Adoptive immunotherapy of lung cancer with immobilized anti-TCRγδ antibody-expanded human γδ T Cells in peripheral blood

Abstract

Lung cancer is the leading cause of cancer death. The prognosis of metastatic lung cancer is poor. We had previously established the condition to expand human γδ T cells in peripheral blood and tumor infiltrating T lymphocytes with immobilized anti-TCRγδ antibody. Such expanded γδ T cells exhibited potent cytolytic activity to different tumor cell lines in vitro and in vivo. Here we further characterized human anti-TCRγδ-expanded γδ T cells and tested their anti-tumor function in treatment for lung cancer in nude mice. In comparison to γδ T cells activated by phosphoantigen, a prevalent Vδ2 stimulus, anti-TCRγδ-expanded γδ T cells had similar major subset with Vδ2 phenotype, but they had about 10% of Vδ1 subsets and high percentages of CD27-CD45RA- and CD27-CD45RA+ effector cells. They also displayed TCR diversity of multiple clones. Importantly, the antibody-expanded γδ T cells showed strong cytotoxicity to three lung cancer cell lines and had significant antitumor effect on squamous lung carcinoma in nude mice. The ex vivo anti-TCRγδ-expanded γδ T cells prolonged tumor bearing mouse survival and slowed down tumor growth, with similar efficacy to chemotherapy by cis-platinum. Moreover, adoptively transferred human γδ T cells survived for more than one month in vivo. Finally, γδ T cells derived from 11 cases of patients with lung cancer had proliferative activity after TCRγδ ligandation, displayed marked cytotoxicity to lung cancer cells and expressed cytotoxicity- or antitumor activity-related molecules, such as perforin, granzyme A and B, Fas ligand, TNF-α and IFN-γ. Taken together, our finding suggests that anti-TCRγδ expanded γδ T cells may be used as cellular therapy in treatment of lung cancer.