Hepatocellular carcinoma-infiltrating γδ T cells are functionally defected and allogenic Vδ2(+) γδ T cell can be a promising complement.
Hepatocellular carcinoma-infiltrating γδ T cells are functionally defected and allogenic Vδ2(+) γδ T cell can be a promising complement.
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DOI：
10.1002/ctm2.800
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发表时间：
2022-04
影响因子：
10.6
通讯作者：
Wu Y
中科院分区：
文献类型：
--
作者：
He W;Hu Y;Chen D;Li Y;Ye D;Zhao Q;Lin L;Shi X;Lu L;Yin Z;He X;Gao Y;Wu Y
在肝细胞癌 (HCC) 中，γδ T 细胞参与介导抗肿瘤反应，并与积极的预后相关。然而，这些细胞可以在肿瘤微环境（TME）中变成促肿瘤细胞。我们的目的是破译 HCC 浸润 γδ T 细胞的免疫景观和功能状态，为 HCC 免疫治疗中同种异体 Vδ2+ γδ T 细胞的过继转移提供基础证据。我们对源自 HCC 肿瘤和健康供体肝脏的 γδ T 细胞进行了单细胞 RNA 测序 (scRNA-seq)。应用共聚焦显微镜、流式细胞术和 Luminex 测定来验证 scRNA-seq 结果。 HCC TME 中的 γδ T 细胞进入 G2/M 细胞周期停滞，并表达细胞毒性分子，如干扰素 γ 和颗粒酶 B，但基因和蛋白 LAG3 表达上调表明其功能已耗尽。 HCC TME 中的 γδ T 细胞以 LAG3+Vδ1+ 群体为主，而 Vδ2+ γδ T 群体大大减少。此外，在谷氨酰胺缺乏的 TME 中，γδ T 细胞的谷氨酰胺代谢显着上调。体外和体内实验均表明谷氨酰胺缺乏会上调 LAG3 的表达。最后，我们的结果表明，来自健康供体的离体扩增的 Vδ2+ γδ T 细胞可以补充 HCC 衍生的 γδ T 细胞的 T 细胞受体克隆性和效应器功能的损失。这项工作破译了 HCC TME 中 HCC 浸润 γδ T 细胞的功能障碍特征，为在 HCC 细胞治疗中使用同种异体 Vδ2+ γδ T 细胞提供了科学支持。 HCC 浸润的 γδ T 细胞失去了 T 细胞受体 (TCR) 多样性，并且 G2/M 细胞周期停滞。 HCC 中的 γδ T 细胞功能障碍依赖于 LAG3。 HCC 中谷氨酰胺代谢介导的 γδ T 细胞功能障碍。同种异体 Vδ2+ γδ T 细胞可以补充 HCC 中 γδ T 细胞的功能缺陷。
In hepatocellular carcinoma (HCC), γδ T cells participate in mediating the anti‐tumour response and are linked with a positive prognosis. However, these cells can become pro‐tumoural in the tumour microenvironment (TME). We aimed to decipher the immune landscape and functional states of HCC‐infiltrating γδ T cells to provide fundamental evidence for the adoptive transfer of allogeneic Vδ2+ γδ T cells in HCC immunotherapy. We performed single‐cell RNA sequencing (scRNA‐seq) on γδ T cells derived from HCC tumours and healthy donor livers. Confocal microscopy, flow cytometry and a Luminex assay were applied to validate the scRNA‐seq findings. The γδ T cells in the HCC TME entered G2/M cell cycle arrest, and expressed cytotoxic molecules such as interferon‐gamma and granzyme B, but were functionally exhausted as indicated by upregulated gene and protein LAG3 expression. The γδ T cells in the HCC TME were dominated by the LAG3+Vδ1+ population, whereas the Vδ2+ γδ T population was greatly depleted. Moreover, glutamine metabolism of γδ T cells was markedly upregulated in the glutamine‐deficient TME. Both in vitro and in vivo experiments showed that glutamine deficiency upregulated LAG3 expression. Finally, our results indicated that ex vivo‐expanded Vδ2+ γδ T cells from healthy donor could complement the loss of T cell receptor clonality and effector functions of HCC‐derived γδ T cells. This work deciphered the dysfunctional signatures of HCC‐infiltrating γδ T cells in the HCC TME, providing scientific support for the use of allogeneic Vδ2+ γδ T cells in HCC cellular therapy. HCC‐infiltrating γδ T cells lost T cell receptor (TCR) diversity and were G2/M cell cycle arrested. γδ T cell dysfunction in HCC was LAG3 dependent. Glutamine metabolism‐mediated γδ T cell dysfunction in HCC. Allogeneic Vδ2+ γδ T cells can complement functional deficiency of γδ T cells in HCC.
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影响因子：
16.6
作者：
Ho DW;Tsui YM;Chan LK;Sze KM;Zhang X;Cheu JW;Chiu YT;Lee JM;Chan AC;Cheung ET;Yau DT;Chia NH;Lo IL;Sham PC;Cheung TT;Wong CC;Ng IO
通讯作者：
Ng IO
影响因子：
16.6
作者：
MacParland SA;Liu JC;Ma XZ;Innes BT;Bartczak AM;Gage BK;Manuel J;Khuu N;Echeverri J;Linares I;Gupta R;Cheng ML;Liu LY;Camat D;Chung SW;Seliga RK;Shao Z;Lee E;Ogawa S;Ogawa M;Wilson MD;Fish JE;Selzner M;Ghanekar A;Grant D;Greig P;Sapisochin G;Selzner N;Winegarden N;Adeyi O;Keller G;Bader GD;McGilvray ID
通讯作者：
McGilvray ID
DOI：
10.1126/science.aah3374
发表时间：
2016-09-30
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Mao X;Ou MT;Karuppagounder SS;Kam TI;Yin X;Xiong Y;Ge P;Umanah GE;Brahmachari S;Shin JH;Kang HC;Zhang J;Xu J;Chen R;Park H;Andrabi SA;Kang SU;Gonçalves RA;Liang Y;Zhang S;Qi C;Lam S;Keiler JA;Tyson J;Kim D;Panicker N;Yun SP;Workman CJ;Vignali DA;Dawson VL;Ko HS;Dawson TM
通讯作者：
Dawson TM
影响因子：
11.2
作者：
Lim S;Phillips JB;Madeira da Silva L;Zhou M;Fodstad O;Owen LB;Tan M
通讯作者：
Tan M
影响因子：
64.8
作者：
La Manno G;Soldatov R;Zeisel A;Braun E;Hochgerner H;Petukhov V;Lidschreiber K;Kastriti ME;Lönnerberg P;Furlan A;Fan J;Borm LE;Liu Z;van Bruggen D;Guo J;He X;Barker R;Sundström E;Castelo-Branco G;Cramer P;Adameyko I;Linnarsson S;Kharchenko PV
通讯作者：
Kharchenko PV