In Vitro T Cell Exhaustion Modeling and High Throughput Screening

To develop methods to generate exhausted/dysfunction "TIL-like" cells in vitro to facilitate small molecule and genetic based screens.


  • Iterative in vitro testing of conditions
  • Use in vivo generated TEX as gold standard comparison (phenotype, function, transcriptional comparisons)
  • Test transcriptional, metabolic and other potential “drivers” of exhaustion
  • Develop transcriptional reporters for selected aspects of exhaustion
  • Develop medium to high throughput screening approaches to modulate exhaustion


  • Ex vivo blockade of epigenetic silencers in exhausted T cells results in improvement in T cell function.
  • Have expanded and improved the specificity of the library of inhibitors against epigenetic enzymes
  • Established a new high-throughput screening system to replace manual flow cytometric analysis
  • Established in vitro T cell exhaustion (TEX) model that replicates high inhibitory receptor expression, TF signature, and dampened cytokine production.
  • In vitro generated TEX cell phenotype is maintained following transfer in vivo

Project Participants: John Wherry, Sara Cherry and screening core, Omar Khan, and Jennifer Wu (PICI@Penn Directory)