Abstract A16: The crosstalk between Indoleamine 2,3 Dioxygenase (IDO) and cancer stem cells in murine melanoma: A potential modality of local control

Abstract

Abstract Introduction: Indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme of tryptophan catabolism, has been strongly associated with the progression of malignancy and poor survival in melanoma patients. As a result, IDO is a leading target for interventions aimed at restoring melanoma immune surveillance. IDO, which is produced by cells including dendritic cells, macrophages, stem cells, and most tumor cells, potently suppresses immune responses by depleting local tryptophan and allowing the accumulation of tryptophan metabolites. However, the actual cellular and molecular mechanisms underlying the immunoregulatory function of IDO remain largely unknown. The relatively newly described cancer stem cells (CSCs) are tumor-initiating cells (TICs) that often survive therapy and give rise to second-line tumors by self-renewal and differentiation into multiple cell types. CSCs are proposed to persist in tumors as a distinct population and to cause relapse and metastasis by giving rise to new tumors. Therefore, development of specific therapies targeted at CSCs holds hope for improvement of survival and quality of life of cancer patients, especially those with metastatic disease. Methods: C57/BL6 mice were injected with B16F10 murine melanoma cell line (1 x 106 cells/mouse, subcutaneous). Tumor growth monitored. At 3mm, tumors were injected with an IDO Inhibitor (1 MT) (Group 1) twice weekly (20 mg/mouse per injection). Controls (Group 2) received vehicle only (PBS), Group 3 weekly Cisplatin (5mg/kg), and Group 4 both Cisplatin and 1MT (IDO inhibitor). Once the first tumor reached 12mm in size, the mice were sacrificed and tumor cells subjected to flow-cytometry, and statistical analysis, and p-values <0.05 considered significant. Results: Our data showed for the first time that IDO was expressed by CSCs in a murine melanoma model. These IDO-expressing CSCs may be capable of suppressing T lymphocyte infiltration into the tumor microenvironment, which was reversed by the IDO inhibitor, 1-methyl-tryptophan. Conclusion: Our findings offer an important new line of evidence that interventional targeting of IDO activity could be used to restore tumor immunity by relieving IDO-mediated immune suppression of CSCs in the tumor microenvironment as well as in tumor cells themselves. Citation Format: Marsha Kocherla, Blake Christianson, James Walker, Xu Qin, Jack C. Yu, Babak Baban. The crosstalk between Indoleamine 2,3 Dioxygenase (IDO) and cancer stem cells in murine melanoma: A potential modality of local control. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr A16.