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  • Mélanome

BRAF Inhibition Increases Tumor Infiltration by T cells and Enhances the Anti-tumor Activity of Adoptive Immunotherapy in Mice

Menée à l'aide de xénogreffes, cette étude évalue l'intérêt d'une stratégie combinant un inhibiteur de BRAF et un transfert adoptif de lymphocytes T pour le traitement de patients atteints d'un mélanome

Purpose:Treatment of melanoma patients with selective BRAF inhibitors results in objective clinical responses in the majority of patients with BRAF mutant tumors. However, resistance to these inhibitors develops within a few months. In this study, we test the hypothesis that BRAF inhibition in combination with adoptive T-cell transfer (ACT) will be more effective at inducing long-term clinical regressions of BRAF-mutant tumors. Experimental Design:BRAF-mutated human melanoma tumor cell lines transduced to express gp100 and H-2Db to allow recognition by gp100-specific pmel-1 T-cells were used as xenograft models to assess melanocyte differentiation antigen-independent enhancement of immune responses by BRAF inhibitor PLX4720. Luciferase expressing pmel-1 T cells were generated to monitor T-cell migration in vivo. The expression of vascular endothelial growth factor (VEGF) was determined by enzyme-linked immunosorbent assay, protein array and immunohistochemistry. Importantly, VEGF expression after BRAF inhibition was tested in a set of patient samples. Results:We found that administration of PLX4720 significantly increased tumor infiltration of adoptively transferred T cells in vivo and enhanced the antitumor activity of ACT. This increased T-cell infiltration was primarily mediated by the ability of PLX4720 to inhibit melanoma tumor cell production of VEGF by reducing the binding of c-myc to the VEGF promoter. Furthermore, analysis of human melanoma patient tumor biopsies before and during BRAF inhibitor treatment showed downregulation of VEGF consistent with the pre-clinical murine model. Conclusions:These findings provide a strong rationale to evaluate the potential clinical application of combining BRAF inhibition with T-cell based immunotherapy for the treatment of melanoma patients.

Clinical Cancer Research

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