Isopentenyl pyrophosphate-activated CD516+ γδ T lymphocytes display potent antitumor activity toward human squamous cell carcinoma

Purpose: The expression of CD56, a natural killer cell-associated molecule, on alpha beta T lymphocytes correlates with their increased antitumor effector function. CD56 is also expressed on a subset of gamma delta T cells. However, antitumor effector functions of CD56(+) gamma delta T cells are poorly characterized. Experimental Design: To investigate the potential effector role of CD56(+) gamma delta T cells in tumor killing, we used isopentenyl pyrophosphate and interleukin-2-expanded gamma delta T cells from peripheral blood mononuclear cells of healthy donors. Results: Thirty to 70% of expanded gamma delta T cells express C though both CD56(+) and CD56(-) gamma delta T cells express comparable levels of receptors involved in the regulation of gamma delta T-cell cytotoxicity (e.g., NKG2D and CD94), only CD56(+), gamma delta 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(+) gamma delta 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-gamma delta T-cell receptor + anti-NKG2D monoclonal antibody, suggesting that the lytic activity of CD56(+) gamma delta T cells involves the perforin-granzyme pathway and is mainly gamma delta T-cell receptor/NKG2D-expressing gamma delta T lymphocytes are resistant to Fas ligand and dependent. Importantly, CD56 chemically induced apoptosis. Conclusions: Our data indicate that CD56+ gamma delta T cells 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.