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

AI Article Synopsis

  • Research shows that T cell growth and longevity after adoptive cell transfer (ACT) are linked to better patient outcomes in cancer therapy.
  • A study identified that the protein FasL, which can trigger T cell death, is often overproduced in many tumor environments, while its receptor, Fas, is found in high amounts on T cells used in ACT.
  • By engineering T cells to block Fas signaling, researchers found these modified T cells survived longer and worked more effectively against various cancers, suggesting this approach could improve ACT treatment across different cancer types.

Article Abstract

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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436880PMC
http://dx.doi.org/10.1172/JCI121491DOI Listing

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