Paradoxical activation of T cells via augmented ERK signaling mediated by a RAF inhibitor

Margaret K. Callahan, Gregg Masters, Christine A. Pratilas, Charlotte Ariyan, Jessica Katz, Shigehisa Kitano, Valerie Russell, Ruth A.nn Gordon, Shachi Vyas, Jianda Yuan, Ashok Gupta, Jon M. Wigginton, Neal Rosen, Taha Merghoub, Maria Jure-Kunkel, Jedd D. Wolchok

Research output: Contribution to journalArticle

Abstract

RAF inhibitors selectively block ERK signaling in BRAF-mutant melanomas and have defined a genotype-guided approach to care for this disease. RAF inhibitors have the opposite effect in BRAF wild-type tumor cells, where they cause hyperactivation of ERK signaling. Here, we predict that RAF inhibitors can enhance T cell activation, based upon the observation that these agents paradoxically activate ERK signaling in BRAF wild-type cells. To test this hypothesis, we have evaluated the effects of the RAF inhibitor BMS908662 on T cell activation and signaling in vitro and in vivo. We observe that T cell activation is enhanced in a concentration-dependent manner and that this effect corresponds with increased ERK signaling, consistent with paradoxical activation of the pathway. Furthermore, we find that the combination of BMS908662 with CTLA-4 blockade in vivo potentiates T cell expansion, corresponding with hyperactivation of ERK signaling in T cells detectable ex vivo. Lastly, this combination demonstrates superior anti-tumor activity, compared to either agent alone, in two transplantable tumor models. This study provides clear evidence that RAF inhibitors can modulate T cell function by potentiating T cell activation in vitro and in vivo. Paradoxical activation of ERK signaling in T cells offers one mechanism to explain the enhanced antitumor activity seen when RAF inhibitors are combined with CTLA-4 blockade in preclinical models.

Original languageEnglish (US)
Pages (from-to)70-79
Number of pages10
JournalCancer Immunology Research
Volume2
Issue number1
DOIs
StatePublished - Jan 1 2014

Keywords

  • BRAF
  • CTLA-4
  • Melanoma
  • RAF inhibitors
  • T cell
  • immunotherapy

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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  • Cite this

    Callahan, M. K., Masters, G., Pratilas, C. A., Ariyan, C., Katz, J., Kitano, S., Russell, V., Gordon, R. A. N., Vyas, S., Yuan, J., Gupta, A., Wigginton, J. M., Rosen, N., Merghoub, T., Jure-Kunkel, M., & Wolchok, J. D. (2014). Paradoxical activation of T cells via augmented ERK signaling mediated by a RAF inhibitor. Cancer Immunology Research, 2(1), 70-79. https://doi.org/10.1158/2326-6066.CIR-13-0160