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Increased Frequency of CD4⁺ Cells Expressing CD161 in Cancer Patients

Authors' Affiliations: ¹ Cancer Immunology and Immunotherapy Center, ² Department of Clinical Oncology, and ³ Breast Cancer Clinic, Saint Savas Cancer Hospital, Athens, Greece

Requests for reprints: Sonia Perez, Cancer Immunology Immunotherapy Center, Saint Savas Cancer Hospital, 171 Alexandras Avenue, Athens 115-22, Greece. Phone: 30-210-6409459; Fax: 30-210-6409516; E-mail: perez{at}ciic.gr.

Purpose: Although the function of natural killer receptors on T cells infiltrating tumors and their potential effect on antitumor immunity has been investigated, little is known about T cells expressing NKR-P1A (CD161) in cancer patients. In the present study, we examined T cells expressing CD161 in the peripheral blood, the tumor tissue and in malignant effusions of patients with several types of malignancies.

Experimental Design: Expression of CD161 in CD4⁺ or CD8⁺ (lacking CD56) T cells isolated from peripheral blood (n = 61), tumor specimens (n = 8), and malignant effusions (n = 37) of cancer patients was examined using four-color flow cytometry. Proliferative capacity and cytokine production of purified CD4⁺CD161⁺CD56^– cells were studied after weak or strong stimulation, with or without costimulation, in the presence or absence of interleukin 2. The possible regulatory function of activated CD4⁺CD161⁺CD56^– cells on T-cell alloresponses was also investigated.

Results: CD4⁺ cells expressing CD161 were increased in cancer patients, compared with healthy individuals. This increase in the peripheral blood of cancer patients positively correlated with disease stage and was augmented at the tumor site. Phenotypic analysis revealed that CD4⁺CD161⁺ cells are memory T cells, with low expression of activation markers. CD4⁺CD161⁺ cells play an immunoregulatory role through cytokine production, because upon receiving costimulatory signals via CD28, they exert suppressive activity on autologous peripheral blood mononuclear cell alloresponses.

Conclusions: CD4⁺CD161⁺CD56^– cells represent a distinct memory T-cell population significantly increased in cancer patients. Depending on the type of signals provided by the tumor microenvironment, CD4⁺CD161⁺ cells may regulate the immune response.

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