title: Combined VEGFR and CTLA-4 blockade increases the antigen-presenting function of intratumoral DCs and reduces the suppressive capacity of intratumoral MDSCs.
abstract: Melanoma brain metastases (MBM) occur in 10% to 50% of melanoma patients. They are often associated with a high morbidity and despite the improvements in the treatment of advanced melanoma, including immunotherapy, patients with MBM still have a poor prognosis. Antiangiogenic treatment was shown to reduce the immunosuppressive tumor microenvironment. Therefore we investigated the effect of the combination of VEGFR- and CTLA-4 blockade on the immune cells within the tumor microenvironment. In this study we investigated the effect of the combination of axitinib, a TKI against VEGFR-1, -2 and -3, with therapeutic inhibition of CTLA-4 in subcutaneous and intracranial mouse melanoma models. The combination of axitinib with αCTLA-4 reduced tumor growth and increased survival in both intracranial and subcutaneous models. Investigation of the splenic immune cells showed an increased number of CD4+and CD8+T cells after combination treatment. Moreover, combination treatment increased the number of intratumoral dendritic cells (DCs) and monocytic myeloid-derived suppressor cells (moMDSCs). When these immune cell populations were sorted from the subcutaneous and intracranial tumors of mice treated with axitinib+αCTLA-4, we observed an increased antigen-presenting function of DCs and a reduced suppressive capacity of moMDSCs on a per cell basis. Our results suggest that the combination of antiangiogenesis and checkpoint inhibition can lead to an enhanced antitumor effect leading to increased survival. We found that this effect is in part due to an enhanced antitumor immune response generated by an increased antigen-presenting function of intratumoral DCs in combination with a reduced suppressive capacity of intratumoral moMDSCs.
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel Laarbeeklaan 103E, 1090, Brussels, Belgium.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Du Four
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel Laarbeeklaan 103E, 1090, Brussels, Belgium.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Maenhout
authors.affiliation: NORLUX Neuro-Oncology Laboratory, Luxembourg Institute of Health (LIH) Luxembourg.
authors.forename: Simone P
authors.initials: SP
authors.lastname: Niclou
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Vrije Universiteit BrusselLaarbeeklaan 103E, 1090, Brussels, Belgium; Department of Medical OncologyUZ Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium.
authors.forename: Kris
authors.initials: K
authors.lastname: Thielemans
authors.affiliation: Department of Medical Oncology UZ Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Neyns
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel Laarbeeklaan 103E, 1090, Brussels, Belgium.
authors.forename: Joeri L
authors.initials: JL
authors.lastname: Aerts
keywords: CTLA-4 blockade; DCs; MDSC; antiangiogenesis; melanoma brain metastases; tumor microenvironment