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

• Published in: eLife 2016, Vol.5
• Main Authors: Ku, Amy W, Muhitch, Jason B, Powers, Colin A, Diehl, Michael, Kim, Minhyung, Fisher, Daniel T, Sharda, Anand P, Clements, Virginia K, O'Loughlin, Kieran, Minderman, Hans, Messmer, Michelle N, Ma, Jing, Skitzki, Joseph J, Steeber, Douglas A, Walcheck, Bruce, Ostrand-Rosenberg, Suzanne, Abrams, Scott I, Evans, Sharon S
• Format: Report
• Language: English
• Subjects: Cancer cells; Health aspects; Heart cells; Immune response; Lymph nodes; Observations
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.17375

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. DOI: