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Functional Anti-TIGIT Antibodies Regulate Development of Autoimmunity and Antitumor Immunity


Dixon, Karen O; Schorer, Michelle; Nevin, James; Etminan, Yassaman; Amoozgar, Zohreh; Kondo, Takaaki; Kurtulus, Sema; Kassam, Nasim; Sobel, Raymond A; Fukumura, Dai; Jain, Rakesh K; Anderson, Ana C; Kuchroo, Vijay K; Joller, Nicole (2018). Functional Anti-TIGIT Antibodies Regulate Development of Autoimmunity and Antitumor Immunity. Journal of Immunology, 200(8):3000-3007.

Abstract

Coinhibitory receptors, such as CTLA-4 and PD-1, play a critical role in maintaining immune homeostasis by dampening T cell responses. Recently, they have gained attention as therapeutic targets in chronic disease settings where their dysregulated expression contributes to suppressed immune responses. The novel coinhibitory receptor TIGIT (T cell Ig and ITIM domain) has been shown to play an important role in modulating immune responses in the context of autoimmunity and cancer. However, the molecular mechanisms by which TIGIT modulates immune responses are still insufficiently understood. We have generated a panel of monoclonal anti-mouse TIGIT Abs that show functional properties in mice in vivo and can serve as important tools to study the underlying mechanisms of TIGIT function. We have identified agonistic as well as blocking anti-TIGIT Ab clones that are capable of modulating T cell responses in vivo. Administration of either agonist or blocking anti-TIGIT Abs modulated autoimmune disease severity whereas administration of blocking anti-TIGIT Abs synergized with anti-PD-1 Abs to affect partial or even complete tumor regression. The Abs presented in this study can thus serve as important tools for detailed analysis of TIGIT function in different disease settings and the knowledge gained will provide valuable insight for the development of novel therapeutic approaches targeting TIGIT.

Abstract

Coinhibitory receptors, such as CTLA-4 and PD-1, play a critical role in maintaining immune homeostasis by dampening T cell responses. Recently, they have gained attention as therapeutic targets in chronic disease settings where their dysregulated expression contributes to suppressed immune responses. The novel coinhibitory receptor TIGIT (T cell Ig and ITIM domain) has been shown to play an important role in modulating immune responses in the context of autoimmunity and cancer. However, the molecular mechanisms by which TIGIT modulates immune responses are still insufficiently understood. We have generated a panel of monoclonal anti-mouse TIGIT Abs that show functional properties in mice in vivo and can serve as important tools to study the underlying mechanisms of TIGIT function. We have identified agonistic as well as blocking anti-TIGIT Ab clones that are capable of modulating T cell responses in vivo. Administration of either agonist or blocking anti-TIGIT Abs modulated autoimmune disease severity whereas administration of blocking anti-TIGIT Abs synergized with anti-PD-1 Abs to affect partial or even complete tumor regression. The Abs presented in this study can thus serve as important tools for detailed analysis of TIGIT function in different disease settings and the knowledge gained will provide valuable insight for the development of novel therapeutic approaches targeting TIGIT.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Experimental Immunology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2018
Deposited On:30 Aug 2018 09:11
Last Modified:30 Aug 2018 09:13
Publisher:American Association of Immunologists
ISSN:0022-1767
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.4049/jimmunol.1700407
PubMed ID:29500245
Project Information:
  • : FunderSNSF
  • : Grant IDPP00P3_150663
  • : Project TitleImmune Regulation through Infection History
  • : FunderH2020
  • : Grant ID677200
  • : Project TitleHow Infection History Shapes the Immune System: Pathogen-induced Changes in Regulatory T Cells
  • : FunderZUNIV-FAN
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  • : FunderOlga Mayenfisch Stiftung
  • : Grant ID
  • : Project Title
  • : FunderANRF
  • : Grant ID
  • : Project Title
  • : FunderNIH
  • : Grant ID
  • : Project Title
  • : FunderNCI
  • : Grant ID
  • : Project Title

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