Search

The persistence of latent HIV-1 reservoirs in cells presents a formidable challenge towards a complete HIV cure. Edelfosine is an FDA-approved investigational, anti-neoplastic drug. In this study, we aimed to investigate its role as a HIV-1 Latency Reversal Agent (LRA) using latency model cell lines. Our findings demonstrated that edelfosine reactivated latent HIV-1 viruses in myeloid cells in a dose and time-dependent manner. The mechanism of reactivation by edelfosine involved the activation of NF-κB and AP1 pathways in these cells. The reactivated virus was non-infectious. Delineating the mechanism of non-infectious virus production revealed an increased stabilization of cellular APOBEC3G protein as well as its enhanced incorporation into the released viruses. Thus, our study demonstrated for the first time an additional role of edelfosine in reactivation of latent HIV-1 and production of non-infectious virus. Our results have paved the way for repurposing of edelfosine as a novel HIV-1 latency reversal agent.

Implanted biomaterials have transformed healthcare and the treatment of injury and disease, but their influence on the local immune landscape remains unclear. Here we discovered that degradation-resistant titanium-based implants establish an immunosuppressive microenvironment by recruiting myeloid cells, including monocytes, macrophages, neutrophils, and myeloid-lineage dendritic cells. Unlike normal tissues, the tissues nearby implants exhibit an chronic inflamed and immunosuppressive status characterised by myeloid-rich, T cell-exhaustion gene signature by single-cell RNA sequencing. Vitamin C treatment provides an effective strategy to rescue the immunosuppressive microenvironment, which can be used as a regular supplement to reduce the risk of malignant cell survival around the implants.

Transcription factor MYB is a key regulator of gene expression in hematopoietic cells and has emerged as a novel drug target for acute myeloid leukemia (AML). Studies aiming to identify potential MYB inhibitors have found that the natural compound helenalin acetate (HA) inhibits viability and induces cell death and differentiation of AML cells by disrupting the MYB-induced gene expression program. Interestingly, CCAAT-box/enhancer binding protein β (C/EBPβ), a transcription factor known to cooperate with MYB and the co-activator p300 in myeloid cells, rather than MYB itself, was identified as the primary target of HA. This supports a model in which MYB, C/EBPβ, and p300 form the core of a transcriptional module that is essential for maintenance of the proliferative potential of AML cells, highlighting a novel role for C/EBPβ as a proleukemogenic factor.

Immune checkpoint blockade has dramatically improved cancer therapy but remains ineffective for most colorectal tumors. In this issue of Immunity, Peuker et al. describe a microbiota-myeloid-tumor cell crosstalk that inhibits CD8

Previous researches have suggested that soluble triggering receptor expressed on myeloid cells 2 (sTREM2) plays a pivotal role in central nervous system pathologies and the development of neurodegenerative disorders. This study aimed to prospectively investigate the association between plasma sTREM2 levels and post-stroke cognitive impairment (PSCI).A sample of 599 consecutive acute ischemic stroke patients with sTREM2 measurements from the China Antihypertensive Trial in Acute Ischemic Stroke were eventually included in this analysis. Cognitive impairment was defined as a score of25 for Mini-Mental State Examination, measured at 3-month follow up. Binary logistic regression was used to estimate the odds ratios (ORs) of plasma sTREM2 levels on the risk of PSCI.Of the 599 participants (mean age, 60.0 ± 10.4 years; male, 70.5%), 228 (38.1%) patients were diagnosed as PSCI. The risk of PSCI elevated significantly with higher plasma sTREM2 levels (p for trend0.01). After adjusting for several confounding factors, the ORs for the highest quartile of sTREM2 compared with the lowest quartile was 2.06 (95% confidence interval, 1.20-3.53) for PSCI. Moreover, the addition of sTREM2 to the conventional model with established risk factors significantly improved risk discrimination (C-statistics increased from 0.668 to 0.691, p = 0.02) and reclassification (net reclassification improvement: 32.2%, p 0.001; integrated discrimination improvement: 1.3%, p = 0.01) for PSCI.Results might be subject to selective bias and potential confounding.The present study demonstrated that elevated level of plasma sTREM2 may be associated with PSCI, and sTREM2 has potential value in predicting PSCI.

Background & aimsNonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide. The NLRP3 inflammasome, a platform for caspase-1 activation and release of interleukin 1β, is increasingly recognized in the induction of inflammation and liver fibrosis during NAFLD. However, the cell-specific contribution of NLRP3 inflammasome activation in NAFLD remains unknown.MethodsTo investigate the role of NLRP3 inflammasome activation in hepatocytes, hepatic stellate cells (HSCs) and myeloid cells, a conditional Nlrp3 knock-out mouse was generated and bred to cell-specific Cre mice. Both acute and chronic liver injury models were used: lipopolysaccharide/adenosine-triphosphate to induce invivo NLRP3 activation, choline-deficient, L-amino acid-defined high-fat diet, and Western-type diet to induce fibrotic nonalcoholic steatohepatitis (NASH). Invitro co-culture studies were performed to dissect the crosstalk between myeloid cells and HSCs.ResultsMyeloid-specific deletion of Nlrp3 blunted the systemic and hepatic increase in interleukin 1β induced by lipopolysaccharide/adenosine-triphosphate injection. In the choline-deficient, L-amino acid-defined high-fat diet model of fibrotic NASH, myeloid-specific Nlrp3 knock-out but not hepatocyte- or HSC-specific knock-out mice showed significant reduction in inflammation independent of steatosis development. Moreover, myeloid-specific Nlrp3 knock-out mice showed ameliorated liver fibrosis and decreased HSC activation. These results were validated in the Western-type diet model. Invitro co-cultured studies with human cell lines demonstrated that HSC can be activated by inflammasome stimulation in monocytes, and this effect was significantly reduced if NLRP3 was downregulated in monocytes.ConclusionsThe study provides new insights in the cell-specific role of NLRP3 in liver inflammation and fibrosis. NLRP3 inflammasome activation in myeloid cells was identified as crucial for the progression of NAFLD to fibrotic NASH. These results may have implications for the development of cell-specific strategies for modulation of NLRP3 activation for treatment of fibrotic NASH.

