MDSC: Markers, development, states, and unaddressed complexity

Abstract

Myeloid-derived suppressor cells (MDSCs) are one of the most discussed biological entities in immunology. While the context and classification of this group of cells has evolved, MDSCs most commonly describe cells arising during chronic inflammation, especially late-stage cancers, and are defined by their T cell immunosuppressive functions. This MDSC concept has helped explain myeloid phenomena associated with disease outcome, but currently lacks clear definitions and a unifying framework across pathologies. Here, we propose such a framework to classify MDSCs as discrete cell states based on activation signals in myeloid populations leading to suppressive modes characterized by specific, measurable effects. Developing this level of knowledge of myeloid states across pathological conditions may ultimately transform how disparate diseases are grouped and treated.

Figure 1.. Myeloid suppressive states are highly heterogenous and context dependent

(A) The dominant view of MDSC phenomena defines two major subtypes of suppressive cells (Mo-MDSC and PMN-MDSC) with ontological and functional differences. In the field of cancer biology, these cells are often described as immature cells expanded in an inflammatory context. Although these cell types can be immunosuppressive through diverse mechanisms, the true complexity of these myeloid populations has only recently been recognized through advances in disease-modeling and higher-resolution techniques. (B) The emergent view of MDSCs as a facet of emergency hematopoiesis captures the heterogeneity and plasticity of these myeloid cell states in a more “ruffled” ontogenetic landscape. The suppressive nature of these cells can thus be de-coupled from their immaturity and/or location. This view also considers the strong influence of the tissue microenvironment, proximal inflammatory cues, and trained immunity or innate memory on establishment of suppressive states. Abbreviations are as follows: GMP, granulocyte-monocyte progenitor; MDP, monocyte-dendritic cell progenitor; cMoP, common monocyte progenitor; proNeu, neutrophil progenitor.

Figure 2.. Myeloid suppression across diseases need to be reframed

Myeloid immune suppression and regulation occur via multiple pathways in different diseases. Studies should identify key mediators at multiple layers of biological inquiry, i.e., disease setting, pathological stimulus, target myeloid cells, how suppressive signal is integrated, and how/where suppression is engendered. The envisioned framework (shown here with key factors, mechanisms, and cell types as nodes) can help identify the predominant manner by which myeloid cells become suppressive for a specific inflammatory context (exemplified here as solid red connections). As the complexity of these “nodes” increases with our understanding of cellular interactions, it will become important to identify suppressive “archetypes” with consensus across fields of research.

Figure 3.. Classifying myeloid suppressive pathology into archetypes can accelerate clinical targeting

Utilizing the new framework, empirical MDSC phenomena can be distilled into archetypes where dominant multi-level mechanisms of immunosuppression are defined. These myeloid archetypes (here shown as gray, green, or blue circuitry) can identify commonalities across diseases and help establish more targeted treatment approaches (here shown as example strategies in red circles). As a result, clinical targeting of MDSC-like phenomena is not biased by any one factor (e.g., inflammatory chemokine or type of myeloid cell). Abbreviations are as follows: IBD, inflammatory bowel disease; NASH, non-alcoholic steatohepatitis; TLR, toll-like receptor; SLE, systemic lupus erythematosus.