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Induction of regulatory T cell-resistant helper CD4+ T cells by bacterial vector

Hiroyoshi Nishikawa1, Takemasa Tsuji, Elke Jäger

  • 1Ludwig Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

Blood
|November 8, 2007
PubMed

Insights

Engineered Salmonella typhimurium delivering NY-ESO-1 cancer antigen elicits potent T-cell responses. These responses overcome regulatory T cells, offering a promising cancer vaccine strategy.

Area of Science:

  • Immunology
  • Oncology
  • Microbial Engineering

Background:

  • Salmonella typhimurium engineered to deliver cancer/testis antigen NY-ESO-1 (S typhimurium-NY-ESO-1) shows promise as a cancer vaccine.
  • Individuals lacking spontaneous NY-ESO-1 immunity possess high-avidity T-cell precursors suppressed by regulatory T cells (Tregs).

Purpose of the Study:

  • To investigate the capacity of S typhimurium-NY-ESO-1 to elicit functional T-cell responses in individuals without pre-existing NY-ESO-1 immunity.
  • To determine if S typhimurium-NY-ESO-1 can overcome Treg-mediated suppression of T-cell responses.

Main Methods:

  • In vitro stimulation of T cells from healthy donors and melanoma patients using S typhimurium-NY-ESO-1.
  • Analysis of T helper 1 (Th1) cell induction, antigen recognition, and sensitivity to regulatory T cell (Treg) suppression.
  • Investigation of the roles of interleukin-6 and glucocorticoid-induced TNF receptor (GITR) signaling.

Main Results:

  • S typhimurium-NY-ESO-1 induced NY-ESO-1-specific CD4(+) T helper 1 (Th1) cells from naive precursors in individuals without spontaneous immunity.
  • Unlike peptide stimulation, S typhimurium-NY-ESO-1 did not require Treg depletion for Th1 cell induction.
  • S typhimurium-induced Th1 cells exhibited higher GITR expression and resistance to Treg suppression, partly mediated by IL-6 and GITR signaling.

Conclusions:

  • S typhimurium-NY-ESO-1 is an effective vaccine construct for inducing antigen-specific T-cell immunity.
  • The engineered Salmonella vaccine promotes T-cell responses resistant to regulatory T cell suppression, a critical step towards effective cancer immunotherapy.

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