Bouet-Toussaint Francoise, Cabillic Florian, Toutirais Olivier, Le Gallo Matthieu, Thomas de la Pintière Cécile, Daniel Pascale, Genetet Noëlle, Meunier Bernard, Dupont-Bierre Eric, Boudjema Karim, Catros Véronique
UPRES EA 3891, Faculté de Médecine de Rennes, 2 Avenue du Pr Léon Bernard, CS34317, 35043, Rennes cedex, France.
Cancer Immunol Immunother. 2008 Apr;57(4):531-9. doi: 10.1007/s00262-007-0391-3. Epub 2007 Sep 1.
Vgamma9Vdelta2 T lymphocytes are reported to participate in the anti-tumor immune surveillance in human. They are known to recognize phosphoantigens and molecules expressed on cells undergoing neoplasic transformation. In this study, we investigated phenotype and anti-tumor cytotoxicity of ex vivo expanded Vgamma9Vdelta2 T cells in view of adoptive immunotherapy.
Experiments were performed with peripheral blood samples from eleven patients [six colorectal carcinoma (CRC), four hepatocellular carcinoma (HCC), one sarcoma] and sixteen healthy donors.
RESULTS/DISCUSSION: Ex vivo expansion of Vgamma9Vdelta2 T cells could be achieved by a single dose of phosphoantigen, either bromohydrin pyrophosphate or zoledronate, and supported by exogenous IL-2. After 2 weeks, expanded Vgamma9Vdelta2 T lymphocytes acquired the effector memory phenotype CD45RA(-)CD45RO(high)CD27(-). They expressed NKG2D and CD161 and the proinflammatory CXCR3 and CCR5 chemokine receptors. Vgamma9Vdelta2 T cells displayed a strong lytic activity toward a broad panel of tumor cell lines or primary cultures. Interestingly, HCC and CRC primary cells could be lysed by autologous Vgamma9Vdelta2 T cells whereas autologous normal cells were not sensitive to the lysis. mAbs blocking assays demonstrated that TCR was the most important receptor involved in the lysis of tumor cells. However, NKG2D receptor could deliver a costimulatory signal enhancing the lysis of HCC and CRC tumors expressing MICA/B. Treatment of tumor cells by the mevalonate pathway inhibitor, zoledronate, enhanced the killing of both HCC and CRC. Expansion index of Vgamma9Vdelta2 T cells was in similar levels in healthy donors or in cancer patients and total expansion was suitable for adoptive immunotherapy.
These results provide a rationale for the clinical evaluation of Vgamma9Vdelta2 T lymphocytes in HCC and CRC.
据报道，Vγ9Vδ2 T淋巴细胞参与人体的抗肿瘤免疫监视。已知它们可识别磷酸抗原以及肿瘤转化细胞上表达的分子。在本研究中，我们鉴于过继性免疫疗法研究了体外扩增的Vγ9Vδ2 T细胞的表型和抗肿瘤细胞毒性。
实验采用了11例患者（6例结直肠癌、4例肝细胞癌、1例肉瘤）和16名健康供者的外周血样本。
结果/讨论：单剂量的磷酸抗原（溴代焦磷酸酯或唑来膦酸）可实现Vγ9Vδ2 T细胞的体外扩增，并由外源性白细胞介素-2支持。2周后，扩增的Vγ9Vδ2 T淋巴细胞获得效应记忆表型CD45RA(-)CD45RO(高)CD27(-)。它们表达NKG2D和CD161以及促炎趋化因子受体CXCR3和CCR5。Vγ9Vδ2 T细胞对多种肿瘤细胞系或原代培养物表现出强烈杀伤活性。有趣的是，肝细胞癌和结直肠癌原代细胞可被自体Vγ9Vδ2 T细胞裂解，而自体正常细胞对裂解不敏感。单克隆抗体阻断试验表明，TCR是参与肿瘤细胞裂解的最重要受体。然而，NKG2D受体可传递共刺激信号，增强对表达MICA/B的肝细胞癌和结直肠癌肿瘤的裂解。甲羟戊酸途径抑制剂唑来膦酸处理肿瘤细胞可增强对肝细胞癌和结直肠癌的杀伤。Vγ9Vδ2 T细胞的扩增指数在健康供者或癌症患者中处于相似水平，总体扩增适合过继性免疫疗法。
这些结果为肝细胞癌和结直肠癌中Vγ9Vδ2 T淋巴细胞的临床评估提供了理论依据。
