Response to Comment on “Myeloid-Derived Suppressor Cells Suppress Antitumor Immune Responses through IDO Expression and Correlate with Lymph Node Metastasis in Patients with Breast Cancer”

Thank you for your comments on our paper, a report on our study of the regulatory role of IDO in myeloid-derived suppressor cell (MDSC) suppression of antitumor immunity and the correlation between lymph node metastasis and IDO expression in MDSCs in patients with breast cancer. Indeed, IDO-expressing cells, including dendritic cells and MDSCs, interact with various immunoregulatory cells and mediate the establishment and maintenance of the tumor-suppressive milieu (1). Thus, there are increasing scientific interests in IDO as a novel therapeutic target for the development of new cancer therapies. 1-methyl-tryptophan is a well-studied IDO inhibitor that acts as a competitive inhibitor of L-tryptophan binding to and metabolization by IDO, and its phase II clinical trial has been initiated (2). Despite this progress, some challenges regarding IDO targeting therapy remain. First, most IDO inhibitors exert only mild effects on IDO’s enzymatic and cellular activities (3). Second, IDO can serve as an intracellular signal transducer in the cytoplasm (4), and current inhibitors are not designed to block its signaling functions (5). Third, a recent study published in 2011 (6) found that 1-methyl-tryptophan increased the expression of IDO mRNA and protein, which raises concerns for disadvantageous IDO-dependent immunosuppression after 1-methyl-L-tryptophan treatment and indicates that further investigations are needed. Therefore, it is questionable whether current IDO inhibitors are optimal candidates for clinical application, and more therapeutic strategies targeting IDO are needed. As reported in your study (7), the strategy of inducing endogenic cytotoxic immune cells, such as “supporter T cells,” to suppress IDO⁺ cells provides new insights into clinical regulation of IDO. In addition, targeting the signaling pathway mediating IDO expression is also a promising strategy that attracts considerable research interests (3). In our previous work, we demonstrated that IDO-aberrant expression in MDSCs correlated with upregulated STAT3 activation. Our study has identified that activation of the noncanonical NF-κB pathway is involved in STAT3-mediated IDO gene transcription. We hope that these results will provide insights into the molecular mechanism underlying IDO-aberrant expression in immune cells, and promote IDO-based therapeutic strategies for cancer treatment.

• Copyright © 2013 by The American Association of Immunologists, Inc.