The ability of the innate and adaptive immune systems to communicate with each other is central to protective immune responses and maintenance of host health. Myeloid cells of the innate immune system are able to sense microbial ligands, perturbations in cellular homeostasis, and virulence factors, thereby allowing them to relay distinct pathogen-specific information to naïve T cells in the form of pathogen-derived peptides and a unique cytokine milieu. Once primed, effector T helper cells produce lineage-defining cytokines to help combat the original pathogen, and a subset of these cells persist as memory or effector-memory populations. These memory T cells then play a dual role in host protection by not only responding rapidly to reinfection, but by also directly instructing myeloid cells to express licensing cytokines. This means there is a bi-directional flow of information first from the innate to the adaptive immune system, and then from the adaptive back to innate immune system. Here, we focus on how signals, first from pathogens and then from primed effector and memory T cells, are integrated by myeloid cells and its consequences for protective immunity or systemic inflammation.

Myeloid cells (macrophages, monocytes, dendritic cells, and granulocytes) survey the body for signs of infection and tissue damage and regulate tissue homeostasis, organogenesis, and immunity. They express receptors that initiate the inflammatory response, send signals that alter the vascular and cytokine milieu, and oversee the recruitment, differentiation, and activation of other myeloid and adaptive immune cells. Their activation must therefore be tightly regulated, optimized for maximal innate-immune protection with a minimum of collateral tissue damage or disorganization. In this review we discuss what it means for myeloid cells to become activated, with emphasis on the receptors and signaling molecules important for the recognition of pathogen- and damage-associated molecular patterns. We also outline how these signals are regulated by the steric properties of proteins, by adhesive and cytoskeletal interactions, and by negative feedback to keep inflammation in check and support healthy tissue development and homeostasis. Throughout the text we highlight recent publications and reviews that illustrate key elements of myeloid-cell regulation and direct readers therein for a comprehensive bibliography.

The ability of myeloid regulatory cells (MRCs) to control immune responses and to promote tolerance has prompted enormous interest in exploiting them therapeutically to treat inflammation, autoimmunity, or to improve outcomes in transplantation. While immunomodulatory small-molecule compounds and antibodies have provided relief for some patients, the dosing entails high systemic drug exposures and thus increased risk of off-target adverse effects. More recently, MRC-based cell-therapy products have entered clinical testing for tolerance induction. However, the elaborate and expensive protocols currently required to manufacture engineered MRCs ex vivo put this approach beyond the reach of many patients who might benefit. A solution could be to directly program MRCs in vivo. Here we describe a targeted nanocarrier that delivers in vitro-transcribed mRNA encoding a key anti-inflammatory mediator. We demonstrate in models of systemic lupus erythematosus that infusions of nanoparticles formulated with mRNA encoding glucocorticoid-induced leucine zipper (GILZ) effectively control the disease. We further establish that these nanoreagents are safe for repeated dosing. Implemented in the clinic, this new therapy could enable physicians to treat autoimmune disease while avoiding systemic treatments that disrupt immune homeostasis.

Understanding the mechanisms of tissue and organ regeneration in adult animals and humans is of great interest from a basic biology as well as a medical, therapeutical point of view. It is increasingly clear that the relatively limited ability to regenerate tissues and organs in mammals as oppose to lower vertebrates is the consequence of evolutionary trade-offs and changes during development and aging. Thus, the coordinated interaction of the immune system, particularly the innate part of it, and the injured, degenerated parenchymal tissues such as skeletal muscle, liver, lung, or kidney shape physiological and also pathological processes. In this review, we provide an overview of how morphologically and functionally complete (ad integrum) regeneration is achieved using skeletal muscle as a model. We will review recent advances about the differentiation, activation, and subtype specification of circulating monocyte to resolution or repair-type macrophages during the process we term regenerative inflammation, resulting in complete restoration of skeletal muscle in murine models of toxin-induced injury.

In this issue of Cancer Cell, Long et al. demonstrate that tumors can reprogram erythroid progenitors into myeloid-erythroid cells that promote immunosuppression. Erythroid-differentiated myeloid cells (EDMCs) expand in cancer-bearing individuals, resemble the functionality of myeloid-derived suppressor cells (MDSCs), and correlate with poor response to immune-checkpoint inhibitors (ICIs) and tumor-related anemia.

Viruses are the second leading cause of cancer worldwide, and human papillomavirus (HPV)-associated head and neck cancers are increasing in incidence in the United States. HPV preferentially infects the crypts of the tonsils rather than the surface epithelium. The present study sought to characterize the unique microenvironment within the crypts to better understand the viral tropism of HPV to a lymphoid-rich organ. Laser-capture microdissection of distinct anatomic areas (crypts, surface epithelium, and germinal centers) of the tonsil, coupled with transcriptional analysis and multiparameter immunofluorescence staining demonstrated that the tonsillar crypts are enriched with myeloid populations that co-express multiple canonical and noncanonical immune checkpoints, including PD-L1, CTLA-4, HAVCR2 (TIM-3), ADORA2A, IDO1, BTLA, LGALS3, CDH1, CEACAM1, PVR, and C10orf54 (VISTA). The resident monocytes may foster a permissive microenvironment that facilitates HPV infection and persistence. Furthermore, the myeloid populations within HPV-associated tonsil cancers co-express the same immune checkpoints, providing insight into potential novel immunotherapeutic targets for HPV-associated head and neck cancers.

The glioma microenvironment is heavily infiltrated by non-neoplastic myeloid cells, including bone marrow-derived macrophages and central nervous system-resident microglia. As opposed to executing the antitumor functions of immune surveillance, antigen presentation, and phagocytosis, these tumor-associated myeloid cells are co-opted to promote an immunosuppressive milieu and support tumor invasion and angiogenesis. This review explores evolving evidence and the research paradigms used to determine the interplay of tumor genetics, immune cell composition, and immune function in gliomas. Understanding these cells and how they are reprogrammed will be instrumental in finding new and effective treatments for these lethal tumors.

Drug resistance remains the major obstacle limiting the effectiveness of chemotherapy for esophageal squamous cell carcinoma (ESCC)[1]. However, how stromal cells cooperate with immune cells to contribute to drug resistance is not yet fully understood. In this study, we observed that monocytic myeloid-derived suppressor cells (M-MDSCs) were correlated with cisplatin resistance in patients with ESCC. Furthermore, CAFs promoted differentiation of monocytes into M-MDSCs phenotypically and functionally in vitro. Mechanically, both interleukin (IL)-6 and exosome-packed microRNA-21 (miR-21) secreted by CAFs synergistically promoted the generation of M-MDSCs via activating the signal transducing activator of transcription 3 (STAT3) by IL-6 in an autocrine manner. Combined blocking of IL-6 receptor and inhibition of miR-21 significantly reversed CAF-mediated M-MDSC generation. Notably, the effects of CAFs on M-MDSC induction were abolished by inhibiting STAT3 signaling. Functionally, CAF-induced M-MDSCs promoted drug resistance of tumor cells upon cisplatin treatment. Clinically, ESCC patients with high infiltration of CAFs and CD11b+ myeloid cells had unfavorable predicted overall survival both in our cohort and in TCGA data. Taken together, our study reveals a paracrine and autocrine of IL-6 caused by CAFs co-activate STAT3 signaling, promoting the generation of M-MDSCs, and highlights the important role of CAFs in cooperation with M-MDSCs in promoting drug resistance, thus providing potential opportunities for reversing drug resistance through inhibition of STAT3 signaling.

Polycythemia vera (PV) is a Philadelphia-negative myeloproliferative neoplasm characterized by excessive myeloid cells production, mostly secondary to mutations in the Janus kinase 2 (JAK2) gene. PV natural history might be burdened by thrombotic events (TEs) and evolution into post-PV myelofibrosis (PPV-MF) or blast phase (BP). To date, no treatment strategies have been shown to have disease modifying effects, so therapy is directed at preventing TEs. All patients require phlebotomies (PHLs) to keep hematocrit below 45% and once-daily low dose aspirin (if not contraindicated). Apart from patients at "high risk" because of age over 60 years or a thrombosis history, cytoreductive therapies (CT) should be given to patients with relevant signs of myeloproliferation or intolerance to PHLs. Approved choices both for first and second line CT are hydroxyurea (HU) and pegylated forms of interferon (peg-IFN), the latter probably being better for young patients, and subjects without critical and recent vascular events or massive splenomegaly. The JAK1/2 inhibitor ruxolitinib is the treatment of choice in case of resistance/intolerance to HU, with proved efficacy in terms of thrombotic prevention. Data are too preliminary to consider CT for "low risk" PV cases, but ropeg-IFN is being studied in this setting with a short follow-up. A careful monitoring for signs of evolution into PPV-MF is fundamental for optimizing patient management.

Aging is associated with excessive bone loss that is not counteracted with the development of new bone. However, the mechanisms underlying age-related bone loss are not completely clear. Myeloid-derived suppressor cells (MDSCs) are a population of heterogenous immature myeloid cells with immunosuppressive functions that are known to stimulate tumor-induced bone lysis. In this study, we investigated the association of MDSCs and age-related bone loss in mice. Our results shown that aging increased the accumulation of MDSCs in the bone marrow and spleen, while in the meantime potentiated the osteoclastogenic activity of the CD11b(+)Ly6C(hi)Ly6G(+) monocytic subpopulation of MDSCs. In addition, CD11b(+)Ly6C(hi)Ly6G(+) MDSCs from old mice exhibited increased expression of c-fms compared to young mice, and were more sensitive to RANKL-induced osteoclast gene expression. On the other hand, old mice showed elevated production of IL-6 and receptor activator of nuclear factor kappa-B ligand (RANKL) in the circulation. Furthermore, IL-6 and RANKL were able to induce the proliferation of CD11b(+)Ly6C(hi)Ly6G(+) MDSCs and up-regulate c-fms expression. Moreover, CD11b(+)Ly6C(hi)Ly6G(+) MDSCs obtained from old mice showed increased antigen-specific T cell suppressive function, pStat3 expression, and cytokine production in response to inflammatory stimulation, compared to those cells obtained from young mice. Our findings suggest that CD11b(+)Ly6C(hi)Ly6G(+) MDSCs are a source of osteoclast precursors that together with the presence of persistent, low-grade inflammation, contribute to age-associated bone loss in mice.

Dentritic cells (DCs) dysfunction has been verified detrimental for sepsis and B and T lymphocyte attenuator (BTLA) is an immune-regulatory receptor shown to be associated with DCs dysfunction. However, the role of BTLA expression in myeloid DCs (mDCs) in neonatal sepsis is unknown. In the current study, we found BTLA-expressing mDCs were elevated in neonates with sepsis and the BTLA expression level in mDCs was positively correlated to the severity of sepsis. The presence of BTLA negatively regulated the phagocytosis capacity and bactericidal ability of mDCs as well as the maturation markers expression of mDCs. Our data also showed BTLA+mDCs shifted into an anti-inflammatory phenotype with decreased expression of IL-6, TNF-α and IL-12, but increased IL-10. in addition, we found BTLA expression indeedly altered the mDCs allo-stimulatory capacity. Therefore, BTLA expression in mDCs could be a useful predictive marker for neonatal sepsis and targeting BTLA expression in mDCs may be a new therapeutic strategy.

