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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Am+J+Cancer+Res
2016 ; 6
(11
): 2514-2531
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Combined VEGFR and CTLA-4 blockade increases the antigen-presenting function of
intratumoral DCs and reduces the suppressive capacity of intratumoral MDSCs
#MMPMID27904768
Du Four S
; Maenhout SK
; Niclou SP
; Thielemans K
; Neyns B
; Aerts JL
Am J Cancer Res
2016[]; 6
(11
): 2514-2531
PMID27904768
show ga
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 ?CTLA-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+?CTLA-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.