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Protection of Regulatory T Cells from Fragility and Inactivation in the Tumor Microenvironment.

Publication ,  Journal Article
Zhang, H; Tomar, VS; Li, J; Basavaraja, R; Yan, F; Gui, J; McBrearty, N; Costich, TL; Beiting, DP; Blanco, MA; Conejo-Garcia, JR; Saggu, G ...
Published in: Cancer Immunol Res
December 2, 2022

Fragility of regulatory T (Treg) cells manifested by the loss of neuropilin-1 (NRP1) and expression of IFNγ undermines the immune suppressive functions of Treg cells and contributes to the success of immune therapies against cancers. Intratumoral Treg cells somehow avoid fragility; however, the mechanisms by which Treg cells are protected from fragility in the tumor microenvironment are not well understood. Here, we demonstrate that the IFNAR1 chain of the type I IFN (IFN1) receptor was downregulated on intratumoral Treg cells. Downregulation of IFNAR1 mediated by p38α kinase protected Treg cells from fragility and maintained NRP1 levels, which were decreased in response to IFN1. Genetic or pharmacologic inactivation of p38α and stabilization of IFNAR1 in Treg cells induced fragility and inhibited their immune suppressive and protumorigenic activities. The inhibitor of sumoylation TAK981 (Subasumstat) upregulated IFNAR1, eliciting Treg fragility and inhibiting tumor growth in an IFNAR1-dependent manner. These findings describe a mechanism by which intratumoral Treg cells retain immunosuppressive activities and suggest therapeutic approaches for inducing Treg fragility and increasing the efficacy of immunotherapies.

Duke Scholars

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Published In

Cancer Immunol Res

DOI

EISSN

2326-6074

Publication Date

December 2, 2022

Volume

10

Issue

12

Start / End Page

1490 / 1505

Location

United States

Related Subject Headings

  • Tumor Microenvironment
  • T-Lymphocytes, Regulatory
  • Neuropilin-1
  • Neoplasms
  • Immunotherapy
  • Humans
  • 3211 Oncology and carcinogenesis
  • 3204 Immunology
  • 1115 Pharmacology and Pharmaceutical Sciences
  • 1112 Oncology and Carcinogenesis
 

Citation

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Zhang, H., Tomar, V. S., Li, J., Basavaraja, R., Yan, F., Gui, J., … Fuchs, S. Y. (2022). Protection of Regulatory T Cells from Fragility and Inactivation in the Tumor Microenvironment. Cancer Immunol Res, 10(12), 1490–1505. https://doi.org/10.1158/2326-6066.CIR-22-0295
Zhang, Hongru, Vivek S. Tomar, Jinyang Li, Raghavendra Basavaraja, Fangxue Yan, Jun Gui, Noreen McBrearty, et al. “Protection of Regulatory T Cells from Fragility and Inactivation in the Tumor Microenvironment.Cancer Immunol Res 10, no. 12 (December 2, 2022): 1490–1505. https://doi.org/10.1158/2326-6066.CIR-22-0295.
Zhang H, Tomar VS, Li J, Basavaraja R, Yan F, Gui J, et al. Protection of Regulatory T Cells from Fragility and Inactivation in the Tumor Microenvironment. Cancer Immunol Res. 2022 Dec 2;10(12):1490–505.
Zhang, Hongru, et al. “Protection of Regulatory T Cells from Fragility and Inactivation in the Tumor Microenvironment.Cancer Immunol Res, vol. 10, no. 12, Dec. 2022, pp. 1490–505. Pubmed, doi:10.1158/2326-6066.CIR-22-0295.
Zhang H, Tomar VS, Li J, Basavaraja R, Yan F, Gui J, McBrearty N, Costich TL, Beiting DP, Blanco MA, Conejo-Garcia JR, Saggu G, Berger A, Nefedova Y, Gabrilovich DI, Fuchs SY. Protection of Regulatory T Cells from Fragility and Inactivation in the Tumor Microenvironment. Cancer Immunol Res. 2022 Dec 2;10(12):1490–1505.

Published In

Cancer Immunol Res

DOI

EISSN

2326-6074

Publication Date

December 2, 2022

Volume

10

Issue

12

Start / End Page

1490 / 1505

Location

United States

Related Subject Headings

  • Tumor Microenvironment
  • T-Lymphocytes, Regulatory
  • Neuropilin-1
  • Neoplasms
  • Immunotherapy
  • Humans
  • 3211 Oncology and carcinogenesis
  • 3204 Immunology
  • 1115 Pharmacology and Pharmaceutical Sciences
  • 1112 Oncology and Carcinogenesis