Glucocorticoids (GCs) constitute one of the most powerful classes of anti-inflammatory agents and are used for the treatment of a plethora of diseases related to autoimmunity, allergy, cancer, and infection. In the last two decades, multiple studies using genetically engineered mice with targeted deletions of the GC receptor (GR) in individual cell types have provided insights into the mechanisms of GCs in the control of the immune system. The characterization of GR expression in these mouse models, however, mostly relied on the analysis of mRNA expression or reporter gene activity. In contrast, approaches directly detecting the GR protein on a cellular level are scarce. Thus, we here used a flow cytometric method to analyze mice in which the GR gene locus was disrupted with the help of a Cre recombinase expressed under the control of either the lck or the lysM promoter. Measuring GR protein expression in immune cell subpopulations unveiled an efficient and highly selective depletion in both strains of knock-out mice in accordance with the expected cellular specificity of the employed promoters for T cells or myeloid cells, respectively. The flow cytometric data were well in line with those from the analysis of GR mRNA expression in magnetically sorted immune cell subpopulations but they could be obtained much more quickly. In summary, our data indicate that flow cytometry is a powerful tool with which to define GR protein content at a single cell level when studying the function of GCs in the immune system.

RUNX3, a transcription factor, has been implicated as a tumor suppressor in various cancers, including hematological malignancies; however, recent studies revealed an oncogenic function of RUNX3 in the pathogenesis of myeloid malignancies, such as myelodysplastic syndrome and acute myeloid leukemia. In contrast to the high frequency of mutations in the RUNX1 gene, deletion of and loss-of-function mutations in RUNX3 are rarely detected in patients with hematopoietic malignancies. Although RUNX3 is expressed in normal hematopoietic stem and progenitor cells, its expression decreases with aging in humans. The loss of Runx3 did not result in the development of lethal hematological diseases in mice despite the expansion of myeloid cells. Therefore, RUNX3 does not appear to initiate the transformation of normal hematopoietic stem cells. However, the overexpression of RUNX3 inhibits the expression and transcriptional function of the RUNX1 gene, but activates the expression of key oncogenic pathways, such as MYC, resulting in the transformation of premalignant stem cells harboring a driver genetic mutation. We herein discuss the mechanisms by which RUNX3 is activated and how RUNX3 exerts oncogenic effects on the cellular function of and transcriptional program in premalignant stem cells to drive myeloid transformation.

Summary 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.

Retinol is shuttled to myeloid cells for conversion to retinoic acid, but the receptor facilitating uptake of SAA:retinol complexes on myeloid cells is unknown. In a recent issue of Science, Bang et al. (2021) use genetic and biochemical approaches to reveal this critical receptor to be LRP1 and show that this axis is essential for intestinal innate and adaptive immune responses.

Bone metastases are devastating complications of cancer. They are particularly common in prostate cancer (PCa), represent incurable disease, and are refractory to immunotherapy. We seek to define distinct features of the bone marrow (BM) microenvironment by analyzing single cells from bone metastatic prostate tumors, involved BM, uninvolved BM, and BM from cancer-free, orthopedic patients, and healthy individuals. Metastatic PCa is associated with multifaceted immune distortion, specifically exhaustion of distinct T cell subsets, appearance of macrophages with states specific to PCa bone metastases. The chemokine CCL20 is notably overexpressed by myeloid cells, as is its cognate CCR6 receptor on T cells. Disruption of the CCL20-CCR6 axis in mice with syngeneic PCa bone metastases restores T cell reactivity and significantly prolongs animal survival. Comparative high-resolution analysis of PCa bone metastases shows a targeted approach for relieving local immunosuppression for therapeutic effect.

Active inflammation generally promotes immune activation. However, in the tumor microenvironment (TME), active inflammation occurs in parallel with immunosuppression, and both contribute to tumor growth. Why inflammation does not lead to immune activation in TME remains unclear. In this study, using the immune checkpoint inhibitor-insensitive mouse cancer model and single-cell RNA sequencing, we show that PGE₂-EP2/EP4 signaling simultaneously promotes active inflammation by inducing expression of the NF-κB genes in myeloid cells and elicits immunosuppression by driving the mregDC (mature DC enriched in immunoregulatory molecules)-Treg (regulatory T cell) axis for Treg recruitment and activation in the tumor. Importantly, the EP2/EP4 expression level is strongly correlated with the gene signatures of both active inflammation and the mregDC-Treg axis and has significant prognosis value in various human cancers. Thus, PGE₂-EP2/EP4 signaling functions as the key regulatory node linking active inflammation and immunosuppression in TME, which can be targeted by EP2 and EP4 antagonists for cancer therapeutics., EP2/4阻害薬による抗腫瘍作用の機序解明 --新しいがん免疫治療薬の開発に向けて--. 京都大学プレスリリース. 2022-06-08.

Chronic inflammation is a hallmark of myeloproliferative neoplasms (MPNs), with elevated levels of proinflammatory cytokines being commonly found in all 3 subtypes. Systemic inflammation is responsible for the constitutional symptoms, thrombosis risk, premature atherosclerosis, and disease evolution in MPN. Although the neoplastic clone and their differentiated progeny drive the inflammatory process, they also induce ancillary cytokine secretion from nonmalignant cells. Here, the authors describe the inflammatory milieu in MPN based on soluble factors and cellular mediators. They also discuss the prognostic value of cytokine measurements in patients with MPN and potential therapeutic strategies that target the cellular players in inflammation.

