Targeting TGFβ with chimeric switch receptor and secreted trap to improve T cells anti-tumor activity

Tatyana Matikhina, Cyrille J. Cohen

Research output: Contribution to journalArticlepeer-review

Abstract

Introduction: TGFβ is a major immunoinhibitory factor present in the microenvironment of solid tumors. Various cancer types acquire the ability to overexpress TGFβ to escape immune response. Specifically, TGFβ dampens cytotoxic T cell activity, and its presence has been correlated with tumor invasion and poor prognosis. Methods: In this study, we developed two approaches to counteract the effects of TGFβ and provide a functional advantage to genetically engineered T cells in the immunoinhibitory tumor milieu. We designed a TGFβRI-based co-stimulatory switch receptor (CSRI), comprising the TGFβ receptor I extracellular binding domain and a 4-1BB co-stimulatory signaling moiety. Additionally, we tested the efficacy of a TGFβ-binding scFv trap produced by T cells. Results: We demonstrated that both approaches enhanced tumor-specific T cell cytokine secretion, upregulated activation markers, and reduced inhibition markers upon co-culture with melanoma targets. Furthermore, CSRI and the anti-TGFβ trap exhibited improved anti-tumor function in vivo. Conclusion: Overall, we show that targeting the TGFβ pathway can enhance cellular immunotherapy.

Original languageEnglish
Article number1460266
JournalFrontiers in Immunology
Volume15
DOIs
StatePublished - 2024

Keywords

  • T cells
  • TCR-T cells
  • TGF-β
  • cellular immunotherapy
  • chimeric cytokine receptor

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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