Type I cytokines synergize with oncogene inhibition to induce tumor growth arrest

Nicolas Acquavella, David Clever, Zhiya Yu, Melody Roelke-Parker, Douglas C. Palmer, Liqiang Xi, Holger Pflicke, Yun Ji, Alena Gros, Ken Ichi Hanada, Ian S. Goldlust, Gautam U. Mehta, Christopher A. Klebanoff, Joseph G. Crompton, Madhusudhanan Sukumar, James J. Morrow, Zulmarie Franco, Luca Gattinoni, Hui Liu, Ena WangFrancesco Marincola, David F. Stroncek, Chyi Chia R. Lee, Mark Raffeld, Marcus W. Bosenberg, Rahul Roychoudhuri, Nicholas P. Restifo

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Both targeted inhibition of oncogenic driver mutations and immune-based therapies show efficacy in treatment of patients with metastatic cancer, but responses can be either short lived or incompletely effective. Oncogene inhibition can augment the efficacy of immune-based therapy, but mechanisms by which these two interventions might cooperate are incompletely resolved. Using a novel transplantable BRAFV600E-mutant murine melanoma model (SB-3123), we explored potential mechanisms of synergy between the selective BRAFV600E inhibitor vemurafenib and adoptive cell transfer (ACT)-based immunotherapy. We found that vemurafenib cooperated with ACT to delay melanoma progression without significantly affecting tumor infiltration or effector function of endogenous or adoptively transferred CD8+ T cells, as previously observed. Instead, we found that the T-cell cytokines IFNγ and TNFα synergized with vemurafenib to induce cell-cycle arrest of tumor cells in vitro. This combinatorial effect was recapitulated in human melanoma-derived cell lines and was restricted to cancers bearing a BRAF600E mutation. Molecular profiling of treated SB-3123 indicated that the provision of vemurafenib promoted the sensitization of SB-3123 to the antiproliferative effects of T-cell effector cytokines. The unexpected finding that immune cytokines synergize with oncogene inhibitors to induce growth arrest has major implications for understanding cancer biology at the intersection of oncogenic and immune signaling and provides a basis for design of combinatorial therapeutic approaches for patients with metastatic cancer.

Original languageEnglish
Pages (from-to)37-47
Number of pages11
JournalCancer Immunology Research
Volume3
Issue number1
DOIs
Publication statusPublished - Jan 2015

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ASJC Scopus subject areas

  • Immunology
  • Cancer Research

Cite this

Acquavella, N., Clever, D., Yu, Z., Roelke-Parker, M., Palmer, D. C., Xi, L., Pflicke, H., Ji, Y., Gros, A., Hanada, K. I., Goldlust, I. S., Mehta, G. U., Klebanoff, C. A., Crompton, J. G., Sukumar, M., Morrow, J. J., Franco, Z., Gattinoni, L., Liu, H., ... Restifo, N. P. (2015). Type I cytokines synergize with oncogene inhibition to induce tumor growth arrest. Cancer Immunology Research, 3(1), 37-47. https://doi.org/10.1158/2326-6066.CIR-14-0122