CpG oligonucleotides are short single-stranded synthetic DNA molecules. Upon binding to Toll-like receptor 9 (TLR9), CpG activates immune cells in humans and mice. This results in robust Th1 type immunity potentially resulting in clearance of pathogens, reduction of allergy and anti-tumor immunity. However, the effectiveness of CpG as an adjuvant depends on its administration route, with only strong effects seen when CpG is administered locally. As local administration is not always feasible, we generated conjugates to specifically deliver CpG to myeloid cells often abundantly present in tumors. For this we coupled CpG (3'-Thiol-modified phosphorothioate (PTO) CpG-ODN1826 type B (5'-tccatgacgttcctgacgtt-3')) to monoclonal antibodies (mAbs) directed against the myeloid cell marker CD11b using maleimide-thiol coupling. The CD11b-CpG mAb (αCD11b-CpG) conjugates contained about four CpG molecules/conjugate and displayed binding and internalization characteristics similar to unconjugated CD11b mAbs (αCD11b). The αCD11b-CpG conjugates readily induced maturation of murine dendritic cells (DCs) in a TLR9-dependent manner in vitro. Following intravenous injection, αCD11b-CpG conjugates efficiently targeted CD11b+ immune cells in the blood, lymph nodes and spleen. Finally, injection of αCD11b-CpG conjugates, but not untargeted conjugates, induced maturation of CD11b+ cell subsets in vivo. In conclusion, conjugating CpG to αCD11b enabled specific targeting and activation of myeloid cells in vivo.

Background Myeloid cells play an important role in a wide variety of cardiovascular disorders, including both ischemic and non-ischemic cardiomyopathies. Neuregulin-1 (NRG-1)/ErbB signaling has recently emerged as an important factor contributing to the control of inflammatory activation of myeloid cells after an ischemic injury. However, the role of ErbB signaling in myeloid cells in non-ischemic cardiomyopathy is not fully understood. This study investigated the role of ErbB3 receptors in the regulation of early adaptive response using a mouse model of transverse aortic constriction (TAC) for non-ischemic cardiomyopathy. Methods and results TAC surgery was performed in groups of age- and sex-matched myeloid cell-specific ErbB3-deficient mice (ErbB3MyeKO) and control animals (ErbB3MyeWT). The number of cardiac CD45 immune cells, CD11b myeloid cells, Ly6G neutrophils, and Ly6C monocytes was determined using flow cytometric analysis. Five days after TAC, survival was dramatically reduced in male but not female ErbB3MyeKO mice or control animals. The examination of lung weight to body weight ratio suggested that acute pulmonary edema was present in ErbB3MyeKO male mice after TAC. To determine the cellular and molecular mechanisms involved in the increased mortality in ErbB3MyeKO male mice, cardiac cell populations were examined at day 3 post-TAC using flow cytometry. Myeloid cells accumulated in control but not in ErbB3MyeKO male mouse hearts. This was accompanied by increased proliferation of Sca-1 positive non-immune cells (endothelial cells and fibroblasts) in control but not ErbB3MyeKO male mice. No significant differences in intramyocardial accumulation of myeloid cells or proliferation of Sca-1 cells were found between the groups of ErbB3MyeKO and ErbB3MyeWT female mice. An antibody-based protein array analysis revealed that IGF-1 expression was significantly downregulated only in ErbB3MyeKO mice hearts compared to control animals after TAC. Conclusion Our data demonstrate the crucial role of myeloid cell-specific ErbB3 signaling in the cardiac accumulation of myeloid cells, which contributes to the activation of cardiac endothelial cells and fibroblasts and development of an early adaptive response to cardiac pressure overload in male mice.

Sticholysins (Sts) I and II (StI and StII) are pore-forming proteins (PFPs), purified from the Caribbean Sea anemone Stichodactyla helianthus. StII encapsulated into liposomes induces a robust antigen-specific cytotoxic CD8+ T lymphocytes (CTL) response and in its free form the maturation of bone marrow-derived dendritic cells (BM-DCs). It is probable that the latter is partially supporting in part the immunomodulatory effect on the CTL response induced by StII-containing liposomes. In the present work, we demonstrate that the StII's ability of inducing maturation of BM-DCs is also shared by StI, an isoform of StII. Using heat-denatured Sts we observed a significant reduction in the up-regulation of maturation markers indicating that both PFP's ability to promote maturation of BM-DCs is dependent on their conformational characteristics. StII-mediated DC maturation was abrogated in BM-DCs from toll-like receptor (TLR) 4 and myeloid differentiation primary response gene 88 (MyD88)-knockout mice but not in cells from TLR2-knockout mice. Furthermore, the antigen-specific CTL response induced by StII-containing liposomes was reduced in TLR4-knockout mice. These results indicate that StII, and probably by extension StI, has the ability to induce maturation of DCs through a TLR4/MyD88-dependent pathway, and that this activation contributes to the CTL response generated by StII-containing liposomes.

IL-33 is an IL-1 family cytokine that signals through its cognate receptor, ST2, to regulate inflammation. Whether IL-33 serves a pathogenic or protective role during inflammatory bowel disease is controversial. Herein, two different strains of cell-specific conditionally deficient mice were used to compare the role of myeloid- versus intestinal epithelial cell–derived IL-33 during dextran sodium sulfate–induced colitis. Data show that loss of CD11c-restricted IL-33 exacerbated tissue pathology, coinciding with increased tissue Il6 levels and loss of intestinal forkhead box p3(+) regulatory T cells. Surprisingly, the lack of intestinal epithelial cell–derived IL-33 had no impact on disease severity or tissue recovery. Thus, we show that myeloid-derived IL-33 functionally restrains colitic disease, whereas intestinal epithelial cell–derived IL-33 is dispensable.

Background & Aims Rev-erbα represents a powerful transcriptional repressor involved in immunity. However, the regulation, function, and clinical relevance of Rev-erbα in Helicobacter pylori infection are presently unknown. Methods Rev-erbα was examined in gastric samples from H pylori-infected patients and mice. Gastric epithelial cells (GECs) were isolated and infected with H pylori for Rev-erbα regulation assays. Gastric tissues from Rev-erbα–/– and wild-type (littermate control) mice or these mice adoptively transferred with CD4+ T cells from IFN-γ–/– and wild-type mice, bone marrow chimera mice and mice with in vivo pharmacological activation or inhibition of Rev-erbα were examined for bacteria colonization. GECs, CD45+CD11c–Ly6G–CD11b+CD68– myeloid cells and CD4+ T cells were isolated, stimulated and/or cultured for Rev-erbα function assays. Results Rev-erbα was increased in gastric mucosa of H pylori-infected patients and mice. H pylori induced GECs to express Rev-erbα via the phosphorylated cagA that activated ERK signaling pathway to mediate NF-κB directly binding to Rev-erbα promoter, which resulted in increased bacteria colonization within gastric mucosa. Mechanistically, Rev-erbα in GECs not only directly suppressed Reg3b and β-defensin-1 expression, which resulted in impaired bactericidal effects against H pylori of these antibacterial proteins in vitro and in vivo; but also directly inhibited chemokine CCL21 expression, which led to decreased gastric influx of CD45+CD11c–Ly6G–CD11b+CD68– myeloid cells by CCL21-CCR7-dependent migration and, as a direct consequence, reduced bacterial clearing capacity of H pylori-specific Th1 cell response. Conclusions Overall, this study identifies a model involving Rev-erbα, which collectively ensures gastric bacterial persistence by suppressing host gene expression required for local innate and adaptive defense against H pylori., Graphical abstract

The rapidly evolving area of immunometabolism has shed new light on the fundamental properties of products and intermediates of cellular metabolism (metabolites), highlighting their key signaling roles in cell-to-cell communication. Recent evidence identifies the succinate-succinate receptor 1 (SUCNR1) axis as an essential regulator of tissue homeostasis. Succinate signaling via SUCNR1 guides divergent responses in immune cells, which are tissue and context dependent. Herein, we explore the main cellular pathways regulated by the succinate-SUCNR1 axis and focus on the biology of SUCNR1 and its roles influencing the function of myeloid cells. Hence, we identify new therapeutic targets and putative therapeutic approaches aimed at resolving detrimental myeloid cell responses in tissues, including those occurring in the persistently inflamed central nervous system (CNS).

The type II interferon (IFNγ) promotes resistance to intracellular pathogens. Most immune and somatic cells also express the IFNγ receptor (IFNGR) and respond to IFNγ. While myeloid cell have been implicated as important targets of IFNγ, it remains unknown if IFNγ signaling to myeloid cell types suffices for resistance to infection. Here, we addressed this question by generating mice in which IFNGR1 is selectively expressed by myeloid cells. These “MSGR1” (myeloid selective IFNGR1) mice express an epitope-tagged Ifngr1 transgene (fGR1) from the myeloid-specific c-fms promoter in a background lacking endogenous Ifngr1. IFNGR staining was selectively observed on myeloid cells in the MSGR1 mice and correlated with responsiveness of these cells to IFNγ. During systemic infection by the bacterium Listeria monocytogenes, activation marker staining was comparable on monocytes from MSGR1 and control B6 mice. Bacterial burdens and survival were also equivalent in MSGR1 and wildtype B6 animals at a timepoint when B6.Ifngr1−/− mice began to succumb. These data confirm that activation of inflammatory monocytes and neutrophils is a key mechanism by which IFNγ promotes innate anti-bacterial immunity and suggest that IFNγ targeting of myeloid cells is largely sufficient to mediate protection against systemic L. monocytogenes.

The CNS accommodates a diverse myeloid immune cell compartment that maintains CNS homeostasis in the steady state while contributing to tissue injury during infectious, autoimmune, and neurodegenerative disease conditions. Autophagy and autophagy proteins play fundamental roles in myeloid cell-related immune functions. Many of these processes do not necessarily involve the canonical formation of a double-membrane structure known as the 'autophagosome' and reflect noncanonical functions of the autophagy machinery. Here, we illustrate recent insights, concepts, and outstanding questions regarding how autophagy pathways in myeloid cells contribute to brain health and disease.

Alopecia areata (AA), which is defined as an autoimmune hair loss disease, has a serious impact on the quality of life for patients with AA worldwide. In this study, to our knowledge, a previously unreported method of AA induction in C3H mice has been established and validated. Using this method, we showed that dermal injection of 1-3 million of a mixture of skin cells freshly isolated from AA-affected skin induces AA in more than 80% of healthy mice. Contrary to the previous protocol, the induction of AA by this approach does not need any surgical AA skin grafting, cell manipulation, or high number of activated T cells. We also showed that dermal injection of adherent myeloid cells (mainly CD11b+) in healthy mice is as potent as a mixture of none adherent CD3+ T cells and CD19+ B cells in the induction of AA. Interestingly, most of the mice (7 out of 8) that received non-adherent cells developed AA universalis, whereas most of the mice (5 out of 7) that received adherent cells developed patchy AA. Finally, we found a high number of stage-specific embryonic antigen-expressing cells whose expression in monocytes in an inflammatory disease causes the release of inflammatory cytokines, TNF-α and IL-1β, from these cells in AA-affected skin.

The interaction between myeloid cells and the extracellular matrix is important for tissue homeostasis and pathophysiology. In this issue of Immunity, Keerthivasan et al. reveal crosstalk dependent on the collagen receptor LAIR1 that regulates the dynamics of monocytes and macrophages during steady-state and cancer.

Tumor cells undergo rapid aerobic glycolysis to fuel growth and proliferation. A recent finding in Nature reveals that tumor-infiltrating myeloid cells demonstrate greater capacity for glucose uptake than tumor cells and consume significant amounts within the tumor milieu. Unexpectedly, tumor cells account for the highest glutamine utilization in the tumor microenvironment.

Interferon regulatory factors (IRFs) are a family of central transcriptional regulators that produce type I interferon and regulate innate and adaptive immune responses. Interferon regulatory factor 8 (IRF8) exists mainly in hematopoietic cells and is essential for the development of several myeloid lineages, including monocytes/macrophages and dendritic cells. In recent years, an increasing number of studies have focused on the roles of IRF8 in the differentiation of myeloid pedigree and MDSC aggregation in diseases such as tumors. In this review, we provide a comprehensive overview of the roles of IRF8 in the regulation of myeloid cell development, with particular reference to multiple disease conditions. Clarifying the various functions of IRF8 may suggest targets for therapeutic interventions.

