Selective BRAF inhibition decreases tumor-resident lymphocyte frequencies in a mouse model of human melanoma

• DOI: 10.4161/onci.20226
• Publication Date: 2012-04-20T17:30:50Z
• Authors: Anna Hooijkaas; Jules Gadiot; Michelle Morrow; Ross Stewart; Ton Schumacher; Christian U. Blank
• Keywords: Dabrafenib

The development of targeted therapies and immunotherapies has markedly advanced the treatment metastasized melanoma. While with selective BRAF(V600E) inhibitors (like vemurafenib or dabrafenib) leads to high response rates but short duration, CTLA-4 blocking induce sustained responses, only in a limited number patients. combination these diametric approaches may further improve survival, pre-clinical data concerning this approach is limited. We investigated, using Tyr::CreER(T2)PTEN(F-/-)BRAF(F-V600E/+) inducible melanoma mice, whether inhibition can synergize anti-CTLA-4 mAb treatment, focusing on interaction between inhibitor PLX4720 immune system. strongly decreased tumor growth, it did not cell death BRAF(V600E)/PTEN(-/-) melanomas. More strikingly, led frequency tumor-resident T cells, NK-cells, MDSCs macrophages, which could be restored by addition mAb. As effect was observed upon BRAF wild-type B16F10 tumors, we conclude that cells correlates due an off-target cells. Furthermore, mice treated result enhanced control, while tumor-vaccination B16F10-inoculated mice. Our suggest negatively affect activity within tumor. Therefore, potential therapy tumor-microenvironment should taken into consideration design clinical trials combining immunotherapy.