title: Tumor-induced MDSC act via remote control to inhibit L-selectin-dependent adaptive immunity in lymph nodes.
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.
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, United States.
authors.forename: Amy W
authors.initials: AW
authors.lastname: Ku
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, United States.|Department of Urology, Roswell Park Cancer Institute, Buffalo, United States.
authors.forename: Jason B
authors.initials: JB
authors.lastname: Muhitch
authors.affiliation: Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, United States.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Powers
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Diehl
authors.affiliation: Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, United States.
authors.forename: Minhyung
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, United States.|Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, United States.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Fisher
authors.affiliation: Department of Urology, Roswell Park Cancer Institute, Buffalo, United States.
authors.forename: Anand P
authors.initials: AP
authors.lastname: Sharda
authors.affiliation: Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, United States.
authors.forename: Virginia K
authors.initials: VK
authors.lastname: Clements
authors.affiliation: Flow and Image Cytometry, Roswell Park Cancer Institute, Buffalo, United States.
authors.forename: Kieran
authors.initials: K
authors.lastname: O'Loughlin
authors.affiliation: Flow and Image Cytometry, Roswell Park Cancer Institute, Buffalo, United States.
authors.forename: Hans
authors.initials: H
authors.lastname: Minderman
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, United States.
authors.forename: Michelle N
authors.initials: MN
authors.lastname: Messmer
authors.affiliation: Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, United States.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Skitzki
authors.affiliation: Department of Biological Sciences, University of Wisconsin-Milwaukee, Milwaukee, United States.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Steeber
authors.affiliation: Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, United States.
authors.forename: Bruce
authors.initials: B
authors.lastname: Walcheck
authors.affiliation: Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, United States.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Ostrand-Rosenberg
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, United States.
authors.forename: Scott I
authors.initials: SI
authors.lastname: Abrams
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, United States.
authors.forename: Sharon S
authors.identifier: 0000-0003-2958-6642
authors.initials: SS
authors.lastname: Evans
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D007108:Immune Tolerance; D019041:L-Selectin / Q000096:biosynthesis*; D008198:Lymph Nodes / Q000276:immunology*; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000072737:Myeloid-Derived Suppressor Cells / Q000502:physiology*; D009369:Neoplasms / Q000276:immunology / Q000503:physiopathology*; D034622:RNA Interference; D014183:Transplantation, Heterologous
chemical_list: D019041:L-Selectin
keywords: L-selectin; T cell trafficking; cancer biology; human; immunology; lymph node; mouse; myeloid-derived suppressor cells