Apoptosis, Pyroptosis, and Ferroptosis Conspiringly Induce Immunosuppressive Hepatocellular Carcinoma Microenvironment and γδ T-Cell Imbalance.
Apoptosis, Pyroptosis, and Ferroptosis Conspiringly Induce Immunosuppressive Hepatocellular Carcinoma Microenvironment and γδ T-Cell Imbalance.
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DOI：
10.3389/fimmu.2022.845974
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发表时间：
2022
影响因子：
7.3
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中科院分区：
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肝细胞癌（HCC）是一种高度恶性的肿瘤，由于肿瘤微环境（TME）的异质性和免疫抑制性，容易发生转移。程序性细胞死亡（PCD）包括细胞凋亡、铁凋亡和焦凋亡通常发生在HCC TME中，并参与肿瘤发生。然而，如何凋亡，ferroptosis，pyroptosis参与的免疫抑制TME的建设和他们的潜在的串扰仍有待进一步揭示。在这项工作中，我们破译了HCC TME的免疫抑制景观，其表现出抑制性检查点分子的高表达和促肿瘤免疫细胞的浸润，但抗肿瘤效应免疫细胞的浸润较低。进一步的研究明确显示，细胞凋亡，ferroptosis和pyroptosis的标记基因与抑制性检查点分子和免疫细胞的表达和浸润密切相关，并且较高的“-optosis”与较差的患者预后相关。值得注意的是，这三种类型的“-optosis”在基因和蛋白质水平上相互作用，表明它们合谋诱导免疫抑制性HCC TME的建立。有趣的是，HCC患者中循环γδ T细胞的检查揭示了明显的功能障碍表型。Vδ1+/V δ2+比值的显著升高提示Vδ1+/Vδ2+比值可能是HCC诊断和预后的一个潜在生物标志物。总之，本研究彻底揭示了细胞凋亡、铁凋亡和焦凋亡与免疫抑制性HCC TME形成之间的潜在关系，同时表明同种异体Vδ2+ γδ T细胞转移将是一种有前途的辅助策略，可使循环γδ T细胞重新正常化，从而获得良好的抗HCC临床疗效。
Hepatocellular carcinoma (HCC) is highly malignant and prone to metastasize due to the heterogeneous and immunosuppressive tumor microenvironment (TME). Programmed cell deaths (PCDs) including apoptosis, ferroptosis, and pyroptosis routinely occur in the HCC TME and participate in tumorigenesis. However, how apoptosis, ferroptosis, and pyroptosis are involved in constructions of the immunosuppressive TME and their underlying cross-talk remains to be further unveiled. In this work, we deciphered the immunosuppressive landscape of HCC TME, which demonstrated high expressions of inhibitory checkpoint molecules and infiltration of protumor immune cells but low infiltration of antitumor effector immune cells. Further investigations unequivocally revealed that marker genes of apoptosis, ferroptosis, and pyroptosis are closely correlated with expressions and infiltrations of inhibitory checkpoint molecules and immune cells and that higher “-optosis” links to poorer patient prognosis. Notably, such three types of “-optosis” interact with each other at both the gene and protein levels, suggesting that they conspiringly induce the establishment of the immunosuppressive HCC TME. Interestingly, examinations of circulating γδ T cells in HCC patients revealed a noticeable dysfunction phenotype. The strikingly elevated ratio of the Vδ1+ versus the Vδ2+ subset suggested that the Vδ1+/Vδ2+ ratio would be a potential biomarker for the diagnosis and prognosis in HCC patients. Altogether, this work thoroughly decrypted the underlying correlations between apoptosis, ferroptosis, and pyroptosis and the formation of immunosuppressive HCC TME and, meanwhile, indicated that allogeneic Vδ2+ γδ T-cell transfer would be a promising adjuvant strategy for renormalizing circulating γδ T cell and thus achieving sound clinical efficacy against HCC.