Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function

Andrea Boni, Alexandria P. Cogdill, Ping Dang, Durga Udayakumar, Ching Ni Jenny Njauw, Callum M. Sloss, Cristina R. Ferrone, Keith T. Flaherty, Donald P. Lawrence, David E. Fisher, Hensin Tsao, Jennifer A. Wargo

Research output: Contribution to journalArticle

462 Citations (Scopus)

Abstract

Targeted therapy against the BRAF/mitogen-activated protein kinase (MAPK) pathway is a promising new therapeutic approach for the treatment of melanoma. Treatment with selective BRAF inhibitors results in a high initial response rate but limited duration of response. To counter this, investigators propose combining this therapy with other targeted agents, addressing the issue of redundancy and signaling through different oncogenic pathways. An alternative approach is combining BRAF/MAPK-targeted agents with immunotherapy. Preliminary evidence suggests that oncogenic BRAF (BRAFV600E) contributes to immune escape and that blocking its activity via MAPK pathway inhibition leads to increased expression of melanocyte differentiation antigens (MDA). Recognition of MDAs is a critical component of the immunologic response to melanoma, and several forms of immunotherapy capitalize on this recognition. Among the various approaches to inhibiting BRAF/MAPK, broad MAPK pathway inhibition may have deleterious effects on T lymphocyte function. Here, we corroborate the role of oncogenic BRAF in immune evasion by melanoma cells through suppression of MDAs. We show that inhibition of the MAPK pathway with MAPK/extracellular signal-regulated kinase kinase (MEK) inhibitors or a specific inhibitor of BRAFV600E in melanoma cell lines and tumor digests results in increased levels of MDAs, which is associated with improved recognition by antigen-specific T lymphocytes. However, treatment with MEK inhibitors impairs T lymphocyte function, whereas T-cell function is preserved after treatment with a specific inhibitor of BRAFV600E. These findings suggest that immune evasion of melanomas mediated by oncogenic BRAF may be reversed by targeted BRAF inhibition without compromising T-cell function. These findings have important implications for combined kinase-targeted therapy plus immunotherapy for melanoma.

Original languageEnglish (US)
Pages (from-to)5213-5219
Number of pages7
JournalCancer Research
Volume70
Issue number13
DOIs
StatePublished - Jul 1 2010

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Mitogen-Activated Protein Kinases
Melanoma
Lymphocytes
T-Lymphocytes
Immunotherapy
Immune Evasion
Therapeutics
MAP Kinase Kinase Kinases
Melanocytes
Differentiation Antigens
Mitogen-Activated Protein Kinase Kinases
Extracellular Signal-Regulated MAP Kinases
Tumor Cell Line
Phosphotransferases
Research Personnel
Antigens

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. / Boni, Andrea; Cogdill, Alexandria P.; Dang, Ping; Udayakumar, Durga; Njauw, Ching Ni Jenny; Sloss, Callum M.; Ferrone, Cristina R.; Flaherty, Keith T.; Lawrence, Donald P.; Fisher, David E.; Tsao, Hensin; Wargo, Jennifer A.

In: Cancer Research, Vol. 70, No. 13, 01.07.2010, p. 5213-5219.

Research output: Contribution to journalArticle

Boni, A, Cogdill, AP, Dang, P, Udayakumar, D, Njauw, CNJ, Sloss, CM, Ferrone, CR, Flaherty, KT, Lawrence, DP, Fisher, DE, Tsao, H & Wargo, JA 2010, 'Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function', Cancer Research, vol. 70, no. 13, pp. 5213-5219. https://doi.org/10.1158/0008-5472.CAN-10-0118
Boni, Andrea ; Cogdill, Alexandria P. ; Dang, Ping ; Udayakumar, Durga ; Njauw, Ching Ni Jenny ; Sloss, Callum M. ; Ferrone, Cristina R. ; Flaherty, Keith T. ; Lawrence, Donald P. ; Fisher, David E. ; Tsao, Hensin ; Wargo, Jennifer A. / Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. In: Cancer Research. 2010 ; Vol. 70, No. 13. pp. 5213-5219.
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