T cells genetically engineered to overcome death signaling enhance adoptive cancer immunotherapy

J Clin Invest. 2019 Feb 25;129(4):1551-1565. doi: 10.1172/JCI121491.


Across clinical trials, T cell expansion and persistence following adoptive cell transfer (ACT) have correlated with superior patient outcomes. Herein, we undertook a pan-cancer analysis to identify actionable ligand-receptor pairs capable of compromising T cell durability following ACT. We discovered that FASLG, the gene encoding the apoptosis-inducing ligand FasL, is overexpressed within the majority of human tumor microenvironments (TMEs). Further, we uncovered that Fas, the receptor for FasL, is highly expressed on patient-derived T cells used for clinical ACT. We hypothesized that a cognate Fas-FasL interaction within the TME might limit both T cell persistence and antitumor efficacy. We discovered that genetic engineering of Fas variants impaired in the ability to bind FADD functioned as dominant negative receptors (DNRs), preventing FasL-induced apoptosis in Fas-competent T cells. T cells coengineered with a Fas DNR and either a T cell receptor or chimeric antigen receptor exhibited enhanced persistence following ACT, resulting in superior antitumor efficacy against established solid and hematologic cancers. Despite increased longevity, Fas DNR-engineered T cells did not undergo aberrant expansion or mediate autoimmunity. Thus, T cell-intrinsic disruption of Fas signaling through genetic engineering represents a potentially universal strategy to enhance ACT efficacy across a broad range of human malignancies.

Keywords: Cancer gene therapy; Cancer immunotherapy; Immunology; Oncology.

Publication types

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

MeSH terms

  • Adoptive Transfer*
  • Animals
  • Fas Ligand Protein / genetics
  • Fas Ligand Protein / immunology
  • Fas-Associated Death Domain Protein / genetics
  • Fas-Associated Death Domain Protein / immunology
  • Female
  • Genetic Engineering*
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / immunology
  • Neoplasms, Experimental / pathology
  • Neoplasms, Experimental / therapy*
  • Receptors, Chimeric Antigen* / genetics
  • Receptors, Chimeric Antigen* / immunology
  • Receptors, Chimeric Antigen* / therapeutic use
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology*
  • fas Receptor / genetics
  • fas Receptor / immunology


  • FADD protein, human
  • FAS protein, human
  • FASLG protein, human
  • Fadd protein, mouse
  • Fas Ligand Protein
  • Fas protein, mouse
  • Fas-Associated Death Domain Protein
  • Receptors, Chimeric Antigen
  • fas Receptor