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.DOI: http://dx.doi.org/10.7554/eLife.17375.001

Role of l‐arginine and CD11b+Gr‐1+ cells in immunosuppression induced by Heligmosomoides polygyrus bakeri

“…When co‐cultured with naïve T cells, Gr‐1+ cells from infected animals only hampered CD4+ proliferation in response to anti‐TCR stimulation. However, this was dependent on the origin of the cells, as shown also in other studies . Gr‐1+ cells derived from spleen of tumour‐bearing mice are weakly suppressive—high ratios of MDSCs:T cells are required to observe reduced lymphocyte proliferation .…”

“…Only spleen and intestine‐derived control cells did not affect the CD4+ proliferation. But also parasite‐derived Gr‐1+ cells from spleen and intestine had weaker suppressive potential, similarly as in tumour models . Peritoneal and mesenteric lymph node MDSCs from infected mice were the most suppressive and it was not dependent on the day post‐infection.…”

“…However, this was dependent on the origin of the cells, as shown also in other studies. 20 Gr-1+ cells derived from spleen of tumour-bearing mice are weakly suppressive-high ratios of MDSCs:T cells are required to observe reduced lymphocyte proliferation. 20 In our study, we tested several ratios of those cell populations in culture and as low as 1:40 was enough to observe significant reduction of proliferation of CD3/ CD28-stimulated CD4+ cells.…”

The expanding family of noncanonical regulatory cell subsets

“…Therefore, it will be essential to determine the mechanisms of suppression by MDSC for the development of future strategies for tumor immunotherapy. Immunosuppression by MDSC in peripheral lymphoid organs involves multiple mechanisms: generation of nitric oxide (NO) and reactive oxygen species causing nitration of TCRs and chemokines that subsequently induce T‐cell migration, or induce apoptosis of T cells and NK cells; production of vascular endothelial growth factor and basic fibroblast growth factor, which promote tumor neoangiogenesis; disruption of the homing process of T cells (through the expression of ADAM17, which is also called tumor necrosis factor‐α‐converting enzyme); production of immunosuppressive cytokines (TGF‐β and IL‐10), and induction of Tregs. …”

“…disruption of the homing process of T cells (through the expression of ADAM17, which is also called tumor necrosis factor‐α‐converting enzyme);…”