Reversal of Tumor Immune Inhibition Using a Chimeric Cytokine Receptor

Mol Ther. 2014 Jun;22(6):1211-1220. doi: 10.1038/mt.2014.47. Epub 2014 Mar 20.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adoptive Transfer
  • Animals
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • Interleukin-4 Receptor alpha Subunit / genetics*
  • Interleukin-4 Receptor alpha Subunit / immunology
  • Lymphocyte Activation
  • Mice, SCID
  • Neoplasms, Experimental / immunology*
  • Neoplasms, Experimental / therapy*
  • Receptors, Interleukin-7 / genetics*
  • Receptors, Interleukin-7 / immunology
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / transplantation
  • Transgenes / immunology
  • Tumor Microenvironment*
  • Xenograft Model Antitumor Assays

Substances

  • Interleukin-4 Receptor alpha Subunit
  • Receptors, Interleukin-7
  • Recombinant Fusion Proteins