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

Alan A.Z. Alexander, Amudhan Maniar, Jean Saville Cummings, Andrew M. Hebbeler, Dan H. Schulze, Brian R. Gastman, C. David Pauza, Scott E. Strome, Andrei Chapoval

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)4232-4240
Number of pages9
JournalClinical Cancer Research
Volume14
Issue number13
DOIs
StatePublished - Jul 1 2008
Externally publishedYes

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Human Activities
Squamous Cell Carcinoma
T-Lymphocytes
Tumor Cell Line
T-Cell Antigen Receptor
Granzymes
Perforin
Fas Ligand Protein
T-Lymphocyte Subsets
Head and Neck Neoplasms
Natural Killer Cells
Interleukin-2
isopentenyl pyrophosphate
Blood Cells
Neoplasms
Research Design
Monoclonal Antibodies
Tissue Donors
Apoptosis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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

In: Clinical Cancer Research, Vol. 14, No. 13, 01.07.2008, p. 4232-4240.

Research output: Contribution to journalArticle

Alexander, AAZ, Maniar, A, Cummings, JS, Hebbeler, AM, Schulze, DH, Gastman, BR, Pauza, CD, Strome, SE & Chapoval, A 2008, 'Isopentenyl pyrophosphate-activated CD56+ γδ T lymphocytes display potent antitumor activity toward human squamous cell carcinoma', Clinical Cancer Research, vol. 14, no. 13, pp. 4232-4240. https://doi.org/10.1158/1078-0432.CCR-07-4912
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. / Isopentenyl pyrophosphate-activated CD56+ γδ T lymphocytes display potent antitumor activity toward human squamous cell carcinoma. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 13. pp. 4232-4240.
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abstract = "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.",
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AU - Alexander, Alan A.Z.

AU - Maniar, Amudhan

AU - Cummings, Jean Saville

AU - Hebbeler, Andrew M.

AU - Schulze, Dan H.

AU - Gastman, Brian R.

AU - Pauza, C. David

AU - Strome, Scott E.

AU - Chapoval, Andrei

PY - 2008/7/1

Y1 - 2008/7/1

N2 - 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.

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