Tumor-induced MDSC act via remote control to inhibit L-selectin-dependent adaptive immunity in lymph nodes

  1. Amy W Ku
  2. Jason B Muhitch
  3. Colin A Powers
  4. Michael G Diehl
  5. Minhyung Kim
  6. Daniel T Fisher
  7. Anand P Sharda
  8. Virginia K Clements
  9. Kieran O'Loughlin
  10. Hans Minderman
  11. Michelle N Messmer
  12. Jing Ma
  13. Joseph J Skitzki
  14. Douglas A Steeber
  15. Bruce Walcheck
  16. Suzanne Ostrand-Rosenberg
  17. Scott I Abrams
  18. Sharon S Evans  Is a corresponding author
  1. Roswell Park Cancer Institute, United States
  2. University of Maryland, Baltimore County, United States
  3. University of Minnesota, United States
  4. University of Wisconsin-Milwaukee, United States

Abstract

Myeloid-derived suppressor cells (MDSC) contribute to an immunosuppressive network that drives cancer escape by disabling T cell adaptive immunity. The prevailing view is that MDSC-mediated immunosuppression is restricted to tissues where MDSC co-mingle with T cells. Here we show that splenic or, unexpectedly, blood-borne MDSC execute far-reaching immune suppression by reducing expression of the L-selectin lymph node (LN) homing receptor on naïve T and B cells. MDSC-induced L-selectin loss occurs through a contact-dependent, post-transcriptional mechanism that is independent of the major L-selectin sheddase, ADAM17, but results in significant elevation of circulating L-selectin in tumor-bearing mice. Even moderate deficits in L-selectin expression disrupt T cell trafficking to distant LN. Furthermore, T cells preconditioned by MDSC have diminished responses to subsequent antigen exposure, which in conjunction with reduced trafficking, severely diminishes antigen-driven expansion in widely-dispersed LN. These results establish novel mechanisms for MDSC-mediated immunosuppression that have unanticipated implications for systemic cancer immunity.

Article and author information

Author details

  1. Amy W Ku

    Department of Immunology, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jason B Muhitch

    Department of Immunology, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Colin A Powers

    Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Michael G Diehl

    Department of Immunology, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Minhyung Kim

    Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Daniel T Fisher

    Department of Immunology, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Anand P Sharda

    Department of Urology, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Virginia K Clements

    Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Kieran O'Loughlin

    Department of Flow and Image Cytometry, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Hans Minderman

    Department of Flow and Image Cytometry, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Michelle N Messmer

    Department of Immunology, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Jing Ma

    Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Joseph J Skitzki

    Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Douglas A Steeber

    Department of Biological Sciences, University of Wisconsin-Milwaukee, Milwaukee, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Bruce Walcheck

    Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Suzanne Ostrand-Rosenberg

    Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Scott I Abrams

    Department of Immunology, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Sharon S Evans

    Department of Immunology, Roswell Park Cancer Institute, Buffalo, United States
    For correspondence
    sharon.evans@roswellpark.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2958-6642

Funding

National Institutes of Health (CA79765)

  • Sharon S Evans

UB Mark Diamond Research Fund

  • Amy W Ku

Jennifer Linscott Tietgen Family Foundation

  • Joseph J Skitzki
  • Sharon S Evans

Breast Cancer Coalition of Rochester

  • Scott I Abrams
  • Sharon S Evans

NCI Cancer Center Support Grant (5P30 CA016056)

  • Kieran O'Loughlin
  • Hans Minderman

National Institutes of Health (1R50CA211108)

  • Hans Minderman

National Institutes of Health (AI082039)

  • Sharon S Evans

National Institutes of Health (T32 CA085183)

  • Amy W Ku

National Institutes of Health (5T32 CA108456)

  • Colin A Powers

National Institutes of Health (CA203348)

  • Bruce Walcheck

National Institutes of Health (GM021248)

  • Suzanne Ostrand-Rosenberg

National Institutes of Health (CA115880)

  • Suzanne Ostrand-Rosenberg

National Institutes of Health (CA140622)

  • Scott I Abrams

National Institutes of Health (CA172105)

  • Scott I Abrams

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in accordance with the recommendations in the NIH Guide for the Care and Use of Laboratory Animals. All of the animals were handled according to approved IACUC protocols at participating institutions (i.e., 859M and 1117M at Roswell Park Cancer Institute; SO01691417 at University of Maryland, Baltimore County; 15-16 #11 at University of Wisconsin, Milwaukee; and 1401-31272A at University of Minnesota). All surgery was performed under appropriate anesthesia and analgesia to minimize suffering and pain. The use of human PBMCs from anonymous, de-identified donors was classified as non-human subject research in accordance with federal regulations and thus not subjected to formal IRB review, but can be accessed through Roswell Park Clinical Research Services under the reference number BDR 069116.

Reviewing Editor

  1. Ronald N Germain, National Institute of Allergy and Infectious Diseases, United States

Publication history

  1. Received: April 29, 2016
  2. Accepted: December 7, 2016
  3. Accepted Manuscript published: December 8, 2016 (version 1)
  4. Version of Record published: December 29, 2016 (version 2)

Copyright

© 2016, Ku et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Amy W Ku
  2. Jason B Muhitch
  3. Colin A Powers
  4. Michael G Diehl
  5. Minhyung Kim
  6. Daniel T Fisher
  7. Anand P Sharda
  8. Virginia K Clements
  9. Kieran O'Loughlin
  10. Hans Minderman
  11. Michelle N Messmer
  12. Jing Ma
  13. Joseph J Skitzki
  14. Douglas A Steeber
  15. Bruce Walcheck
  16. Suzanne Ostrand-Rosenberg
  17. Scott I Abrams
  18. Sharon S Evans
(2016)
Tumor-induced MDSC act via remote control to inhibit L-selectin-dependent adaptive immunity in lymph nodes
eLife 5:e17375.
https://doi.org/10.7554/eLife.17375

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