Myeloid-derived suppressor cells (MDSCs IntroductionA major barrier to effective cancer immunotherapy is immune suppression, and the accumulation of myeloid-derived suppressor cells (MDSCs) has recently been recognized as a major mechanism to promote immune suppression (1, 2). MDSCs comprise a mixture of myeloid cells reflecting various stages of differentiation, and in mouse models, these cells are typically distinguished from other inhibitory myeloid populations based on their unique coexpression of macrophage (CD11b) and granulocyte (Gr-1) markers (1).Tumor-induced MDSCs are further dichotomized into monocytic and granulocytic subsets based on the differential expression of the Ly6G and Ly6C epitopes (3, 4). Intriguingly, granulocytic MDSCs outnumber monocytic MDSCs in numerous mouse tumor models (3, 5), although the basis for this subset dichotomy remains unclear. The phenotypes in humans are more complex and vary with tumor type. However, there is general agreement that a common lineage-negative MDSC subset observed among a range of human cancers bears the core phenotype CD33 + HLA-DR -(6-11). Interestingly, this subset resembles promyelocytes, a granulocytic population reflecting an early stage of differentiation (6, 7).Although many studies have been dedicated to the phenotypic characterization of MDSCs and unraveling mechanisms by which these cells mediate tumor progression, a large gap remains in our understanding of the mechanisms that initiate their development. It is known, however, that MDSC subsets emerge in response to tumor-derived factors (TDFs) and the signaling pathways these molecules engage. As a number of TDFs engage the STAT3 or STAT5 signaling pathway, STAT3 or STAT5 activation has been associated with various stages in MDSC biology (1,(12)(13)(14)(15)(16)(17)(18)(19).

Immune function relies on an appropriate balance of the lymphoid and myeloid responses. In the case of neoplasia, this balance is readily perturbed by the dramatic expansion of immature or dysfunctional myeloid cells accompanied by a reciprocal decline in the quantity/quality of the lymphoid response. In this review, we seek to: 1) define the nature of the atypical myelopoiesis observed in cancer patients and the impact of this perturbation on clinical outcomes; 2) examine the potential mechanisms underlying these clinical manifestations; and 3) explore potential strategies to restore normal myeloid cell differentiation to improve activation of the host antitumor immune response. We posit that fundamental alterations in myeloid homeostasis triggered by the neoplastic process represent critical checkpoints that govern therapeutic efficacy, as well as offer novel cellular-based biomarkers for tracking changes in disease status or relapse.

Alterations in myelopoiesis are common across various tumor types, resulting in immature populations termed myeloid-derived suppressor cells (MDSCs). MDSC burden correlates with poorer clinical outcomes, credited to their ability to suppress antitumor immunity. MDSCs consist of two major subsets, monocytic and polymorphonuclear (PMN). Intriguingly, the latter subset predominates in many patients and tumor models, though the mechanisms favoring PMN-MDSC responses remain poorly understood. Ordinarily, lineage-restricted transcription factors regulate myelopoiesis that collectively dictate cell fate. One integral player is interferon regulatory factor-8 (IRF8), which promotes monocyte/dendritic cell differentiation while limiting granulocyte development. We recently showed that IRF8 inversely controls MDSC burden in tumor models, particularly the PMN-MDSC subset. However, where IRF8 acts in the pathway of myeloid differentiation to influence PMN-MDSC production has remained unknown. Here, we showed that: 1) tumor growth was associated with a selective expansion of newly defined IRF8lo granulocytic progenitors (GPs); 2) tumor-derived GPs had an increased ability to form PMN-MDSCs; 3) tumor-derived GPs shared gene expression patterns with IRF8−/− GPs, suggesting that IRF8 loss underlies GP expansion; and 4) enforced IRF8 overexpression in vivo selectively constrained tumor-induced GP expansion. These findings support the hypothesis that PMN-MDSCs result from selective expansion of IRF8lo GPs, and that strategies targeting IRF8 expression may limit their load to improve immunotherapy efficacy.

Tissue-resident memory CD8 T (TRM) cells defend against microbial reinfections at mucosal barriers; determinants driving durable TRM cell responses in non-mucosal tissues, which often harbor opportunistic persistent pathogens, are unknown. JC polyomavirus (JCPyV) is a ubiquitous constituent of the human virome. With altered immunological status, JCPyV can cause the oft-fatal brain demyelinating disease progressive multifocal leukoencephalopathy (PML). JCPyV is a human-only pathogen. Using the mouse polyomavirus (MuPyV) encephalitis model, we demonstrate that CD4 T cells regulate development of functional antiviral brain-resident CD8 T cells (bTRM) and renders their maintenance refractory to systemic CD8 T cell depletion. Acquired CD4 T cell deficiency, modeled by delaying systemic CD4 T cell depletion until MuPyV-specific CD8 T cells have infiltrated the brain, impacted the stability of CD8 bTRM, impaired their effector response to reinfection, and rendered their maintenance dependent on circulating CD8 T cells. This dependence of CD8 bTRM differentiation on CD4 T cells was found to extend to encephalitis caused by vesicular stomatitis virus. Together, these findings reveal an intimate association between CD4 T cells and homeostasis of functional bTRM to CNS viral infection.

A major mechanism by which cancers escape control by the immune system is by blocking the differentiation of myeloid cells into dendritic cells (DCs), immunostimulatory cells that activate anti-tumor T cells. Tumor-dependent activation of signal transducer and activator of transcription 3 (STAT3) signaling in myeloid progenitor cells is thought to cause this block in their differentiation. In addition, a signaling pathway through protein kinase C βII (PKCβII) is essential for the differentiation of myeloid cells into DCs. Here, we found in humans and mice that breast cancer cells substantially decreased the abundance of PKCβII in myeloid progenitor cells through a mechanism involving the enhanced activation of STAT3 signaling by soluble, tumor-derived factors (TDFs). STAT3 bound to previously undescribed negative regulatory elements within the promoter of PRKCB, which encodes PKCβII. We also found a previously undescribed counter-regulatory mechanism through which the activity of PKCβII inhibited tumor-dependent STAT3 signaling by decreasing the abundance of cell-surface receptors, such as cytokine and growth factor receptors, that are activated by TDFs. Together, these data suggest that a previously unrecognized crosstalk mechanism between the STAT3 and PKCβII signaling pathways provides the molecular basis for the tumor-induced blockade in the differentiation of myeloid cells, and suggest that enhancing PKCβII activity may be a therapeutic strategy to alleviate cancer-mediated suppression of the immune system.