Subpopulations of myeloid‐derived suppressor cells impair T cell responses through independent nitric oxide‐related pathways

Abstract

The accumulation of myeloid-derived suppressor cells (MDSC) in tumor-bearing hosts is a hallmark of malignancy-associated inflammation and a major mediator for the induction of T cell suppression in cancer. MDSC can be divided phenotypically into granulocytic (G-MDSC) and monocytic (Mo-MDSC) subgroups. Several mechanisms mediate the induction of T cell anergy by MDSC; however, the specific role of these pathways in the inhibitory activity of MDSC subpopulations remains unclear. Therefore, we aimed to determine the effector mechanisms by which subsets of tumor-infiltrating MDSC block T cell function. We found that G-MDSC had a higher ability to impair proliferation and expression of effector molecules in activated T cells, as compared to Mo-MDSC. Interestingly, both MDSC subgroups inhibited T cells through nitric oxide (NO)-related pathways, but expressed different effector inhibitory mechanisms. Specifically, G-MDSC impaired T cells through the production of peroxynitrites (PNT), while Mo-MDSC suppressed by the release of NO. The production of PNT in G-MDSC depended on the expression of gp91phox and endothelial NO synthase (eNOS), while inducible NO synthase (iNOS) mediated the generation of NO in Mo-MDSC. Deletion of eNOS and gp91phox or scavenging of PNT blocked the suppressive function of G-MDSC and induced anti-tumoral effects, without altering Mo-MDSC inhibitory activity. Furthermore, NO-scavenging or iNOS knockdown prevented Mo-MDSC function, but did not affect PNT production or suppression by G-MDSC. These results suggest that MDSC subpopulations utilize independent effector mechanisms to regulate T cell function. Inhibition of these pathways is expected to specifically block MDSC subsets and overcome immune suppression in cancer.

NADPH oxidase deficiency underlies dysfunction of aged CD8+ Tregs

“…Adoptive transfer of NOX2-deficient CD4 T cells into RAG-deficient mice increases arthritic inflammation (50), suggesting that CD4 T cells are subject to the antiinflammatory effect of NOX2. Deletion of NOX2/gp91phox can limit the suppressive function of granulocytic myeloid-derived suppressor cells and contribute to antitumor effects (52,53). In studies of mice deficient in Ncf1 (also known as p47phox), both the CD4 Treg and targeted T effector cell require functional p47phox for optimal suppression (54).…”

Programming of the Development of Tumor-Promoting Neutrophils by Mesenchymal Stromal Cells

“…Saa3 is one of the ligands known to activate TLR-4 signaling, and elevation of TLR-4 is involved in promoting tumor progression [22]. Recent studies show that G-MDSCs impair T cell responses through nitric oxide (NO) dependent pathways [23]. (ii) increased levels of anti-inflammatory cytokines and their receptors IL-10, IL-6, IL-4R, IL-10R that are known to promote tumor progression.…”

Nitric oxide antagonism to glioblastoma photodynamic therapy and mitigation thereof by BET bromodomain inhibitor JQ1

“…Low level reactive oxygen species (ROS) as well as nitric oxide (NO) generated by inducible nitric oxide synthase (iNOS/NOS2) play important roles in many of these processes (3)(4)(5)(6). There is now compelling evidence that endogenous iNOS/NO not only supports growth and progression of many tumors, but also plays a key role in pro-tumor immunosuppression (7,8) as well as resistance to chemotherapeutic and radiotherapeutic interventions (9)(10)(11). A less common intervention for solid tumors is photodynamic therapy (PDT), which employs non-ionizing radiation.…”