Article


Lysis of aminobisphosphonate-sensitized MCF-7 breast tumor cells by Vγ9Vδ2 T cells

Swati Dhar and Shubhada V. Chiplunkar

Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India

Communicated by: PK Srivastava

Keywords: cultured tumor cells, breast cancer, aminobisphosphonate, T lymphocytes, immunologic cytotoxicity


Abstract

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.