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Selective inhibition of TGF-β1 produced by GARP-expressing Tregs overcomes resistance to PD-1/PD-L1 blockade in

Grégoire de Streel1, Charlotte Bertrand1, Nicolas Chalon1

  • 1de Duve Institute, Université catholique de Louvain, 1200, Brussels, Belgium.

Nature Communications
|September 12, 2020
PubMed

Insights

Selective blockade of TGF-β1 from Tregs using GARP:TGF-β1 antibodies can overcome resistance to anti-PD-1 immunotherapy, leading to tumor regression. This approach enhances anti-tumor CD8+ T cell function without depleting Tregs.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Transforming growth factor-beta (TGF-β) isoforms (β1, β2, β3) have diverse roles in cancer, potentially promoting tumor progression or suppression.
  • Global TGF-β inhibition risks unintended tumor-promoting effects.
  • Regulatory T cells (Tregs) can produce TGF-β1, influencing the tumor microenvironment.

Purpose of the Study:

  • To investigate the efficacy of selectively blocking TGF-β1 produced by Tregs in overcoming resistance to anti-PD-1 immunotherapy.
  • To explore the therapeutic potential of antibodies targeting GARP:TGF-β1 complexes.

Main Methods:

  • Utilized antibodies targeting GARP:TGF-β1 complexes for selective blockade of TGF-β1 production by Tregs.
  • Assessed tumor regressions in mouse models resistant to anti-PD-1 immunotherapy.
  • Analyzed immune responses, including CD8+ T cell effector functions and Treg infiltration.
  • Examined GARP-expressing Tregs and TGF-β1 production in human melanoma metastases.

Main Results:

  • Selective blockade of GARP:TGF-β1 complexes induced regressions in mouse tumors resistant to anti-PD-1 therapy.
  • Combined GARP:TGF-β1 and PD-1 blockade enhanced anti-tumor CD8+ T cell effector functions.
  • These effects were immune-mediated and did not require FcγR-dependent functions or Treg depletion.
  • GARP-expressing Tregs producing TGF-β1 were identified in human melanoma metastases.

Conclusions:

  • Selective targeting of Treg-derived TGF-β1 via anti-GARP:TGF-β1 antibodies offers a promising strategy to overcome resistance to PD-1/PD-L1 blockade.
  • This approach may enhance anti-tumor immunity and improve patient outcomes in cancer immunotherapy.

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