Characterisation and induction of tissue-resident gamma delta T-cells to target hepatocellular carcinoma.
Characterisation and induction of tissue-resident gamma delta T-cells to target hepatocellular carcinoma.
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DOI：
10.1038/s41467-022-29012-1
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发表时间：
2022-03-16
影响因子：
16.6
通讯作者：
Maini MK
中科院分区：
文献类型：
--
作者：
Zakeri N;Hall A;Swadling L;Pallett LJ;Schmidt NM;Diniz MO;Kucykowicz S;Amin OE;Gander A;Pinzani M;Davidson BR;Quaglia A;Maini MK
免疫治疗是目前晚期肝细胞癌（HCC）的标准治疗方法，但许多患者对免疫治疗无效。一个未实现的主要目标是促进具有强HCC反应性和组织驻留记忆t细胞（TRM）保护优势的t细胞。在这里，我们发现更高的肿瘤内γδ t细胞频率与HCC患者生存率的提高有关，γδ t细胞具有hla无限制肿瘤反应性的潜力。我们证明了γδ t细胞在人类肝脏和HCC中表现出真正的组织驻留，γδ trm显示不从肝脏血管输出，持续10年，并且具有优异的抗肿瘤细胞因子生产能力。在HCC中，v γ - 9v - δ2 t细胞亚群被选择性地耗尽，但可以有效地靶向氨基二膦酸唑来膦酸对异戊基焦磷酸积累敏感的HCC细胞系。以氨基二膦酸盐为基础的外周Vγ9Vδ2 t细胞扩增重现TRM表型并增强细胞毒性潜能。因此，我们的数据表明，通过联合氨基双膦酸盐诱导能够补充耗尽池的v - γ 9v δ 2trm，并通过额外的肿瘤内递送使HCC对基于v - γ 9v δ 2trm的靶向敏感，可以实现更普遍有效的HCC免疫治疗。许多癌症免疫治疗方法依赖于hla限制性新抗原特异性T细胞反应。研究表明，唑来膦酸可以扩大并诱导与肝细胞癌有效抗肿瘤免疫应答相关的组织驻留记忆γ - δ T细胞群对肿瘤的识别。
Immunotherapy is now the standard of care for advanced hepatocellular carcinoma (HCC), yet many patients fail to respond. A major unmet goal is the boosting of T-cells with both strong HCC reactivity and the protective advantages of tissue-resident memory T-cells (TRM). Here, we show that higher intratumoural frequencies of γδ T-cells, which have potential for HLA-unrestricted tumour reactivity, associate with enhanced HCC patient survival. We demonstrate that γδ T-cells exhibit bona fide tissue-residency in human liver and HCC, with γδTRM showing no egress from hepatic vasculature, persistence for >10 years and superior anti-tumour cytokine production. The Vγ9Vδ2 T-cell subset is selectively depleted in HCC but can efficiently target HCC cell lines sensitised to accumulate isopentenyl-pyrophosphate by the aminobisphosphonate Zoledronic acid. Aminobisphosphonate-based expansion of peripheral Vγ9Vδ2 T-cells recapitulates a TRM phenotype and boosts cytotoxic potential. Thus, our data suggest more universally effective HCC immunotherapy may be achieved by combining aminobisphosphonates to induce Vγ9Vδ2TRM capable of replenishing the depleted pool, with additional intratumoural delivery to sensitise HCC to Vγ9Vδ2TRM-based targeting. Many cancer immune therapy approaches depend on an HLA-restricted neoantigen-specific T cell response. AUs show here that Zoledronic acid can expand, and induce tumour recognition by, a population of tissue resident memory gamma-delta T cells associated with an efficient anti-tumour immune response in hepatocellular carcinoma.
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影响因子：
11.2
作者：
Dieli F;Vermijlen D;Fulfaro F;Caccamo N;Meraviglia S;Cicero G;Roberts A;Buccheri S;D'Asaro M;Gebbia N;Salerno A;Eberl M;Hayday AC
通讯作者：
Hayday AC
影响因子：
6
作者：
Curbishley, SM;Eksteen, B;Adams, DH
通讯作者：
Adams, DH
影响因子：
16.6
作者：
Davey MS;Willcox CR;Hunter S;Kasatskaya SA;Remmerswaal EBM;Salim M;Mohammed F;Bemelman FJ;Chudakov DM;Oo YH;Willcox BE
通讯作者：
Willcox BE
影响因子：
158.5
作者：
Finn, Richard S.;Qin, Shukui;Cheng, Ann-Lii
通讯作者：
Cheng, Ann-Lii
影响因子：
11.2
作者：
Benzaid, Ismahene;Moenkkoenen, Hannu;Clezardin, Philippe
通讯作者：
Clezardin, Philippe