Cancer immunotherapy with monoclonal antibodies blocking the GARP-dependent production of TGF-β1
(2020)
Files
Thesis_FINAL.pdf
Restricted Access - Adobe PDF
- 72.98 MB
Details
- Authors
- Supervisors
- Lucas, Sophie
- Abstract
- Cancer immunotherapies aim at inducing or stimulating anti-tumor immune responses to eliminate tumor cells and trigger tumor regressions in patients with cancer. Approaches under clinical development comprise cancer vaccines, adoptive transfers of immune cells and immunostimulatory antibodies. Several immunostimulatory antibodies were approved by regulatory agencies for the treatment of various types of cancers. Despite impressive clinical successes, response rates to cancer immunotherapies remain very diverse, and only a minority of patients benefit from the currently available approaches. Novel approaches that target other immunosuppressive pathways are needed to increase the clinical efficacy of cancer immunotherapies. Regulatory T cells or Tregs are immunosuppressive cells that are indispensable to prevent auto-immunity, but in cancer patients they are detrimental because they suppress anti-tumor immunity. Our laboratory previously identified a mechanism of immunosuppression by Tregs which implies production and activation of the immunosuppressive TGF-β1 cytokine. Unlike other cells, activation of TGF-β1 by Tregs requires intervention of two transmembrane proteins named GARP and integrin αvβ8. We developed antibodies against GARP:TGF-β1 complexes that allow to selectively block TGF-β1 activation by Tregs. These could provide significant advantages over global TGF-β1 inhibition, which bears the risk of undesired tumor-promoting effects. Indeed, TGF-β1 exerts vastly diverse effects in cancer, supporting either tumor progression by favoring metastases and inhibiting anti-tumor immunity, or tumor suppression by inhibiting malignant cell proliferation. Here, we show that blocking TGF-β1 activation by Tregs with anti-GARP:TGF-β1 antibodies induces regressions of mouse tumors that are otherwise resistant to anti-PD-1 immunotherapy. We found GARP-expressing Tregs and evidence that they produce TGF-β1 in human melanoma metastases. Finally, we provide evidence that upon administration to tumor-bearing mice, anti-GARP:TGF-β1 antibodies directly bind Tregs and reduce autocrine TGF-β1 signals in these cells. Altogether, our work suggests that blocking production of a single TGF-β isoform emanating from a restricted cellular source is sufficient to potentiate anti-tumor immunity. Anti-GARP:TGF-β1 mAb may serve as a new immunostimulatory drug to improve patient responses to cancer immunotherapies.
- Affiliations
Citations
de Streel, G. (2020). Cancer immunotherapy with monoclonal antibodies blocking the GARP-dependent production of TGF-β1. https://hdl.handle.net/2078.5/116913