Tumor-induced MDSC act via remote control to inhibit L-selectin-dependent adaptive immunity in lymph nodes
- Roswell Park Cancer Institute, United States
- University of Maryland, Baltimore County, United States
- University of Minnesota, United States
- 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.
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Author details
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.
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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