CXCR4 antagonism in combination with IDO1 inhibition weakens immune suppression and inhibits tumor growth in mouse breast cancer bone metastases

PURPOSE: To investigate whether inhibition of the CXCL12/CXCR4 axis or IDO1 could produce antitumor effects in a metastasized breast cancer immunocompetent animal model. METHODS: Breast cancer metastasis models were established in mice. CXCR4 inhibitor and IDO1 inhibitor were used to evaluate the anticancer effects. RESULTS: Combination treatment using the CXCR4 antagonist AMD3465 and the IDO1 inhibitor D1MT successfully delayed the progression of breast cancer bone metastases. AMD3465 reduced the number of intratumoral regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSCs), while D1MT facilitated the antitumor effects of intratumoral CD8+ T-cells. IDO1 inhibition elevated the expression of perforin, granzyme-B, and IFN-γ in CD8+ T-cells, and AMD3465 treatment weakened the potential immune suppressive effects of Tregs and MDSCs. As a result, combination treatment significantly prolonged tumor-bearing mouse survival in two metastasis models, and these antitumor effects relied on overexpression of indoleamine 2, 3-dioxygenase 1 (IDO1), an enzyme that modulates the immune response and impairs immune attack in ovarian cancers CXCR3+ CD8+ cytotoxic T-cell function. CONCLUSION: The current study provides preclinical evidence that AMD3465 treatment in combination with IDO1 inhibition may be a promising therapeutic regimen for refractory metastasized breast cancers.