Myeloid-Derived Suppressor Activity Is Mediated by Monocytic Lineages Maintained by Continuous Inhibition of Extrinsic and Intrinsic Death Pathways

• Genetics of cell death define monocytic MDSCs as the dominant suppressive subset
• c-FLIP is required for monocytic MDSC development and MCL-1 for granulocytic MDSCs
• A1 induction by GM-CSF promotes survival of monocytic MDSCs
• Loss of granulocytic cells does not alter the onset or development of tumors

SummaryNonresolving inflammation expands a heterogeneous population of myeloid suppressor cells capable of inhibiting T cell function. This heterogeneity has confounded the functional dissection of individual myeloid subpopulations and presents an obstacle for antitumor immunity and immunotherapy. Using genetic manipulation of cell death pathways, we found the monocytic suppressor-cell subset, but not the granulocytic subset, requires continuous c-FLIP expression to prevent caspase-8-dependent, RIPK3-independent cell death. Development of the granulocyte subset requires MCL-1-mediated control of the intrinsic mitochondrial death pathway. Monocytic suppressors tolerate the absence of MCL-1 provided cytokines increase expression of the MCL-1-related protein A1. Monocytic suppressors mediate T cell suppression, whereas their granulocytic counterparts lack suppressive function. The loss of the granulocytic subset via conditional MCL-1 deletion did not alter tumor incidence implicating the monocytic compartment as the functionally immunosuppressive subset in vivo. Thus, death pathway modulation defines the development, survival, and function of myeloid suppressor cells.

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