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

Research output: Contribution to journalArticle

156 Citations (Scopus)

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
Externally publishedYes

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Stromal Cells
Interleukin-1
Immunosuppression
Melanoma
Interleukin-1alpha
Melanocytes
T-Lymphocytes
Cell Line
Biopsy
Neoplasm Antigens
Therapeutics
Regulator Genes
Tumor Cell Line
Neoplasms
Research Design
Up-Regulation
Ligands
Gene Expression

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Khalili, J. S., Liu, S., Rodríguez-Cruz, T. G., Whittington, M., Wardell, S., Liu, C., ... 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

Oncogenic BRAF(V600E) promotes stromal cell-mediated immunosuppression via induction of interleukin-1 in melanoma. / Khalili, Jahan S.; Liu, Shujuan; Rodríguez-Cruz, Tania G.; Whittington, Mayra; Wardell, Seth; Liu, Chengwen; Zhang, Minying; Cooper, Zachary A.; Frederick, Dennie T.; Li, Yufeng; Zhang, Min; Joseph, Richard W; Bernatchez, Chantale; Ekmekcioglu, Suhendan; Grimm, Elizabeth; Radvanyi, Laszlo G.; Davis, Richard E.; Davies, Michael A.; Wargo, Jennifer A.; Hwu, Patrick; Lizée, Gregory.

In: Clinical Cancer Research, Vol. 18, No. 19, 01.10.2012, p. 5329-5340.

Research output: Contribution to journalArticle

Khalili, JS, Liu, S, Rodríguez-Cruz, TG, Whittington, M, Wardell, S, Liu, C, Zhang, M, Cooper, ZA, Frederick, DT, Li, Y, Zhang, M, Joseph, RW, Bernatchez, C, Ekmekcioglu, S, Grimm, E, Radvanyi, LG, Davis, RE, Davies, MA, Wargo, JA, Hwu, P & Lizée, G 2012, 'Oncogenic BRAF(V600E) promotes stromal cell-mediated immunosuppression via induction of interleukin-1 in melanoma', Clinical Cancer Research, vol. 18, no. 19, pp. 5329-5340. https://doi.org/10.1158/1078-0432.CCR-12-1632
Khalili, Jahan S. ; Liu, Shujuan ; Rodríguez-Cruz, Tania G. ; Whittington, Mayra ; Wardell, Seth ; Liu, Chengwen ; Zhang, Minying ; Cooper, Zachary A. ; Frederick, Dennie T. ; Li, Yufeng ; Zhang, Min ; Joseph, Richard W ; Bernatchez, Chantale ; Ekmekcioglu, Suhendan ; Grimm, Elizabeth ; Radvanyi, Laszlo G. ; Davis, Richard E. ; Davies, Michael A. ; Wargo, Jennifer A. ; Hwu, Patrick ; Lizée, Gregory. / Oncogenic BRAF(V600E) promotes stromal cell-mediated immunosuppression via induction of interleukin-1 in melanoma. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 19. pp. 5329-5340.
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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.",
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T1 - Oncogenic BRAF(V600E) promotes stromal cell-mediated immunosuppression via induction of interleukin-1 in melanoma

AU - Khalili, Jahan S.

AU - Liu, Shujuan

AU - Rodríguez-Cruz, Tania G.

AU - Whittington, Mayra

AU - Wardell, Seth

AU - Liu, Chengwen

AU - Zhang, Minying

AU - Cooper, Zachary A.

AU - Frederick, Dennie T.

AU - Li, Yufeng

AU - Zhang, Min

AU - Joseph, Richard W

AU - Bernatchez, Chantale

AU - Ekmekcioglu, Suhendan

AU - Grimm, Elizabeth

AU - Radvanyi, Laszlo G.

AU - Davis, Richard E.

AU - Davies, Michael A.

AU - Wargo, Jennifer A.

AU - Hwu, Patrick

AU - Lizée, Gregory

PY - 2012/10/1

Y1 - 2012/10/1

N2 - 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.

AB - 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.

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