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Beware of monocytes bearing gifts

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Science Translational Medicine  20 May 2020:
Vol. 12, Issue 544, eabb7101
DOI: 10.1126/scitranslmed.abb7101

Abstract

Monocytic myeloid-derived suppressor cells accumulate methylglyoxal, which inhibits their metabolic function and can be transferred to CD8+ T cells.

There has been substantial recent interest in the inhibitory role of myeloid-derived suppressor cells (MDSCs) in immunity, particularly in antitumor T cell responses. There are two subsets of MDSCs—monocytic and granulocytic—but the phenotypes proposed to identify either subset in mice or humans are not specific for MDSCs. Thus, phenotypic distinction of MDSCs from normal monocytes or granulocytes is problematic and has contributed to the challenges in reliably defining the frequency and function of MDSCs in various healthy or pathologic immune states.

Studying human monocytic MDSCs (mMDSCs) that were either induced in vitro or isolated from tumors in patients with hepatocellular carcinoma, Baumann and colleagues discovered greatly decreased metabolism. Interestingly, mMDSCs could transfer this reduced metabolism to CD8+ T cells upon coculturing, resulting in reduction of T cell differentiation, proliferation, and inflammatory cytokine production. These effects were opposite from those observed using normal monocytes. The intracellular metabolite methylglyoxal, detected by a cell-permeable fluorescent sensor, appeared to be relatively specific for human mMDSCs but could be transferred rapidly to T cells upon coculturing. Treatment with dimethylbiguanide (DMBG) neutralized methylglyoxal expression within mMDSCs, increased mMDSC metabolism, and impaired the ability of mMDSCs to suppress T cells. This suppressive effect appeared to be dependent on depletion of l-arginine within T cells, which is likely the end mediator of the methylglyoxal-induced paralysis of CD8+ T cells. Lastly, the authors showed in a murine tumor model that DMBG treatment could synergize with immune checkpoint inhibitor therapy, suggesting that overcoming mMDSC–mediated T cell suppression may augment antitumor immunity.

This elegant biochemical and functional analysis provides important insights into the identification and mechanistic functions of mMDSCs. Whether these findings are informative for modulation of antitumor responses in patients alone or in combination with other immunotherapeutic approaches requires further investigation. Furthermore, multiple other mechanisms of suppression have been previously ascribed to mMDSCs, including arginase-1 in this same model. Thus, how broadly these findings are applicable to mMDSC function in various pathophysiologic processes will be critical for the successful clinical translation of these results.

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