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Adapting a transforming growth factor beta-related tumor protection strategy to enhance antitumor immunity

Catherine M Bollard1, Claudia Rössig, M Julia Calonge

  • 1Center for Cell and Gene Therapy, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.

Blood
|April 20, 2002
PubMed

Insights

Tumor cells secrete transforming growth factor beta (TGF-beta) to suppress immune responses. Engineering cytotoxic T lymphocytes (CTLs) with a dominant-negative TGF-beta receptor shields them from this suppression, enhancing anti-tumor immunity.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cancer Research

Background:

  • Transforming growth factor beta (TGF-beta) is a cytokine secreted by human tumors that inhibits tumor-specific cellular immunity.
  • Tumors can evade TGF-beta's effects by expressing nonfunctional TGF-beta receptors, contributing to immune evasion.
  • Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTLs) used in treating EBV-positive Hodgkin disease are susceptible to tumor-derived TGF-beta.

Purpose of the Study:

  • To investigate if manipulating TGF-beta receptor expression can protect tumor-specific CTLs from TGF-beta's inhibitory effects.
  • To determine if engineered CTLs can overcome TGF-beta-mediated immune suppression in the tumor microenvironment.

Main Methods:

  • CTLs were transduced with a retrovirus vector encoding a dominant-negative TGF-beta type II receptor (HATGF-betaRII-Deltacyt).
  • The resistance of engineered CTLs to TGF-beta's antiproliferative and anticytotoxic effects was assessed.
  • The disruption of the Smad2 signaling pathway and the functional capacity of modified CTLs were evaluated.

Main Results:

  • HATGF-betaRII-Deltacyt-transduced CTLs, unlike eGFP-transduced controls, demonstrated resistance to exogenous TGF-beta's inhibitory effects.
  • Engineered CTLs maintained their ability to secrete cytokines upon antigenic stimulation.
  • The TGF-beta signaling pathway via Smad2 phosphorylation was successfully blocked in HATGF-betaRII-Deltacyt-transduced CTLs.
  • Long-term expression of the modified receptor did not compromise CTL function, phenotype, or growth.

Conclusions:

  • Engineering CTLs with a dominant-negative TGF-beta type II receptor confers resistance to tumor-derived TGF-beta.
  • These modified CTLs exhibit enhanced survival and function in the presence of TGF-beta-secreting tumors.
  • This approach holds potential for improving the efficacy of adoptive T cell therapy against TGF-beta-producing cancers.

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