Myeloid suppressor cells regulate the adaptive immune response to cancer
Alan B. Frey
Alan B. Frey
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Commentary

Myeloid suppressor cells regulate the adaptive immune response to cancer

Abstract

Inflammation resultant from tumor growth, infection with certain pathogens, or in some cases, trauma, can result in systemic release of cytokines, especially GM-CSF, that in turn stimulate the abundant production and activation of a population of immature myeloid cells, termed myeloid suppressor cells (MSCs), that have potent immunosuppressive functions. In this issue of the JCI, Gallina and colleagues have illuminated some complex issues concerning the development, activation, and function of MSCs (see the related article beginning on page 2777). They show that activation of MSCs is initiated in response to IFN-γ, presumably produced in situ by antitumor T cells in the tumor microenvironment. After this triggering event, MSCs express 2 enzymes involved in l-arginine metabolism, Arginase I and iNOS, whose metabolic products include diffusible and highly reactive peroxynitrites, the ultimate biochemical mediators of T cell immune suppression. The multifaceted regulation of this complex suppressive effector system provides several potential therapeutic targets.

Authors

Alan B. Frey

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Figure 1

Immunosuppressive effects of tumor-induced MSCs on antitumor CD8+ T lymphocytes.

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Immunosuppressive effects of tumor-induced MSCs on antitumor CD8+ T lymp...
Previous work has shown that certain factors that enhance myelopoiesis are produced either by tumors or in response to tumor growth (i). In this issue of the JCI, Gallina et al. (10) demonstrate that release of IFN-γ by CD8+ T lymphocytes (ii) triggers MSCs to release IL-13 and IFN-γ (iii). This results in the production and activation in an autocrine manner of the enzymes iNOS and Arginase I (iv), the downstream effects of which can inhibit CD8+ T cell proliferation and activation or trigger T cell apoptosis (v). Therapeutic approaches to lifting this MSC-induced immunosuppression during cancer might include targeted deletion of IL-4Rα+ cells (MSCs), blockade of IL-4Rα, inhibition of STAT-3–dependent pre-MSC maturation into active MSCs, and Arginase I or iNOS inhibition. Figure modified from Gallina et al. (10).