ELUCIDATE ACKR3 EXPRESSION AND FUNCTION IN GLIOBLASTOMA-ASSOCIATED MICROENVIRONMENT

Abstract AIMS Glioblastoma is the most prevalent primary brain tumor in adults, leading to a grim prognosis. The development of efficient therapies is limited by several factors, including the immunosuppressive tumor microenvironment. The chemokine receptor CXCR4 has been described as a key player in glioblastoma progression, participating in tumor cell stemness, invasion, angiogenesis and immunosuppression. Accumulating results indicate that ACKR3, the other receptor for the chemokine CXCL12, might also participate in tumor severity. However, its function in cancer remains to be determined. We aim to characterize the expression and function of ACKR3 in glioblastoma-associated microenvironment and evaluate its potential relevance as therapeutic target. METHODS Experiments were carried on using syngeneic murine glioblastoma models, i.e. intracranial engraftment of GL261 cells. The immune landscape of GL261 tumors was characterized by spectral flow cytometry in untreated conditions, or after pharmacological modulation of ACKR3 and CXCR4. RESULTS In our model, CXCR4 is expressed on murine glioblastoma cells, as well as at the surface of cells from the myeloid lineage and NK cells. ACKR3 is nearly absent on tumor cells, but is highly expressed on myeloid, NK and T cells. Pharmacological modulation of the receptors had a systemic effect on CXCL12 plasma concentration in mice, showing a significant increase after administration of ACKR3 and CXCR4 antagonists. Changes in immune cells recruitment to the brain were observed upon receptor modulation. Modulation of ACKR3 and CXCR4 had opposite effects on the recruitment of TAMs. Unlike CXCR4, modulation of ACKR3 also had an impact on the proportion of CD4+ and CD8+ T cells, suggesting its function in immunosurveillance. CONCLUSION These data support the hypothesis that ACKR3, as well as CXCR4, participate to the immunosuppressive mi- croenvironment of glioblastoma. The physiopathological relevance of these findings remain to be addressed regarding the mobilization of cells and their phenotype, as well as its impact on tumor growth.