IDO Is a Nodal Pathogenic Driver of Lung Cancer and Metastasis Development

Abstract

IDO (indoleamine 2,3-dioxygenase) enzyme inhibitors have entered clinical trials for cancer treatment based on preclinical studies indicating that they can defeat immune escape and broadly enhance other therapeutic modalities. However, clear genetic evidence of IDO’s impact on tumorigenesis in physiologic models of primary or metastatic disease is lacking. Investigating the impact of Ido1 gene disruption in mouse models of oncogenic KRAS-induced lung carcinoma and breast carcinoma-derived pulmonary metastasis, we have found that IDO-deficiency resulted in reduced lung tumor burden and improved survival in both models. Micro-CT imaging further revealed that the density of the underlying pulmonary blood vessels was significantly reduced in Ido1-nullizygous mice. During lung tumor and metastasis outgrowth, IL6 induction was greatly attenuated in conjunction with the loss of IDO. Biologically, this resulted in a consequential impairment of pro-tumorigenic MDSCs (myeloid-derived suppressor cells), as restoration of IL6 recovered both MDSC suppressor function and metastasis susceptibility in Ido1-nullizygous mice. Together, our findings define IDO as a prototypical integrative modifier that bridges inflammation, vascularization and immune escape to license primary and metastatic tumor outgrowth.

The Emerging Role of Immunosurveillance in Dictating Metastatic Spread in Breast Cancer

“…In addition, MDSCs isolated from breast cancer tissues have been shown to suppress T-cell response via indoleamine 2,3-dioxygenase (IDO; ref. 33), consistent with findings in mouse models (34). In fact, recent data also support a role for MDSCs in promoting metastasis in other cancers, such as melanoma (35).…”

The Calcineurin-NFAT Axis Controls Allograft Immunity in Myeloid-Derived Suppressor Cells through Reprogramming T Cell Differentiation

“…During lung tumor and metastasis outgrowth, inflammatory cytokines were greatly attenuated in conjunction with the loss of IDO. Biologically, this resulted in a consequential impairment of protumorigenic MDSCs, as restoration of inflammatory cytokines recovered both MDSC suppressive activities and metastasis susceptibility in IDO1-nullizygous mice (54). These results indicate that IDO is a prototypical integrative modifier that bridges inflammation and immune escape to license primary and metastatic tumor outgrowth.…”

Breaking immunotolerance of tumors: A new perspective for dendritic cell therapy

“…A tolerogenic activity of IDO, resulting from tryptophan degradation, is to inhibit proliferation and induce apoptosis of effector T-lymphocytes, while simultaneously stimulating FoxP3 þ T reg cell generation (Godin-Ethier et al, 2011). High IDO expression in cancer tissues is associated with lower numbers and impaired function of CD8 þ T-lymphocytes and NK cells (Ino et al, 2008;Liu et al 2009;Wang et al, 2012;Zhang et al, 2011) and, in turn, correlated with a poorer patient prognosis (Inaba et al, 2009;Smith et al, 2012;Yu et al, 2011). A presence of IDO-DC in tumor-draining lymph nodes might contribute to the immunologic unresponsiveness in cancer patients (Godin-Ethier et al, 2011).…”