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 disc... More
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.
