TGFβ suppresses CD8+ T cell expression of CXCR3 and tumor trafficking

Andrew J. Gunderson, Tomoko Yamazaki, Kayla McCarty, Nathaniel Fox, Michaela Phillips, Alejandro Alice, Tiffany Blair, Mark Whiteford, David O’Brien, Rehan Ahmad, Maria X. Kiely, Amanda Hayman, Todd Crocenzi, Michael J. Gough, Marka R. Crittenden and Kristina H. Young ()
Additional contact information
Andrew J. Gunderson: Earle A. Chiles Research Institute, Providence Cancer Institute
Tomoko Yamazaki: Earle A. Chiles Research Institute, Providence Cancer Institute
Kayla McCarty: Earle A. Chiles Research Institute, Providence Cancer Institute
Nathaniel Fox: Earle A. Chiles Research Institute, Providence Cancer Institute
Michaela Phillips: Earle A. Chiles Research Institute, Providence Cancer Institute
Alejandro Alice: Earle A. Chiles Research Institute, Providence Cancer Institute
Tiffany Blair: Earle A. Chiles Research Institute, Providence Cancer Institute
Mark Whiteford: Earle A. Chiles Research Institute, Providence Cancer Institute
David O’Brien: Earle A. Chiles Research Institute, Providence Cancer Institute
Rehan Ahmad: Earle A. Chiles Research Institute, Providence Cancer Institute
Maria X. Kiely: Earle A. Chiles Research Institute, Providence Cancer Institute
Amanda Hayman: Earle A. Chiles Research Institute, Providence Cancer Institute
Todd Crocenzi: Earle A. Chiles Research Institute, Providence Cancer Institute
Michael J. Gough: Earle A. Chiles Research Institute, Providence Cancer Institute
Marka R. Crittenden: Earle A. Chiles Research Institute, Providence Cancer Institute
Kristina H. Young: Earle A. Chiles Research Institute, Providence Cancer Institute

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract Transforming growth factor beta (TGFβ) is a multipotent immunosuppressive cytokine. TGFβ excludes immune cells from tumors, and TGFβ inhibition improves the efficacy of cytotoxic and immune therapies. Using preclinical colorectal cancer models in cell type-conditional TGFβ receptor I (ALK5) knockout mice, we interrogate this mechanism. Tumor growth delay and radiation response are unchanged in animals with Treg or macrophage-specific ALK5 deletion. However, CD8αCre-ALK5flox/flox (ALK5ΔCD8) mice reject tumors in high proportions, dependent on CD8+ T cells. ALK5ΔCD8 mice have more tumor-infiltrating effector CD8+ T cells, with more cytotoxic capacity. ALK5-deficient CD8+ T cells exhibit increased CXCR3 expression and enhanced migration towards CXCL10. TGFβ reduces CXCR3 expression, and increases binding of Smad2 to the CXCR3 promoter. In vivo CXCR3 blockade partially abrogates the survival advantage of an ALK5ΔCD8 host. These data demonstrate a mechanism of TGFβ immunosuppression through inhibition of CXCR3 in CD8+ T cells, thereby limiting their trafficking into tumors.

Date: 2020
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-020-15404-8 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:11:y:2020:i:1:d:10.1038_s41467-020-15404-8

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

DOI: 10.1038/s41467-020-15404-8

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 ().