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

Amy W. Ku, Jason B. Muhitch, Colin A. Powers, Michael Diehl, Minhyung Kim, Daniel T. Fisher, Anand P. Sharda, Virginia K. Clements, Kieran O’Loughlin, Hans Minderman, Michelle N. Messmer, Jing Ma, Joseph J. Skitzki, Douglas A. Steeber, Bruce Walcheck, Suzanne Ostrand-Rosenberg, Scott I. Abrams, Sharon S. Evans

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

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 restricts antigen-driven expansion in widely-dispersed LN. These results establish novel mechanisms for MDSC-mediated immunosuppression that have unanticipated implications for systemic cancer immunity.

Original languageEnglish (US)
Article numbere17375
JournaleLife
Volume5
Issue numberDECEMBER2016
DOIs
StatePublished - Dec 8 2016

Bibliographical note

Funding Information:
We thank C Netherby for technical assistance on the mammary fat pad model and M Appenheimer for critical reading of the manuscript. This work was supported by the NIH (CA79765 and AI082039 to SS Evans; T32 CA085183 to AW Ku; 5 T32 CA108456 to CA Powers; CA203348 to B Walcheck; GM021248 and CA115880 to S Ostrand-Rosenberg; CA140622 and CA172105 to SI Abrams; 1R50CA211108 to H Minderman); the University at Buffalo Mark Diamond Research Fund (to AW Ku); the Jennifer Linscott Tietgen Family Foundation (to SS Evans and JJ Skitzki); and the Breast Cancer Coalition of Rochester (to SS Evans and SI Abrams). Cytometry services were provided by the Flow and Image Cytometry Shared Resource facility at the Roswell Park Cancer Institute which is supported, in part, by the NCI Cancer Center Support Grant 5P30 CA016056.

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