Reciprocal CD4+ T-Cell Balance of Effector CD62Llow CD4+ and CD62Lhigh CD25+ CD4+ Regulatory T Cells in Small Cell Lung Cancer Reflects Disease Stage

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(+) Tcells with down-regulated expression of CD62L (CD62L(low)) produced IFN-gamma, interleukin (IL)-4, and IL-17, thus considered to be immune effector Tcells (Teff). Significantly moreTeff cell numbers were detected in LD-SCLC patients than that of extended-stage SCLC (ED-SCLC). By contrast, induction of CD62L(high) CD25(+) 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(+) Tcells (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.