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Reciprocal CD4⁺ T-Cell Balance of Effector CD62L^low CD4⁺ and CD62L^highCD25⁺ CD4⁺ Regulatory T Cells in Small Cell Lung Cancer Reflects Disease Stage

Authors' Affiliations: ¹ Division of Respiratory Medicine, Department of Homeostatic Regulation and Development, Course for Biological Functions and Medical Control, Graduate School of Medical and Dental Sciences, Niigata University; ² Bioscience Medical Research Center, Niigata University Medical and Dental Hospital, Niigata, Japan

Requests for reprints: Hiroshi Kagamu, Division of Respiratory Medicine, Department of Homeostatic Regulation and Development, Course for Biological Functions and Medical Control, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-dori, Niigata 951-8520, Japan. Phone: 81-25-227-2200; Fax: 81-25-227-0931; E-mail: hkagamu{at}med.niigata-u.ac.jp.

Purpose: Small cell lung cancer (SCLC) possesses high tendency to disseminate. However, SCLC patients with paraneoplastic syndrome mediated by immunity against onconeural antigens remain in limited-stage disease (LD) without distant metastases. Cumulative evidence regulates that a balance between immune and regulatory T (Treg) cells determines the magnitude of immune responses to not only self-antigens but also tumor-associated antigens. The purpose of this study was to elucidate the immunologic balance induced in SCLC patients.

Experimental Design: We analyzed T cells in the peripheral blood of 35 consecutive SCLC patients, 8 long-term survivors, and 19 healthy volunteers.

Results: Purified CD4⁺ T cells with down-regulated expression of CD62L (CD62L^low) produced IFN-, interleukin (IL)-4, and IL-17, thus considered to be immune effector T cells (Teff). Significantly more Teff cell numbers were detected in LD-SCLC patients than that of extended-stage SCLC (ED-SCLC). By contrast, induction of CD62L^highCD25⁺ CD4⁺ Treg cells was significantly higher in ED-SCLC patients. Long-term survivors of SCLC maintained a high Teff to Treg cell ratio, whereas patients with recurrent disease exhibited a low Teff to Treg cell ratio. Teff cells in LD-SCLC patients included more IL-17–producing CD4⁺ T cells (Th17). Moreover, dendritic cells derived from CD14⁺ cells of LD-SCLC patients secreted more IL-23.

Conclusion: These results show that CD4⁺ T-cell balance may be a biomarker that distinguishes ED-SCLC from LD-SCLC and predicts recurrence. This study also suggests the importance of inducing Teff cells, particularly Th17 cells, while eliminating Treg cells to control systemic dissemination of SCLC.