Isopentenyl pyrophosphate-activated CD56+ {gamma}{delta} T lymphocytes display potent antitumor activity toward human squamous cell carcinoma

• Published in: Clinical cancer research 2008-07, Vol.14 (13), p.4232
• Main Authors: Alexander, Alan A Z, Maniar, Amudhan, Cummings, Jean-Saville, Hebbeler, Andrew M, Schulze, Dan H, Gastman, Brian R, Pauza, C David, Strome, Scott E, Chapoval, Andrei I
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - immunology; Carcinoma, Squamous Cell - metabolism; CD56 Antigen - biosynthesis; Cell Line, Tumor; Flow Cytometry; Granzymes - chemistry; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - immunology; Head and Neck Neoplasms - metabolism; Hemiterpenes - pharmacology; Humans; Immunotherapy - methods; Interleukin-2 - metabolism; Organophosphorus Compounds - pharmacology; Perforin - chemistry; Phenotype; Receptors, Antigen, T-Cell, gamma-delta - metabolism; T-Lymphocytes - immunology; T-Lymphocytes - metabolism
• ISSN: 1078-0432
• DOI: 10.1158/1078-0432.Ccr-07-4912

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