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CD8⁺CD28^– T Regulatory Lymphocytes Inhibiting T Cell Proliferative and Cytotoxic Functions Infiltrate Human Cancers¹

Gilberto Filaci^*,, Daniela Fenoglio^*, Marco Fravega^*, Gianluca Ansaldo, Giacomo Borgonovo, Paolo Traverso, Barbara Villaggio, Alessandra Ferrera^*, Annalisa Kunkl^¶, Marta Rizzi^2,*,, Francesca Ferrera^*, Piercesare Balestra^*, Massimo Ghio^*,, Paola Contini^*,, Maurizio Setti^*,, Daniel Olive^||, Bruno Azzarone^#, Giorgio Carmignani, Jean Louis Ravetti^¶, Giancarlo Torre and Francesco Indiveri^2,*,

^* Centre of Excellence for Biomedical Research and Department of Internal Medicine, University of Genoa, Genoa, Italy; Department of Surgical and Morphological Disciplines and Integrated Methodologies, University of Genoa, Genoa, Italy; Urology Department, University of Genoa, Genoa, Italy; ^¶ Anatomic Pathology, San Martino Hospital, Genoa, Italy; ^|| Laboratoire d’Immunologie des Tumeurs, Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche 599, Institut Paoli-Calmettes, Universite de la Mediterranee, Marseille, France; and ^# Hôpital Paul Brousse, Unité 542 INSERM, Villejuif, France

Tumor growth is allowed by its ability to escape immune system surveillance. An important role in determining tumor evasion from immune control might be played by tumor-infiltrating regulatory lymphocytes. This study was aimed at characterizing phenotype and function of CD8⁺CD28^– T regulatory cells infiltrating human cancer. Lymphocytes infiltrating primitive tumor lesion and/or satellite lymph node from a series of 42 human cancers were phenotypically studied and functionally analyzed by suppressor assays. The unprecedented observation was made that CD8⁺CD28^– T regulatory lymphocytes are almost constantly present and functional in human tumors, being able to inhibit both T cell proliferation and cytotoxicity. CD4⁺CD25⁺ T regulatory lymphocytes associate with CD8⁺CD28^– T regulatory cells so that the immunosuppressive activity of tumor-infiltrating regulatory T cell subsets, altogether considered, may become predominant. The infiltration of regulatory T cells seems tumor related, being present in metastatic but not in metastasis-free satellite lymph nodes; it likely depends on both in situ generation (via cytokine production) and recruitment from the periphery (via chemokine secretion). Collectively, these results have pathogenic relevance and implication for immunotherapy of cancer.

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.

¹ This work was been supported by grants from Comitato Interministeriale per la Programmazione Economica (02/07/2004, Center of Advanced Biotechnology Project) and from Compagnia di San Paolo, Torino, "Analysis of Frequency and Functional Activity of Telomerase-Specific CD8⁺ T Lymphocytes and CD8⁺ T Suppressor Lymphocytes in Cancer Patients" and "Tolerogenic Gene Immunization and Adoptive Suppressor Cell Transfer as Therapies for Systemic Lupus Erythematosus."

² Address correspondence and reprint requests to Dr. Francesco Indiveri, Department of Internal Medicine and Centre of Excellence for Biomedical Research, University of Genoa, Viale Benedetto XV No. 6, 16132, Genova, Italy. E-mail address: frindi{at}unige.it

³ Abbreviations used in this paper: Treg, regulatory T lymphocyte; TIL, tumor-infiltrating lymphocyte.

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