Axitinib increases the infiltration of immune cells and reduces the suppressive capacity of monocytic MDSCs in an intrac

[D.ap]

Axitinib increases the infiltration of immune cells and reduces the suppressive capacity of monocytic MDSCs in an intracranial mouse melanoma model



Abstract

Melanoma patients are at a high risk of developing brain metastases, which are strongly vascularized and therefore have a significant risk of spontaneous bleeding. VEGF not only plays a role in neo-angiogenesis but also in the antitumor immune response. VEGFR-targeted therapy might not only have an impact on the tumor vascularization but also on tumor-infiltrating immune cells. In this study, we investigated the effect of axitinib, a small molecule TKI of VEGFR-1, -2, and -3, on tumor growth and on the composition of tumor-infiltrating immune cells in subcutaneous and intracranial mouse melanoma models. In vivo treatment with axitinib induced a strong inhibition of tumor growth and significantly improved survival in both tumor models. Characterization of the immune cells within the spleen and tumor of tumor-bearing mice respectively showed a significant increase in the number of CD3+CD8+ T cells and CD11b+ cells of axitinib-treated mice. More specifically, we observed a significant increase of intratumoral monocytic myeloid-derived suppressor cells (moMDSCs; CD11b+Ly6ChighLy6G-). Interestingly, in vitro proliferation assays showed that moMDSCs isolated from spleen or tumor of axitinib-treated mice had a reduced suppressive capacity on a per cell basis as compared to those isolated from vehicle-treated mice. Moreover, MDSCs from axitinib-treated animals displayed the capacity to stimulate allogeneic T cells. Thus, treatment with axitinib induces differentiation of moMDSC toward an antigen-presenting phenotype. Based on these observations, we conclude that the impact of axitinib on tumor growth and survival is most likely not restricted to direct anti-angiogenic effects but also involves important effects on tumor immunity.

Keywords: angiogenesis, axitinib, brain metastasis, immune cells, MDSC, melanoma
Abbreviations: BLI, bioluminescent imaging; DCs, Dendritic Cells; FDA, US Food and Drug Administration; grMDSC, granulocytic MDSC, IFNγ: interferon gamma; IL-2, interleukin-2; MDSC, myeloid-derived suppressor cells; moMDSC, monocytic MDSC; OT-1, CD8+ T-cells with transgenic receptor specific for the H-2Kb-restricted ovalbumin (OVA) peptide SIINFEKL; PD-1, programmed death 1; PD-L1, programmed death 1 ligand; PFS, progression-free survival; TNFα, Tumor Necrosis Factor alfa; Treg, regulatory T cells; VEGF, Vascular Endothelial Growth Factor; TKI, Tyrosine Kinase Inhibitor


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485747/

[Olga]

Obviously some immune suppressing might be a good thing if it suppresses the parts of the immune system that help the tumors to evade the immune system discovery, such as T-Regs etc. Immune system is very complex and some parts balance the other ones, otherwise we would die from the allergy for example.