Pathways Mediating the Expansion and Immunosuppressive Activity of Myeloid-Derived Suppressor Cells and Their Relevance to Cancer Therapy

Abstract

Cancer immunotherapy has focused on inducing and expanding CTLs and improving the immune recognition of weak antigenic determinants expressed by tumors. However, few positive clinical outcomes have been reported due, in part, to tumor-associated immunologic tolerance, supporting the need for an emphasis on overcoming immunosuppression. Systemic immunosuppression is associated with abnormal myelopoiesis secondary to tumor growth, myelosuppressive therapy, and growth factor administration and subsequent expansion/mobilization of bone marrowd erived immunosuppressive cells. These myeloid-derived suppressor cells (MDSC) reduce activated T-cell number and inhibit their function by multiple mechanisms, including depletion of L-arginine by arginase-1 (ARG1) production of nitric oxide, reactive oxygen species, and reactive nitrogen oxide species by inducible nitric oxide synthase. Increased numbers of MDSCs are associated with neoplastic, inflammatory, infectious, and graft-versus-host diseases where they restrain exuberant or novel T-cell responses. In this review, we discuss critical components of MDSC-mediated suppression of T-cell function, including cellular expansion and activationinduced secretion of immunosuppressive mediators. Both components of MDSC bioactivity are amenable to pharmacologic intervention as discussed herein. We also focus on the relationship between MDSCs, tumor growth, therapeutic responses, and the mechanisms of cellular expansion, activation, and immunosuppression.Host immunity has a critical role in regulating tumor outgrowth and patient survival; however, the expansion of tumor-specific T cells is also limited by tumor growth. Recently, there has been a resurgence of interest in myeloid-derived cells in association with their role in tumor progression and potential to limit therapeutic responses. Myeloid-derived suppressor cells (MDSC) are increased in numerous pathologic conditions, including infections, inflammatory diseases, graft-versus-host disease, traumatic stress, and neoplastic diseases (1, 2), and serve to limit T-cell responses. Tumor growth results in the expansion of this highly heterogeneous cellular population, which includes granulocytic, macrophage, dendritic cell, and early myeloid progenitors. MDSCs inhibit not only activation of T cells by anti-CD3 and superantigen, but also antigen-specific CD4 + and CD8 + T-cell responses. The mechanisms of MDSC immunosuppression are diverse, including up-regulation of reactive oxygen species (ROS), nitric oxide (NO), and L-arginine metabolism, as well as immunosuppressive cytokines. MDSCs were initially described in the late 1970s when they were identified as natural suppressor cells and defined as cells without lymphocyte-lineage markers that could suppress lymphocyte response to immunogens and mitogens (3 -5). MDSCs in mice are CD11b and Gr1 positive (6, 7) and also express CD31 (8), CD124, interleukin (IL)-4 receptor a-chain (9) and CD115, and macrophage-colony stimulating factor receptor (10). Human MDSC equivalents we...

COX-2 promotes metastasis in nasopharyngeal carcinoma by mediating interactions between cancer cells and myeloid-derived suppressor cells

“…MDSCs enhance tumor growth by negatively regulating immune responses and facilitating tumor metastasis and angiogenesis. 20,21 The reported mechanisms of MDSC-mediated T-cell inhibition include arginase 1 (ARG-1)-mediated depletion of L-arginine, iNOS-mediated and NADPH oxidase (NOX2)-mediated production of reactive nitrogen species and reactive oxygen species (ROS), increased vascular endothelial growth factor (VEGF) expression, cysteine depletion, and T-regulatory (Treg) cell expansion. 22,23 However, a direct link between the non-immune function of tumor-associated MDSC populations and tumor growth and metastasis has yet to be established.…”

Myeloid‐derived suppressor cells are key players in the resolution of inflammation during a model of acute infection

“…They are considered to be one of the major components of the immune suppressive network responsible for suppressing T-cell responses in pathological conditions [1,2] as well as in the regulation of the immune response in healthy individuals [3]. These Correspondence: Dr. Susana Gea e-mail: sgea@fcq.unc.edu.ar myeloid cells are commonly identified in mice by the co-expression of the surface markers CD11b and Gr1 (Ly6G/Ly6C) and have been divided into two subsets: granulocytic (G) MDSCs with a CD11b + LY6G + LY6C low phenotype and monocytic (M) MDSCs with CD11b + LY6G − LY6C high phenotype [3,4].…”

“…They are considered to be one of the major components of the immune suppressive network responsible for suppressing T-cell responses in pathological conditions [1,2] as well as in the regulation of the immune response in healthy individuals [3]. These M-MDSCs and inflammatory monocytes share the same phenotype and morphology, these cells are functionally distinct since M-MDSCs are highly immunosuppressive and they express high levels of both iNOS and arginase-1.…”

“…There is also evidence that MDSCs may suppress immune activation by inducing T regulatory cell expansion [11]. Other suppressive mechanisms that have recently been proposed include the production of TGF-β [12,13], depletion of cysteine [8], induction of COX2 and prostaglandin E2 [1,[14][15][16].Trypanosoma cruzi an obligate intracellular protozoan, is the causative agent of Chagas disease. This disease affects about 20 million people in Latin America, with 120 million persons at risk.…”

Lymphocyte subset recovery following allogeneic bone marrow transplantation: CD4+-cell count and transplant-related mortality

“…Further, there are other cellular components within the stem cell products, including cellular suppressors of T-cell function that might also be controlled to improve T-cell recovery and clinical outcomes. 19 Regardless of these caveats, the report by Berger et al 14 incorporates a large cohort of patients, which suggests that we should focus on CD4 þ -cell recovery to improve clinical outcomes.…”