Heterogeneity induced GZMA-F2R communication inefficient impairs antitumor immunotherapy of PD-1 mAb through JAK2/STAT1 signal suppression in hepatocellular carcinoma.
Heterogeneity induced GZMA-F2R communication inefficient impairs antitumor immunotherapy of PD-1 mAb through JAK2/STAT1 signal suppression in hepatocellular carcinoma.
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异质性诱导的 GZMA-F2R 通讯效率低下，通过抑制 JAK2/STAT1 信号抑制肝细胞癌中的 PD-1 mAb 的抗肿瘤免疫治疗
DOI：
10.1038/s41419-022-04654-7
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发表时间：
2022-03-07
影响因子：
9
通讯作者：
Yang T
中科院分区：
文献类型：
--
作者：
Gao Y;Xu Q;Li X;Guo Y;Zhang B;Jin Y;Zhu C;Shen Y;Yang P;Shi Y;Jin R;Liu D;Ouyang Y;Liu X;Wang W;Chen D;Yang T
肿瘤的异质性与肝细胞癌的免疫治疗和靶向耐药有关。然而，到目前为止，肿瘤和细胞毒细胞之间的联系还知之甚少。在本研究中，通过单细胞测序，在肿瘤组织和邻近组织中发现了31个细胞簇。此外，还观察到TCR和凋亡信号通路在肿瘤中诱导细胞毒细胞数量和功能耗竭。此外，在肝细胞癌患者中还观察到细胞毒细胞的颗粒酶失活。重要的是，细胞毒细胞分泌的GZMA在体内和体外都能与肿瘤细胞表达的F2R相互作用。这种相互作用通过激活JAK2/STAT1信号通路诱导肿瘤抑制和T细胞介导的肿瘤细胞杀伤。在机制上，JAK2/STAT1信号的激活在F2R N端的LDPRSFLL基序的介导下促进了细胞的凋亡，并与GZMA相互作用。此外，在肿瘤组织中，GZMA和F2R与PD-1和PD-L1呈正相关，而在小鼠模型和肝癌患者中，F2R和GZMA的表达促进了PD-1单抗诱导的肿瘤抑制。在肝细胞癌中，GZMA和F2R的低表达与侵袭性临床病理特征和预后不良相关。总之，GZMA-F2R通讯效率低下导致PD-1单抗治疗不足，为肝癌患者的肿瘤抑制提供了一种全新的免疫治疗策略。
Tumor heterogeneity has been associated with immunotherapy and targeted drug resistance in hepatocellular carcinoma (HCC). However, communications between tumor and cytotoxic cells are poorly understood to date. In the present study, thirty-one clusters of cells were discovered in the tumor tissues and adjacent tissues through single-cell sequencing. Moreover, the quantity and function exhaustion of cytotoxic cells was observed to be induced in tumors by the TCR and apoptosis signal pathways. Furthermore, granzyme failure of cytotoxic cells was observed in HCC patients. Importantly, the GZMA secreted by cytotoxic cells was demonstrated to interact with the F2R expressed by the tumor cells both in vivo and in vitro. This interaction induced tumor suppression and T cell-mediated killing of tumor cells via the activation of the JAK2/STAT1 signaling pathway. Mechanistically, the activation of JAK2/STAT1 signaling promoted apoptosis under the mediating effect of the LDPRSFLL motif at the N-terminus of F2R, which interacted with GZMA. In addition, GZMA and F2R were positively correlated with PD-1 and PD-L1 in tumor tissues, while the expressions of F2R and GZMA promoted PD-1 mAb-induced tumor suppression in both mouse model and HCC patients. Finally, in HCC patients, a low expression of GZMA and F2R in the tumor tissues was correlated with aggressive clinicopathological characteristics and poor prognosis. Collectively, GZMA-F2R communication inefficient induces deficient PD-1 mAb therapy and provide a completely novel immunotherapy strategy for tumor suppression in HCC patients.
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影响因子：
30.8
作者：
Hao, Jia-Jie;Lin, De-Chen;Dinh, Huy Q.;Mayakonda, Anand;Jiang, Yan-Yi;Chang, Chen;Jiang, Ye;Lu, Chen-Chen;Shi, Zhi-Zhou;Xu, Xin;Zhang, Yu;Cai, Yan;Wang, Jin-Wu;Zhan, Qi-Min;Wei, Wen-Qiang;Berrnan, Benjamin P.;Wang, Ming-Rong;Koeffler, H. Phillip
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影响因子：
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影响因子：
29.4
作者：
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Wong, Carmen Chak-Lui
影响因子：
64.5
作者：
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通讯作者：
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DOI：
10.1002/wsbm.1461
发表时间：
2019-07-17
影响因子：
7.9
作者：
Chamseddine, Ibrahim M.;Rejniak, Katarzyna A.
通讯作者：
Rejniak, Katarzyna A.