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

OncoTargets and Therapy
Jian ZhangLiulong Zhu

Abstract

To investigate whether inhibition of the CXCL12/CXCR4 axis or IDO1 could produce antitumor effects in a metastasized breast cancer immunocompetent animal model. Breast cancer metastasis models were established in mice. CXCR4 inhibitor and IDO1 inhibitor were used to evaluate the anticancer effects. 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. The current study provides preclinical evidence that AMD3465 treatment in comb...Continue Reading

Citations

Apr 25, 2020·Cancers·Veronica Mendoza-ReinosoPierrick G J Fournier
Dec 25, 2019·Seminars in Cancer Biology·Sara K DanielVenu G Pillarisetty
Jan 6, 2021·Journal of Mammary Gland Biology and Neoplasia·María Belén GiorelloNorma Alejandra Chasseing
May 12, 2021·Cytokine·Paulo Henrique Rosa da SilvaMarcelo José Barbosa Silva
Dec 29, 2020·Physiological Reviews·Philippe ClézardinIngunn Holen
Jul 30, 2021·Frontiers in Cell and Developmental Biology·Lingyun ZhangGuoxiong Xu
Aug 22, 2021·Cellular & Molecular Immunology·Laura A HuppertJames C Lee
Dec 31, 2019·Molecular Immunology·Sean H ColliganScott I Abrams

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Methods Mentioned

BETA
flow cytometry

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