Dhar Swati, Chiplunkar Shubhada V
Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India.
Cancer Immun. 2010 Nov 12;10:10.
Aminobisphosphonates are drugs administered for the treatment of bone resorption. They can indirectly activate peripheral γδ T cells and render tumor cells susceptible to lysis by Vγ9Vδ2 T cells. We have investigated the molecules involved in conjugate formation and killing of aminobisphosphonate-treated MCF-7 breast tumor cells by Vγ9Vδ2 T cells. Lysis of aminobisphosphonate (Pamidronate and Zoledronate)-treated MCF-7 tumor cells by Vγ9Vδ2 T cells was assessed by chromium release assays and time-lapse video microscopy. MCF-7 breast cancer cells were chosen as aminobisphosphonates are employed to alleviate bone resorption in this malignancy. Cell cycle profile and expression of MICA, ICAM-I and FasL on aminobisphosphonate-sensitized MCF-7 breast tumor cells was confirmed by flow cytometry. Involvement of γδ TCR and NKG2D in mediating cytotoxicity of aminobisphosphonate-treated MCF-7 breast tumor cells by Vγ9Vδ2 T cells was assessed using blocking antibodies in chromium release assays. MCF-7 tumor cells pretreated with Pamidronate and Zoledronate were efficiently lysed by Vγ9Vδ2 T cells. Pamidronate and Zoledronate treatment of MCF-7 cells induced S phase arrest and did not alter expression of MICA, ICAM-I and FasL. Blocking γδ TCR and NKG2D on Vγ9Vδ2 T cells inhibited lysis of Pamidronate and Zoledronate-treated MCF-7 cells. Inhibiting the perforin-granzyme pathway in Vγ9Vδ2 T cells using concanamycin A reduced their ability to lyse aminobisphosphonate-treated MCF-7 cells. Vγ9Vδ2 T cells form strong conjugates with aminobisphosphonate-treated MCF-7 breast tumor cells. γδ TCR, NKG2D and perforin-granzyme pathway are involved in the lysis of MCF-7 breast tumor cells treated with aminobisphosphonates by Vγ9Vδ2 T cells.
氨基双膦酸盐是用于治疗骨吸收的药物。它们可间接激活外周γδT细胞，并使肿瘤细胞易于被Vγ9Vδ2T细胞裂解。我们研究了Vγ9Vδ2T细胞与经氨基双膦酸盐处理的MCF-7乳腺肿瘤细胞形成结合物并将其杀伤过程中涉及的分子。通过铬释放试验和延时视频显微镜评估Vγ9Vδ2T细胞对经氨基双膦酸盐（帕米膦酸盐和唑来膦酸盐）处理的MCF-7肿瘤细胞的裂解作用。选择MCF-7乳腺癌细胞是因为在这种恶性肿瘤中使用氨基双膦酸盐来减轻骨吸收。通过流式细胞术确认了经氨基双膦酸盐致敏的MCF-7乳腺肿瘤细胞的细胞周期分布以及MICA、ICAM-1和FasL的表达。在铬释放试验中使用阻断抗体评估γδTCR和NKG2D在介导Vγ9Vδ2T细胞对经氨基双膦酸盐处理的MCF-7乳腺肿瘤细胞的细胞毒性中的作用。用帕米膦酸盐和唑来膦酸盐预处理的MCF-7肿瘤细胞被Vγ9Vδ2T细胞有效裂解。帕米膦酸盐和唑来膦酸盐处理MCF-7细胞诱导S期停滞，且未改变MICA、ICAM-1和FasL的表达。阻断Vγ9Vδ2T细胞上的γδTCR和NKG2D可抑制对经帕米膦酸盐和唑来膦酸盐处理的MCF-7细胞的裂解。使用 concanamycin A抑制Vγ9Vδ2T细胞中的穿孔素-颗粒酶途径会降低它们裂解经氨基双膦酸盐处理的MCF-7细胞的能力。Vγ9Vδ2T细胞与经氨基双膦酸盐处理的MCF-7乳腺肿瘤细胞形成强结合物。γδTCR、NKG2D和穿孔素-颗粒酶途径参与Vγ9Vδ2T细胞对经氨基双膦酸盐处理的MCF-7乳腺肿瘤细胞的裂解。
