Isopentenyl pyrophosphate-activated CD56⁺ γδ T lymphocytes display potent antitumor activity toward human squamous cell carcinoma

Purpose: The expression of CD56, a natural killer cell - associated molecule, on αβ T lymphocytes correlates with their increased antitumor effector function. CD56 is also expressed on a subset of γδ T cells. However, antitumor effector functions of CD56 ⁺ γδ Tcells are poorly characterized. Experimental Design: To investigate the potential effector role of CD56⁺ γδ Tcells in tumor killing, we used isopentenyl pyrophosphate and interleukin-2- expanded γδ T cells from peripheral blood mononuclear cells of healthy donors. Results: Thirty to 70% of expanded γδ Tcells express CD56 on their surface. Interestingly, although both CD56 ⁺ and CD56^- γδ Tcells express comparable levels of receptors involved in the regulation of γδ T-cell cytotoxicity (e.g., NKG2D and CD94), only CD56⁺ γδ T lymphocytes are capable of killing squamous cell carcinoma and other solid tumor cell lines. This effect is likely mediated by the enhanced release of cytolytic granules because CD56⁺ γδ T lymphocytes expressed higher levels of CD107a compared with CD56^- controls following exposure to tumor cell lines. Lysis of tumor cell lines is blocked by concanamycin A and a combination of anti-γδ T-cell receptor + anti-NKG2D monoclonal antibody, suggesting that the lytic activity of CD56⁺ γδ Tcells involves the perforin-granzyme pathway and is mainly γδT-cell receptor/NKG2D dependent. Importantly, CD56-expressing γδT lymphocytes are resistant to Fas ligand and chemically induced apoptosis. Conclusions: Our data indicate that CD56⁺ γδ Tcells are potent antitumor effectors capable of killing squamous cell carcinoma and may play an important therapeutic role in patients with head and neck cancer and other malignancies.