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

Stephanie Du Four; Sarah K Maenhout; Kari De Pierre; Dries Renmans; Simone P Niclou; Kris Thielemans; Bart Neyns; Joeri L Aerts

doi:10.1080/2162402X.2014.998107

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

Oncoimmunology. 2015 Jan 22;4(4):e998107. doi: 10.1080/2162402X.2014.998107. eCollection 2015 Apr.

Authors

Stephanie Du Four¹, Sarah K Maenhout¹, Kari De Pierre², Dries Renmans¹, Simone P Niclou³, Kris Thielemans¹, Bart Neyns⁴, Joeri L Aerts¹

Affiliations

¹ Laboratory of Molecular and Cellular Therapy; Department of Immunology-Physiology; Vrije Universiteit Brussel , Brussels, Belgium.
² Department of Pathology ; UZ Brussel, Brussels, Belgium.
³ NORLUX Neuro-Oncology Laboratory; Luxembourg Institute of Health (LIH) ; Luxembourg.
⁴ Department of Medical Oncology ; UZ Brussel, Brussels, Belgium.

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⁺Ly6C^highLy6G^-). 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: BLI, bioluminescent imaging; DCs, Dendritic Cells; FDA, US Food and Drug Administration; IL-2, interleukin-2; MDSC; MDSC, myeloid-derived suppressor cells; 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; TKI, Tyrosine Kinase Inhibitor; TNFα, Tumor Necrosis Factor alfa; Treg, regulatory T cells; VEGF, Vascular Endothelial Growth Factor; angiogenesis; axitinib; brain metastasis; grMDSC, granulocytic MDSC, IFNγ: interferon gamma; immune cells; melanoma; moMDSC, monocytic MDSC.

Publication types

Research Support, Non-U.S. Gov't