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Isopentenyl Pyrophosphate–Activated CD56⁺ T Lymphocytes Display Potent Antitumor Activity toward Human Squamous Cell Carcinoma

Authors' Affiliations: ¹ Department of Otorhinolaryngology-Head and Neck Surgery, ² Institute of Human Virology, ³ Marlene and Stewart Greenebaum Cancer Center, and ⁴ Department of Medicine, University of Maryland School of Medicine; ⁵ Graduate Program in Molecular Medicine and ⁶ Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland

Requests for reprints: Andrei I. Chapoval, Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland School of Medicine, HSF-1 325C, 685 West Baltimore Street, Baltimore, MD 21201. Phone: 410-706-3094; Fax: 410-706-3090; E-mail: achapoval{at}smail.umaryland.edu.

Purpose: The expression of CD56, a natural killer cell–associated molecule, on β T lymphocytes correlates with their increased antitumor effector function. CD56 is also expressed on a subset of T cells. However, antitumor effector functions of CD56⁺ T cells are poorly characterized.

Experimental Design: To investigate the potential effector role of CD56⁺ T cells in tumor killing, we used isopentenyl pyrophosphate and interleukin-2–expanded T cells from peripheral blood mononuclear cells of healthy donors.

Results: Thirty to 70% of expanded T cells express CD56 on their surface. Interestingly, although both CD56⁺ and CD56^– T cells express comparable levels of receptors involved in the regulation of T-cell cytotoxicity (e.g., NKG2D and CD94), only CD56⁺ 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⁺ 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- T-cell receptor + anti-NKG2D monoclonal antibody, suggesting that the lytic activity of CD56⁺ T cells involves the perforin-granzyme pathway and is mainly T-cell receptor/NKG2D dependent. Importantly, CD56-expressing T lymphocytes are resistant to Fas ligand and chemically induced apoptosis.

Conclusions: Our data indicate that CD56⁺ 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.