Amplification of spatially isolated adenosine pathway by tumor-macrophage interaction induces anti-PD1 resistance in hepatocellular carcinoma.
Amplification of spatially isolated adenosine pathway by tumor-macrophage interaction induces anti-PD1 resistance in hepatocellular carcinoma.
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DOI：
10.1186/s13045-021-01207-x
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发表时间：
2021-11-27
影响因子：
28.5
通讯作者：
Fan J
中科院分区：
文献类型：
--
作者：
Lu JC;Zhang PF;Huang XY;Guo XJ;Gao C;Zeng HY;Zheng YM;Wang SW;Cai JB;Sun QM;Shi YH;Zhou J;Ke AW;Shi GM;Fan J
免疫检查点阻断抗性缩小了癌症免疫疗法的疗效，但潜在的机制仍然难以捉摸。阐明抗PD 1耐药的内在机制对改善晚期HCC患者的预后具有重要意义。通过RNA测序测量抗PD 1治疗的HCC患者中cricTMEM 181的水平，然后通过qPCR和桑格测序确认。采用流式细胞术和免疫组化技术检测肝癌患者和模型小鼠肿瘤微环境中的免疫状态。通过超离心分离来自HCC细胞系的外来体，并且通过免疫荧光证实它们被巨噬细胞内化。SILAC、RNA FISH和RNA免疫沉淀证实了HCC来源的外泌体circTMEM 181对巨噬细胞的潜在机制。通过ATP、AMP和ADO测量和巨噬细胞特异性CD 39敲除小鼠评价HCC-巨噬细胞相互作用扩增的ATP-ADO途径。还在我们的回顾性HCC队列中确定了circTMEM 181在抗PD 1治疗中的作用及其临床意义。在这里，我们发现circTMEM 181在对抗PD 1治疗反应差的肝细胞癌（HCC）患者和术后预后差的HCC患者中升高。此外，我们还发现，高外来体circTMEM 181有利于免疫抑制微环境，并赋予抗PD 1耐药的HCC。在机制上，外泌体circTMEM 181吸收miR-488- 3 p并上调巨噬细胞中的CD 39表达。使用巨噬细胞特异性CD 39基因敲除小鼠和药理学方法，我们揭示了肝癌抗PD 1耐药的新模式。我们发现巨噬细胞中细胞特异性CD 39表达和HCC细胞中CD 73表达协同激活eATP-腺苷途径并产生更多腺苷，从而损害CD 8 + T细胞功能并驱动抗PD 1抗性。总之，HCC衍生的外泌体circTMEM 181通过提高CD 39表达而有助于免疫抑制和抗PD 1抗性，并且通过靶向巨噬细胞上的CD 39来抑制ATP-腺苷途径可以挽救HCC中的抗PD 1治疗抗性。在线版本包含补充材料，可通过10.1186/s13045-021-01207-x获得。
Immune checkpoint blockade resistance narrows the efficacy of cancer immunotherapies, but the underlying mechanism remains elusive. Delineating the inherent mechanisms of anti-PD1 resistance is important to improve outcome of patients with advanced HCC. The level of cricTMEM181 was measured in HCC patients with anti-PD1 therapy by RNA sequencing and then confirmed by qPCR and Sanger sequencing. Immune status in tumor microenvironment of HCC patients or mice models was evaluated by flow cytometry and IHC. Exosomes from HCC cell lines were isolated by ultracentrifugation, and their internalization by macrophage was confirmed by immunofluorescence. The underlying mechanism of HCC-derived exosomal circTMEM181 to macrophage was confirmed by SILAC, RNA FISH and RNA immunoprecipitation. The ATP–ADO pathway amplified by HCC–macrophage interaction was evaluated through ATP, AMP and ADO measurement and macrophage-specific CD39 knockout mice. The role of circTMEM181 in anti-PD1 therapy and its clinical significance were also determined in our retrospective HCC cohorts. Here, we found that circTMEM181 was elevated in hepatocellular carcinoma (HCC) patients responding poorly to anti-PD1 therapy and in HCC patients with a poor prognosis after operation. Moreover, we also found that high exosomal circTMEM181 favored the immunosuppressive microenvironment and endowed anti-PD1 resistance in HCC. Mechanistically, exosomal circTMEM181 sponged miR-488-3p and upregulated CD39 expression in macrophages. Using macrophage-specific CD39 knockout mice and pharmacologic approaches, we revealed a novel mode of anti-PD1 resistance in HCC. We discovered that cell-specific CD39 expression in macrophages and CD73 expression in HCC cells synergistically activated the eATP–adenosine pathway and produced more adenosine, thereby impairing CD8+ T cell function and driving anti-PD1 resistance. In summary, HCC-derived exosomal circTMEM181 contributes to immunosuppression and anti-PD1 resistance by elevating CD39 expression, and inhibiting the ATP–adenosine pathway by targeting CD39 on macrophages can rescue anti-PD1 therapy resistance in HCC. The online version contains supplementary material available at 10.1186/s13045-021-01207-x.
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DOI：
10.4049/jimmunol.1400578
发表时间：
2014-09-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Ryzhov SV;Pickup MW;Chytil A;Gorska AE;Zhang Q;Owens P;Feoktistov I;Moses HL;Novitskiy SV
通讯作者：
Novitskiy SV
环状 RNA circMET 通过 miR-30-5p/snail/DPP4 轴驱动肝细胞癌的免疫抑制和抗 PD1 治疗耐药性。
影响因子：
37.3
作者：
Huang, Xiao-Yong;Zhang, Peng-Fei;Shi, Guo-Ming
通讯作者：
Shi, Guo-Ming
影响因子：
4.8
作者：
Kong, Tianqing;Westerman, Karen A.;Colgan, Sean P.
通讯作者：
Colgan, Sean P.
影响因子：
37.3
作者：
Dong ZR;Ke AW;Li T;Cai JB;Yang YF;Zhou W;Shi GM;Fan J
通讯作者：
Fan J
影响因子：
56.9
作者：
Carette, Jan E.;Guimaraes, Carla P.;Brummelkamp, Thijn R.
通讯作者：
Brummelkamp, Thijn R.