Tumor cells possess altered antigens that can be recognized by T cells, however, lack of danger signals and antigenic similarity to self-somatic cells engage the self-tolerance mechanism. This is one of the major reasons why anti-tumor immunity is hardly acquired. We reported that both antitumor effector T cells and regulatory T cells, which are capable of abrogating all the antitumor reactivity of effector T cells, are generated in the same tumor-draining LNs (TDLN) during tumor progression. CD62Llow TDLN T cells are antitumor effector T cells, which mediate antitumor efficacy in vivo. On the other hand, CD62Lhigh CD25+CD4+ T cells are proven to be tumor-antigen specific regulatory T cells. In this study, we examined if regulatory T cells are induced in small cell lung cancer (SCLC) patients. SCLC is an aggressive disease and has a great tendency to be widely disseminated. Even limited disease (LD), which is proven to have no obvious distant metastases with CT and/or MRI examination, is considered to possess systemic micrometastases. Thus, peripheral blood is a place where SCLC cells could be usually encountered by immunological system. Ten LD patients, 10 extended disease (ED) patients, 8 long survivors and 10 normal volunteers were enrolled in this study. Mononuclear cells (MNC) separated from peripheral blood by Ficoll gradient sedimentation were examined for phenotype. Certain T cells were purified with magnetic beads for functional assays. This study is approved by the Niigata University Ethical Committee. CD62Lhigh CD25+CD4+ T cells in SCLC patients possess regulatory functions, since they suppressed cell proliferation or cytokine production of CD62Llow CD4+ T cells. FCM analysis revealed that only CD62Lhigh CD25+CD4+ T cells are positive for FoxP3. The ratio of CD62Lhigh CD25+CD4+ T cells (Treg) based on total CD4+ cells is significantly (P<0.01) high in ED patients compared with LD patients, long survivors, or normal volunteers. The ratio of CD62Llow CD4+ T cells (Teff) is significantly (P<0.01) high in LD patients and long survivors, compared with ED patients, or normal volunteers. Thus, only ED patients have significantly (P<0.01) high Treg/Teff ratio. No cell biological differences have been observed between cancer cells of LD-SCLC and ED-SCLC. It is demonstrated that SCLC patients comprising paraneoplastic syndrome, such as Lambert-Eaton myasthenic syndrome mediated by immunological mechanisms, have retardated courses of disease and are often found as LD stage after long-term neurological manifestations. Our data suggests that disrupted immunological surveillance system by induced Treg resulted in distant metastases of SCLC. Moreover, Teff dominant CD4+ T cell balance might be important to control micrometastases for long survivors, since recurrent LD-SCLC patients failed to maintain Teff dominant CD4+ T cell balance.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]