Secreted Fas Decoys Enhance the Antitumor Activity of Engineered and Bystander T Cells in Fas Ligand-Expressing Solid Tumors

Pradip Bajgain, Alejandro G.Torres Chavez, Kishore Balasubramanian, Lindsey Fleckenstein, Premal Lulla, Helen E. Heslop, Juan Vera, Ann M. Leen

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

T-cell immunotherapy has demonstrated remarkable clinical outcomes in certain hematologic malignancies. However, efficacy in solid tumors has been suboptimal, partially due to the hostile tumor microenvironment composed of immune-inhibitory molecules. One such suppressive agent abundantly expressed in solid tumors is Fas ligand (FasL), which can trigger apoptosis of Fas-expressing effector cells such as T cells and natural killer (NK) cells. To alleviate this FasL-induced suppression of tumorspecific immune cells in solid tumors, we describe here the development of a Fas decoy that is secreted by engineered cells upon activation and sequesters the ligand, preventing it from engaging with Fas on the surface of effector cells. We further improved the immune-stimulatory effects of this approach by creating a Fas decoy and IL15 cytokine fusion protein, which enhanced the persistence and antitumor activity of decoyengineered as well as bystander chimeric-antigen receptor (CAR) T cells in xenograft models of pancreatic cancer. Our data indicate that secreted Fas decoys can augment the efficacy of both adoptively transferred and endogenous tumor-specific effector cells in FasL-expressing solid tumors.

Original languageEnglish (US)
Pages (from-to)1370-1385
Number of pages16
JournalCancer immunology research
Volume10
Issue number11
DOIs
StatePublished - Nov 2 2022

Keywords

  • Humans
  • Fas Ligand Protein
  • T-Lymphocytes
  • Neoplasms
  • Tumor Microenvironment
  • Killer Cells, Natural

ASJC Scopus subject areas

  • Cancer Research
  • Immunology

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