NKG2D-Mediated Antitumor Activity by Tumor-Infiltrating Lymphocytes and Antigen-Specific T-Cell Clones Isolated from Melanoma Patients
- Cristina Maccalli1,
- Daisuke Nonaka2,
- Adriano Piris2,
- Daniela Pende3,
- Licia Rivoltini1,
- Chiara Castelli1 and
- Giorgio Parmiani1
- Authors' Affiliations:1Unit of Immunotherapy of Human Tumors and 2Department of Pathology, Istituto Nazionale Tumori, Milan, Italy; and 3Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy
- Requests for reprints:
Cristina Maccalli, Unit of Immunobiotherapy of Solid Tumors, Department of Oncology, San Raffaele Foundation Scientific Institute, Via Olgettina, 58, 20132 Milan, Italy. Phone: 39-02-26434625; Fax: 39-02-26434861; E-mail: maccalli.cristina{at}hsr.it.
Abstract
Purpose: The role of NKG2D receptor in antitumor immunosurveillance has not been completely clarified. We addressed this issue by investigating the involvement of this receptor in tumor-specific immunologic response in melanoma patients.
Experimental Design: We determined the presence of NKG2D+ T cells among tumor-infiltrating lymphocytes (TIL) of 10 (one primary and 9 metastatic) melanoma samples and the expression of NKG2D ligands (NKG2DL) by these tumor cells. Moreover, the expression of NKG2D was assessed in a panel of antigen-specific T lymphocytes isolated from melanoma patients and the engagement of NKG2D in antitumor activity mediated by these T cells was determined.
Results: TILs located either in the periphery or within the tumor mass of melanoma samples expressed NKG2D and the expression of this receptor by T cells was retained after in vitro culture. However, NKG2DLs were weakly expressed, or not expressed, by most metastatic lesions with only the primary tumor being positive for all these molecules. In contrast, these ligands were expressed, although heterogeneously, by all in vitro established melanoma lines. Moreover, the engagement of NKG2D occurred in antitumor activity by both freshly isolated and in vitro cultured TILs. However, this receptor was involved to a different extent in the antitumor activity of antigen-specific T-cell clones.
Conclusions: These findings indicate that NKG2D+ T cells have a role in the immunologic response against tumor. Thus, new immunotherapeutic treatments for melanoma patients should be designed aimed at augmenting the NKG2D+ T lymphocyte–mediated immune response.
Footnotes
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Grant support: Associazione Italiana per la Ricerca sul Cancro (Milan, Italy) and European Community (QLK3 1999 00064). C. Maccalli was supported by a fellowship of the Istituto Nazionale Tumori from “Successione Bertaccini”.
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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C. Castelli and G. Parmiani contributed equally to this work. Current address for C. Maccalli and G. Parmiani: Unit of Immunobiotherapy of Solid Tumors, Department of Oncology, San Raffaele Foundation Scientific Institute, Milan, Italy.
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- Accepted July 18, 2007.
- Received May 14, 2007.
- Revision received July 13, 2007.