Inflammation is a hallmark of cancer and supports tumor growth, proliferation, and metastasis, but also inhibits T cell immunosurveillance and the efficacy of immunotherapy. The biology of cancer inflammation is defined by a cycle of distinct immunological steps that begins during disease conception with the release of inflammatory soluble factors. These factors communicate with host organs to trigger bone marrow mobilization of myeloid cells, trafficking of myeloid cells to the tumor, and differentiation of myeloid cells within the tumor bed. Tumor-infiltrating myeloid cells then orchestrate an immunosuppressive microenvironment and assist in sustaining a vicious cycle of inflammation that co-evolves with tumor cells. This Cancer-Inflammation Cycle acts as a rheostat or “inflammostat” that impinges upon T cell immunosurveillance and prevents the development of productive anti-tumor immunity. Here, we define the major nodes of the Cancer-Inflammation Cycle and describe their impact on T cell immunosurveillance in cancer. Additionally, we discuss emerging pre-clinical and clinical data suggesting that intervening upon the Cancer-Inflammation Cycle will be a necessary step for broadening the potential of immunotherapy in cancer.

Tumor-stromal interaction is implicated in tumor progression. Although CCR1 expression in myeloid cells could be associated with pro-tumor activity, it remains elusive whether disruption of CCR1-mediated myeloid cell accumulation can suppress tumor progression. Here, we investigated the role of CCR1 depletion in myeloid cells in two syngeneic colorectal cancer mouse models: MC38, a transplanted tumor model and CMT93, a liver metastasis model. Both cells induced tumor accumulation of CCR1+ myeloid cells that express MMP2, MMP9, iNOS, and VEGF. Lack of the Ccr1 gene in host mice dramatically reduced MC38 tumor growth as well as CMT93 liver metastasis. To delineate the contribution of CCR1+ myeloid cells, we performed bone marrow (BM) transfer experiments in which sub-lethally irradiated wild-type mice were reconstituted with BM from either wild-type or Ccr1-/- mice. Mice reconstituted with Ccr1-/- BM exhibited marked suppression of MC38 tumor growth and CMT93 liver metastasis, compared with control mice. Consistent with these results, administration of a neutralizing anti-CCR1 monoclonal antibody, KM5908, significantly suppressed MC38 tumor growth and CMT93 liver metastases. Our findings highlight the importance of the application of CCR1 blockade as a therapeutic strategy.

Hypoxia, metabolic activity, cell death and immune responses influence the adenosine concentrations in the extracellular space. Cellular responses to hypoxia and inflammation in myeloid cells promote activation of adenosine sensing circuit, which involves increased expression of ectoenzymes that converts phospho-nucleotides such as ATP to adenosine and increased expression of G protein-coupled adenosine receptors. Adenosine sensing circuitry also involves feedforward signaling, which leads to increased expression of hypoxia-inducible factor 1-alpha (HIF1 and feedback signaling, which leads to the suppression of inflammatory transcription factor, the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) activation. In this review we will discuss how different subsets of myeloid cells sense adenosine accumulation and how adenosine sensing by myeloid cells influence progression of different immune-related conditions including cancer.

Summary Age-related clonal hematopoiesis is a major risk factor for myeloid malignancy and myeloid skewing is a hallmark of aging. However, while it is known that non-cell-autonomous components of the microenvironment can also influence this risk, there have been few studies of how the spatial architecture of human bone marrow (BM) changes with aging. Here, we show that BM adiposity increases with age, which correlates with increased density of maturing myeloid cells and CD34+ hematopoietic stem/progenitor cells (HSPCs) and an increased proportion of HSPCs adjacent to adipocytes. However, NGFR+ bone marrow stromal cell (NGFR+ BMSC) density and distance to HSPCs and vessels remained stable. Interestingly, we found that, upon aging, maturing myeloid cell density increases in hematopoietic areas surrounding adipocytes. We propose that increased adjacency to adipocytes in the BM microenvironment may influence myeloid skewing of aging HSPCs, contributing to age-related risk of myeloid malignancies., Highlights • Aging increases adipose, myeloid, and CD34+ HSPC density in the human bone marrow • Human CD34+ HSPC niche is reticular, perivascular, and periadipocytic in aging • Aging increases maturing myeloid cell density surrounding adipocytes, In this article, Dick, Flores-Figueroa, and colleagues show that aging alters the spatial organization between CD34+ hematopoietic stem/progenitor cells and adipocytes within human bone marrow. An increased mature myeloid output correlates with these findings, raising the idea that these age-related changes may influence myeloid skewing and the accompanying risk of myeloid malignancy.

Summary The DNA methylation regulators DNMT3A and TET2 are recurrently mutated in hematological disorders. Despite possessing antagonistic biochemical activities, loss-of-function murine models show overlapping phenotypes in terms of increased hematopoietic stem cell (HSC) fitness. Here, we directly compared the effects of these mutations on hematopoietic progenitor function and disease initiation. In contrast to Dnmt3a-null HSCs, which possess limitless self-renewal in vivo, Tet2-null HSCs unexpectedly exhaust at the same rate as control HSCs in serial transplantation assays despite an initial increase in self-renewal. Moreover, loss of Tet2 more acutely sensitizes hematopoietic cells to the addition of a common co-operating mutation (Flt3ITD) than loss of Dnmt3a, which is associated with a more rapid expansion of committed progenitor cells. The effect of Tet2 mutation manifests more profound myeloid lineage skewing in committed hematopoietic progenitor cells rather than long-term HSCs. Molecular characterization revealed divergent transcriptomes and chromatin accessibility underlying these functional differences., Highlights • Tet2-null HSCs exhaust at the same rate as wild-type HSCs in serial transplantation • Loss of Tet2 sensitizes cells to Flt3ITD mutation more dramatically than Dnmt3a • Loss of Dnmt3a permits epigenetic plasticity between hematopoietic progenitors • Tet2 deficiency manifests profound myeloid lineage skewing in progenitor cells, Challen and colleagues show that Dnmt3a and Tet2 loss-of-function mutations manifest distinct molecular and functional consequences in different hematopoietic stem and progenitor cell compartments. Despite producing superficially similar phenotypes in terms of stem cell function and disease initiation, we show here divergent influences on progenitor cell lineage skewing, stem cell self-renewal, and predisposition to malignant transformation.

