的双线性分化肝癌细胞的耗竭产生高度侵袭性的逃逸变体。

慢性乙型肝炎病毒(HBV)感染中病毒抗原的表达导致肝脏持续炎症，是发生肝癌的主要危险因素之一。HBV具有免疫抑制功能以逃避宿主免疫系统，但其与肝脏肿瘤发展的关系尚不清楚。在这里，我们分析了HBV表面抗原(HBs)在合并肝细胞-胆管癌(cHCC/iCCA)细胞中的表达是否以及如何影响其对CD8 T细胞的抗原性。我们从AlfpCre+-Trp53fl/fl/Alb-HBs+ tg小鼠中随机分离肝脏肿瘤组织，建立了双系(CK7+/HNF4α+) cHCC/iCCA表型的原发性肝癌细胞系(pCCL)。这些pCCL一致表达HBs (HBshi)和低水平MHC-I (MHC-Ilo)，并在IFN-γ处理下瞬间转化为高抗原性(MHC-Ihi)表型。HBshi/pCCL诱导HBs/(Kb/S190-197)特异性CD8 T细胞在皮下移植的C57Bl/6J (B6)小鼠中形成缓慢生长的肿瘤。有趣的是，从HBshi/ pccl诱导的B6和重新移植的肿瘤中建立的pCCL-ex细胞在免疫缺陷的Rag1-/-小鼠中没有显示出主要的改变，如MHC-Ihi表型，突出的生长偏倚基因表达特征，HBs表达显著降低(HBslo)，以及在重新移植的B6或PD-1-/-宿主中切换到快速生长的肿瘤，具有未锁定的PD-1/PD-L1控制系统。CD8 T细胞介导的HBshi/pCCL的消除，以及肿瘤细胞中hbbs的负性约束(如er应激)的衰减，揭示了释放高侵袭性HBslo/pCCL-ex免疫逃逸变体的新机制。在某些条件下，hbs特异性CD8 t细胞反应因此增强肿瘤生长，这是针对慢性HBV感染和肝肿瘤的治疗性疫苗接种策略应考虑的一个方面。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Oncoimmunology ONCOLOGY-IMMUNOLOGY

CiteScore

12.80

自引率

2.80%

发文量

276

期刊介绍： Tumor immunology explores the natural and therapy-induced recognition of cancers, along with the complex interplay between oncogenesis, inflammation, and immunosurveillance. In response to recent advancements, a new journal, OncoImmunology, is being launched to specifically address tumor immunology. The field has seen significant progress with the clinical demonstration and FDA approval of anticancer immunotherapies. There's also growing evidence suggesting that many current chemotherapeutic agents rely on immune effectors for their efficacy. While oncologists have historically utilized chemotherapeutic and radiotherapeutic regimens successfully, they may have unwittingly leveraged the immune system's ability to recognize tumor-specific antigens and control cancer growth. Consequently, immunological biomarkers are increasingly crucial for cancer prognosis and predicting chemotherapy efficacy. There's strong support for combining conventional anticancer therapies with immunotherapies. OncoImmunology will welcome high-profile submissions spanning fundamental, translational, and clinical aspects of tumor immunology, including solid and hematological cancers, inflammation, and both innate and acquired immune responses.