Oncogenic BRAF(V600E) promotes stromal cell-mediated immunosuppression via induction of interleukin-1 in melanoma

Jahan S. Khalili, Shujuan Liu, Tania G. Rodríguez-Cruz, Mayra Whittington, Seth Wardell, Chengwen Liu, Minying Zhang, Zachary A. Cooper, Dennie T. Frederick, Yufeng Li, Min Zhang, Richard W. Joseph, Chantale Bernatchez, Suhendan Ekmekcioglu, Elizabeth Grimm, Laszlo G. Radvanyi, Richard E. Davis, Michael A. Davies, Jennifer A. Wargo, Patrick HwuGregory Lizée

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175 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)5329-5340
Number of pages12
JournalClinical Cancer Research
Volume18
Issue number19
DOIs
StatePublished - Oct 1 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Khalili, J. S., Liu, S., Rodríguez-Cruz, T. G., Whittington, M., Wardell, S., Liu, C., Zhang, M., Cooper, Z. A., Frederick, D. T., Li, Y., Zhang, M., Joseph, R. W., Bernatchez, C., Ekmekcioglu, S., Grimm, E., Radvanyi, L. G., Davis, R. E., Davies, M. A., Wargo, J. A., ... Lizée, G. (2012). Oncogenic BRAF(V600E) promotes stromal cell-mediated immunosuppression via induction of interleukin-1 in melanoma. Clinical Cancer Research, 18(19), 5329-5340. https://doi.org/10.1158/1078-0432.CCR-12-1632