Oncogenic BRAF(V600E) Promotes Stromal Cell-Mediated Immunosuppression Via Induction of Interleukin-1 in Melanoma

摘要: Purpose: In this study, we assessed the specific role of BRAF(V600E) signaling in modulating expression immune regulatory genes melanoma, addition to analyzing downstream induction suppression by primary human melanoma tumor-associated fibroblasts (TAF). Experimental Design: Primary melanocytes and cell lines were transduced express WT or V600E forms BRAF, followed gene analysis. The inhibitor vemurafenib was used confirm targets BRAF(V600E)-positive tumors from patients undergoing treatment. TAF generated patient biopsies tested for their ability inhibit function tumor antigen-specific T cells, before following treatment with BRAF(V600E)-upregulated modulators. Transcriptional analysis treated TAFs conducted identify potential mediators T-cell suppression. Results: Expression induced transcription interleukin 1 alpha (IL-1α) IL-1β lines. Further, reduced IL-1 protein most notably 11 12 Treatment melanoma-patient–derived IL-1α/β significantly enhanced suppress proliferation melanoma-specific cytotoxic inhibition partially attributable upregulation COX-2 PD-1 ligands PD-L1 PD-L2 TAFs. Conclusions: This study reveals a novel mechanism sensitive inhibition, indicates that clinical blockade may benefit BRAF wild-type potentially synergize immunotherapeutic interventions. Clin Cancer Res; 18(19); 5329–40. ©2012 AACR .