Myeloid-Derived Suppressor Cells: Facilitators of Cancer and Obesity-Induced Cancer

Abstract

Immature myeloid cells at varied stages of differentiation, known as myeloid-derived suppressor cells (MDSC), are present in virtually all cancer patients. MDSC are profoundly immune-suppressive cells that impair adaptive and innate antitumor immunity and promote tumor progression through nonimmune mechanisms. Their widespread presence combined with their multitude of protumor activities make MDSC a major obstacle to cancer immunotherapies. MDSC are derived from progenitor cells in the bone marrow and traffic through the blood to infiltrate solid tumors. Their accumulation and suppressive potency are driven by multiple tumor- and host-secreted proinflammatory factors and adrenergic signals that act via diverse but sometimes overlapping transcriptional pathways. MDSC also accumulate in response to the chronic inflammation and lipid deposition characteristic of obesity and contribute to the more rapid progression of cancers in obese individuals. This article summarizes the key aspects of tumor-induced MDSC with a focus on recent progress in the MDSC field. Expected final online publication date for the Annual Review of Cancer Biology, Volume 5 is March 4, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Combined Effects of Myeloid Cells in the Neuroblastoma Tumor Microenvironment

“…Correspondingly, M-MDSC are morphologically similar to mononuclear blood monocytes, while PMN-MDSC resemble polymorphonuclear neutrophils [53]. All MDSC in mouse and human are negative for T cell, B cell, and NK cell lineage markers [78] (Table 1). In mice, MDSC can be characterized by their surface expression of CD11b combined with Ly6C or Ly6G, which are known collectively as Gr-1.…”

“…The predominant population in tumor-bearing mice and cancer patients are often PMN-MDSC, however there are differences between cancer types and inconclusive reports about which population is the most suppressive [49,78]. It has been shown in mice that M-MDSC can be considered more immune suppressive than PMN-MDSC on a per-cell basis.…”

“…Another activator of MDSC is the highly proinflammatory alarmin S100A8/A9 complex, which has been demonstrated to activate Nuclear Factor Kappa B (NF-κB) and STAT3 pathways by binding TLR4 and carboxylated N-glycans on the receptor for advanced glycation end products (RAGE) on MDSC in colon carcinoma-bearing mice [78,127]. Sinha et al have also demonstrated that S100A8/A9 acts as a chemoattractant for MDSC in solid tumors and that MDSC secrete S100A8 and S100A9 in the serum of tumor-bearing mice, thus creating an autocrine feedback loop [128].…”

“…While T cells are their key target, with suppression of T cell proliferation or cytokine release considered one of the hallmarks of defining MDSC [53], other effectors of immunity, including NK cells, APCs, Tregs, and B cells, have also been described to be targeted by MDSC-mediated measures (Figure 2). Importantly, although MDSC possess a multitude of mechanisms to interfere with pathways of the immune system, myeloid populations in the TME are heterogeneous and the predominant mechanisms may change depending on differentiation stage, extracellular milieu, and cellular composition of tumors [78].…”

Pancreatic Cancer Small Extracellular Vesicles (Exosomes): A Tale of Short- and Long-Distance Communication

“…In PDAC patients, MDSC frequency in the peripheral blood is associated with metastatic disease and poor clinical outcome [ 130 ]. According to their origin from either monocytic or granulocytic myeloid cell lineages, MDSCs are classified in two main subgroups: monocytic (M-MDSCs) or granulocytic/polymorphonuclear MDSCs (G/PMN-MDSCs) [ 129 , 131 ]. Upon persistent exposure to inflammatory signals and myeloid growth factors, MDSCs are activated and regulate a variety of immunological and non-immunological pro-tumorigenic functions, including immune evasion, angiogenesis, EMT, and PMN-formation [ 129 , 132 ].…”