Hepatocellular carcinoma (HCC) is the second cause of death for cancer worldwide, justifying the urgent need for novel therapeutic approaches. Immunotherapeutic strategies based on triggering and/or rescuing tumor antigen-specific T cells may be promising particularly if combined together. As preliminary step toward this goal, we have investigated the expression of antigen presenting molecules (HLA class I and class II) and immune checkpoints (PD-1 and PD-L1) in 43 HCC samples from distinct patients and in HCC cell lines. While normal hepatocytes did not express HLA class I and II, HCC cells strongly upregulated HLA class I while remaining negative for HLA class II. The absence of HLA class II expression in HCC cell lines correlated with lack of expression of the HLA class II transactivator, CIITA, which could not be rescued even after interferon-gamma treatment. This was due to high methylation levels of interferon-gamma-sensitive CIITA promoter IV strongly suggesting a biologically relevant developmental silencing of HLA-II expression in liver cell lineage. HCC tumor tissues showed a variable degree of leukocyte infiltration. Infiltrating lymphocytes expressed PD-1, while PD-L1 was expressed in cells with monocyte-macrophage morphology mostly localized at the tumor margin, but not in tumor cells. De novo expression of HLA class I, instrumental for presenting tumor antigens to cytotoxic T lymphocytes, and the correct characterization of the cells expressing checkpoint inhibitors in the tumor tissue should be the ground for setting novel strategies of combined approaches of immunotherapy in HCC based on tumor peptide vaccines and anti-checkpoint inhibitor antibodies.

中文翻译：

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CIITA相关的HLA II类表达阻滞，HLA I类上调以及免疫检查点在肝癌中的异质表达：对新治疗方法的影响。

肝细胞癌（HCC）是全球范围内导致癌症死亡的第二大原因，这证明了迫切需要新颖的治疗方法。基于触发和/或抢救肿瘤抗原特异性T细胞的免疫治疗策略可能很有希望，特别是将它们组合在一起时。作为朝着这个目标迈进的第一步，我们研究了抗原呈递分子（HLA I类和II类）和免疫检查点（PD-1和PD-L1）在来自不同患者和HCC细胞系的43个HCC样品中的表达。正常肝细胞不表达HLA I类和II类，而HCC细胞则强烈上调HLA I类，而HLA II类仍为阴性。HCC细胞系中HLA II类表达的缺失与HLA II类反式激活因子CIITA的表达缺失有关 即使经过γ-干扰素治疗也无法挽救。这是由于干扰素-γ敏感的CIITA启动子IV的甲基化水平很高，强烈暗示了肝细胞谱系中HLA-II表达的生物学相关的发育沉默。HCC肿瘤组织显示出不同程度的白细胞浸润。浸润的淋巴细胞表达PD-1，而PD-L1在单核巨噬细胞形态的细胞中表达，大多数位于肿瘤边缘，但在肿瘤细胞中不表达。从头表达HLA I类，有助于将肿瘤抗原呈递给细胞毒性T淋巴细胞，