CXCR3 is a key regulator during macrophage differentiation and has a significant impact on tumor-associated macrophages

Background It has been appreciated that in the presence of tumors, hematopoetic stem cells have the potential to proliferate and differentiate towards the monocytic and granulocytic lineages resulting in an intratumoral accumulation of suppressive immune cells like tumor-associated macrophages. Furthermore, recent studies have shown that the CXCR3 network is important for the efficacy of immune checkpoint inhibitor therapy and has an influence on the tumor-associated angiogenesis.

Method In vivo, HCC was induced in Cxcr3-/- and wild-type (WT) mice. The HCC-related immune response was analyzed, with focus on tumor-associated macrophages. In vitro, phenotype of Cxcr3-/- and WT hematopoietic progenitor cells, myeloid precursor cells and monocyte-derived macrophages were determined. To define changes in the macrophage lineage an epigenetic sequencing of WT and Cxcr3-/- myeloid precursor cells and monocytes was executed. To elucidate regulatory pathways in monocyte-derived macrophages, we performed multi-kinase arrays.

Results Cxcr3-/- mice displayed a significantly increased tumor burden compared to WT mice. Deletion of Cxcr3 promotes the myeloid progenitor lineage and modulates chromatin accessibility for key transcription factors. Furthermore, deletion of Cxcr3 leads to an altered kinase activity in macrophages and a pro-tumorigenic differentiation. The enhanced secretion of anti-inflammatory, pro-angiogenic and pro-proliferative mitogens characterizes this cell population. In addition, the inactivation of Cxcr3 in monocyte-derived macrophages results in an anti-inflammatory profile compared to WT cells.

Conclusion We here decipher the complex regulatory network of CXCR3 impacting macrophage polarization and cell biology and identify new targets to improve anti-PD-L1 and anti-VEGF therapy in HCC.

Publikationsverlauf

Artikel online veröffentlicht:
26. Januar 2022