Reversal of Tumor Immune Inhibition Using a Chimeric Cytokine Receptor

Ann M. Leen, Sujita Sukumaran, Norihiro Watanabe, Somala Mohammed, Jacqueline Keirnan, Ryu Yanagisawa, Usanarat Anurathapan, David Rendon, Helen E. Heslop, Cliona M. Rooney, Malcolm K. Brenner, Juan F. Vera

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

The success of adoptively transferred tumor-directed T cells requires them to survive and expand in vivo. Most tumors, however, employ immune evasion mechanisms, including the production of inhibitory cytokines that limit in vivo T-cell persistence and effector function. To protect tumor-directed T cells from such negative influences, we generated a chimeric cytokine receptor in which the interleukin (IL) 4 receptor exodomain was fused to the IL7 receptor endodomain. We thereby inverted the effects of tumor-derived IL4 so that the proliferation and activation of tumor directed cytotoxic T cells was enhanced rather than inhibited in the tumor microenvironment, resulting in superior antitumor activity. These transgenic T cells were only activated in the tumor environment since triggering required exposure to both tumor antigen (signal 1) and tumor-derived IL4 (signal 2). This selectivity supports future clinical adaptation.

Original languageEnglish (US)
Pages (from-to)1211-1220
Number of pages10
JournalMolecular Therapy
Volume22
Issue number6
DOIs
StatePublished - Jun 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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