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

Abstract

Jian Zhang,1 Yanxia Pang,2 Tao Xie,1 Liulong Zhu11Department of Orthopaedics, Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310009, People’s Republic of China; 2Taizhou University Medical School, Linhai 318000, People’s Republic of ChinaPurpose: 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.Keywords: breast cancer, immune response, metastasis, IDO1, chemokine

Keywords

• Breast cancer
• immune response
• metastasis
• IDO
• chemokine