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Original research
Immunosuppressive CD29+ Treg accumulation in the liver in mice on checkpoint inhibitor therapy
  1. Benjamin L Green1,
  2. Yuta Myojin1,
  3. Chi Ma1,
  4. Benjamin Ruf1,
  5. Lichun Ma2,
  6. Qianfei Zhang1,
  7. Umberto Rosato1,
  8. Jonathan Qi1,
  9. Mahler Revsine3,
  10. Simon Wabitsch1,
  11. Kylynda Bauer1,
  12. Mohamed-Reda Benmebarek1,
  13. Justin McCallen1,
  14. Amran Nur1,
  15. Xin Wang1,
  16. Vivek Sehra4,
  17. Revant Gupta4,
  18. Manfred Claassen4,
  19. Xin Wei Wang3,5,
  20. Firouzeh Korangy1,
  21. Tim F Greten1,5
  1. 1 Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
  2. 2 Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
  3. 3 Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
  4. 4 Department of Computer Science, University of Tübingen, Tübingen, Germany
  5. 5 NCI CCR Liver Cancer Program, National Institutes of Health, Bethesda, Maryland, USA
  1. Correspondence to Professor Tim F Greten, Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, NCI, Bethesda, MD 20892, USA; tim.greten{at}nih.gov

Abstract

Objective Liver metastases are often resistant to immune checkpoint inhibitor therapy (ICI) and portend a worse prognosis compared with metastases to other locations. Regulatory T cells (Tregs) are one of several immunosuppressive cells implicated in ICI resistance of liver tumours, but the role played by Tregs residing within the liver surrounding a tumour is unknown.

Design Flow cytometry and single-cell RNA sequencing were used to characterise hepatic Tregs before and after ICI therapy.

Results We found that the murine liver houses a Treg population that, unlike those found in other organs, is both highly proliferative and apoptotic at baseline. On administration of αPD-1, αPD-L1 or αCTLA4, the liver Treg population doubled regardless of the presence of an intrahepatic tumour. Remarkably, this change was not due to the preferential expansion of the subpopulation of Tregs that express PD-1. Instead, a subpopulation of CD29+ (Itgb1, integrin β1) Tregs, that were highly proliferative at baseline, doubled its size in response to αPD-1. Partial and full depletion of Tregs identified CD29+ Tregs as the prominent niche-filling subpopulation in the liver, and CD29+ Tregs demonstrated enhanced suppression in vitro when derived from the liver but not the spleen. We identified IL2 as a critical modulator of both CD29+ and CD29 hepatic Tregs, but expansion of the liver Treg population with αPD-1 driven by CD29+ Tregs was in part IL2-independent.

Conclusion We propose that CD29+ Tregs constitute a unique subpopulation of hepatic Tregs that are primed to respond to ICI agents and mediate resistance.

  • liver
  • immunotherapy
  • cancer

Data availability statement

Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as online supplemental information. scRNAseq data have been deposited in the GEO database (GSE221186).

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Data availability statement

Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as online supplemental information. scRNAseq data have been deposited in the GEO database (GSE221186).

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Footnotes

  • Twitter @bengreen_MD, @BenniRuf

  • BLG and YM contributed equally.

  • Contributors Conceptualisation: BLG, YM, CM and TFG; Methodology: BLG, YM, CM, QZ, UR, TFG, LM, MR, VS and RG; Investigation: BLG, YM, JQ, QZ, UR, LM, MR, VS, RG, XW, AN and JM; Visualisation: BLG, YM, TFG, LM and MR; Funding acquisition: TFG, MC and XWW; Project administration: BLG, YM, CM and TFG; Supervision: TFG, FK, MC and XWW; Writing—original draft: BLG and TFG; Writing—review and editing: BLG, YM, CM, BR, LM, QZ, UR, JQ, MR, SW, KB, M-RB, JM, AN, XW, VS, RG, MC, XWW, FK and TFG. Guarantor: TG.

  • Funding BR was supported by the International Liver Cancer Association (ILCA) Fellowship Award 2021. SW was funded by the Deutsche Forschungsgemeinschaft (WA-4610/1-1). TFG was supported by the Intramural Research Program of the NIH, NCI (ZIA BC 011345).

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.