Proteolysis-targeting chimera against BCL-XL destroys tumor-infiltrating regulatory T cells

Ryan Kolb, Umasankar De, Sajid Khan, Yuewan Luo, Myung-Chul Kim, Haijun Yu, Chaoyan Wu, Jiao Mo, Xin Zhang, Peiyi Zhang, Xuan Zhang, Nicholas Borcherding, Daniel Koppel, Yang-Xin Fu, Song Guo Zheng, Dorina Avram, Guangrong Zheng, Daohong Zhou () and Weizhou Zhang ()
Additional contact information
Ryan Kolb: University of Florida
Umasankar De: University of Florida
Sajid Khan: University of Florida
Yuewan Luo: University of Florida
Myung-Chul Kim: University of Florida
Haijun Yu: University of Florida
Chaoyan Wu: University of Florida
Jiao Mo: University of Florida
Xin Zhang: University of Florida
Peiyi Zhang: University of Florida
Xuan Zhang: University of Florida
Nicholas Borcherding: University of Iowa
Daniel Koppel: University of Florida Health Cancer Center, University of Florida
Yang-Xin Fu: University of Texas Southwestern Medical Center
Song Guo Zheng: Ohio State University College of Medicine and Wexner Medical Center
Dorina Avram: University of Florida Health Cancer Center, University of Florida
Guangrong Zheng: University of Florida Health Cancer Center, University of Florida
Daohong Zhou: University of Florida Health Cancer Center, University of Florida
Weizhou Zhang: University of Florida

Nature Communications, 2021, vol. 12, issue 1, 1-9

Abstract: Abstract Regulatory T cells (Tregs) play an important role in maintaining immune homeostasis and, within tumors, their upregulation is common and promotes an immunosuppressive microenvironment. Therapeutic strategies that can eliminate Tregs in the tumor (i.e., therapies that do not run the risk of affecting normal tissues), are urgently needed for the development of cancer immunotherapies. Here we report our discovery of B-cell lymphoma extra-large (BCL-XL) as a potential molecular target of tumor-infiltrating (TI) Tregs. We show that pharmacological degradation of BCL-XL using a newly developed platelet-sparing BCL-XL Proteolysis-targeting chimera (PROTAC) induces the apoptosis of TI-Tregs and the activation of TI-CD8+ T cells. Moreover, these activities result in an effective suppression of syngeneic tumor growth in immunocompetent, but not in immunodeficient or CD8+ T cell-depleted mice. Notably, treatment with BCL-XL PROTAC does not cause detectable damage within several normal tissues or thrombocytopenia. These findings identify BCL-XL as a target in the elimination of TI-Tregs as a component of cancer immunotherapies, and that the BCL-XL-specific PROTAC has the potential to be developed as a therapeutic for cancer immunotherapy.

Date: 2021
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-021-21573-x Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21573-x

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-21573-x

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().