Mononuclear phagocytes are a heterogeneous population of leukocytes essential for immune homeostasis that develop tissue-specific functions due to unique transcriptional programs driven by local microenvironmental cues. Single cell RNA sequencing (scRNA-seq) of colonic myeloid cells from specific pathogen free (SPF) and germ-free (GF) C57BL/6 mice revealed extensive heterogeneity of both colon macrophages (MPs) and dendritic cells (DCs). Modeling of developmental pathways combined with inference of gene regulatory networks indicate two major trajectories from common CCR2+ precursors resulting in colon MP populations with unique transcription factors and downstream target genes. Compared to SPF mice, GF mice had decreased numbers of total colon MPs, as well as selective proportional decreases of two major CD11c+CD206intCD121b+ and CD11c−CD206hiCD121b− colon MP populations, whereas DC numbers and proportions were not different. Importantly, these two major colon MP populations were clearly distinct from other colon MP populations regarding their gene expression profile, localization within the lamina propria (LP) and ability to phagocytose macromolecules from the blood. These data uncover the diversity of intestinal myeloid cell populations at the molecular level and highlight the importance of microbiota on the unique developmental as well as anatomical and functional fates of colon MPs.

The adaptive immune system is essential for host defense against pathogenic challenges, and a major constituent is the CD8(+) cytotoxic T cell. Ordinarily, CD8(+) T cells are endowed with a unique ability to specifically recognize and destroy their targets. However, in cases where disease emerges, especially in cancer, the efficacy of the CD8(+) T cell response is frequently counterbalanced in a ‘tug-of-war’ by networks of tumor-driven mechanisms of immune suppression. As a result, antitumor CD8(+) T cell activity is hampered, which contributes to clinical manifestations of disease. It is now well-recognized that prominent elements of that network include myeloid-derived suppressor cells (MDSC) and macrophages which assume tumor-supportive phenotypes. Both myeloid populations are thought to arise as consequences of chronic inflammatory cues produced during the neoplastic process. Numerous preclinical studies have now shown that inhibiting the production, trafficking and/or function of these immune suppressive myeloid populations restore antitumor CD8(+) T cell responses during both immune surveillance or in response to immune-targeted interventions. Correlative studies in cancer patients support these preclinical findings and, thus, have laid the foundation for ongoing clinical trials in patients receiving novel agents that target such myeloid elements alone or in combination with immunotherapy to potentially improve cancer patient outcomes. Accordingly, this review focuses on how and why it is important to study the myeloid-T cell interplay as an innovative strategy to boost or reinvigorate the CD8(+) T cell response as a critical weapon in the battle against malignancy.

Granulocytic sarcomas are solid, extramedullary-located neoplasms composed of immature myeloid cells, associated with myeloproliferative syndromes. Central nervous system involvement is very rare and may develop either after complete remission, coexist with or precede the systemic disease, being the last one that guides the radiological diagnosis and marks the prognosis. In this work, we report 2 pathologically-verified cases of intracranial granulocytic sarcoma treated by surgical means. Their clinical, diagnostic, therapeutic and prognostic features are discussed in the light of the most relevant scientific literature published to date.

Background The heterogeneous functions of dermal myeloid cells in antigen presentation, and scavenging pathogens and cell debris places them centrally in cutaneous inflammation. Single cell transcriptomics can provide new understanding of the heterogeneity and function of yet incompletely understood human dermal myeloid cell subsets. Objective Investigate the transcriptome landscape of myeloid cells in healthy human skin. Methods Single cell RNA-sequencing was performed on skin biopsies from ten healthy donors and analyzed to identify myeloid cell populations. Results One LIN− HLA-DR+ cluster with expression of myeloid-specific genes was identified as a cluster of myeloid cells. Upon reanalysis of this cluster, we identified three macrophage subsets, marked by high expression of CCR1, MARCO or TREM2; and six dendritic cell subsets, marked by high expression of CLEC9A, CXorf21, MCOLN2, LAMP3, KIAA0101 and Langerin, representing respectively cDC1, two subsets of cDC2, a novel DC type, a cluster of proliferating DC, and a Langerhans cell subset. GO term analysis indicated specialized functions for the discrete rare populations of myeloid cells: TREM2 Mφ in lipid metabolism and LAMP3 DC as a mature cDC. Proliferating DCs appeared to represent cDC2 progenitors. Conclusion The transcriptional landscape of myeloid cell populations in human skin indicates several, novel populations with specialized functions, as well as a rare proliferating DC population that likely accounts for local regeneration or expansion of dermal DCs. We provide robust gene expression markers for each of these populations that should permit better understandings of their roles in various homeostatic and pathologic immune processes in the skin.

Polycomb-group proteins are critical regulators of stem cells. We previously demonstrated that Bmi1, a component of polycomb repressive complex 1, defines the regenerative capacity of hematopoietic stem cells (HSCs). Here, we attempted to ameliorate the age-related decline in HSC function by modulating Bmi1 expression. The forced expression of Bmi1 did not attenuate myeloid-biased differentiation of aged HSCs. However, single cell transplantation assays revealed that the sustained expression of Bmi1 augmented the multi-lineage repopulating capacity of aged HSCs. Chromatin immunoprecipitation-sequencing of Bmi1 combined with an RNA sequence analysis showed that the majority of Bmi1 direct target genes are developmental regulator genes marked with a bivalent histone domain. The sustained expression of Bmi1 strictly maintained the transcriptional repression of their target genes and enforced expression of HSC signature genes in aged HSCs. Therefore, the manipulation of Bmi1 expression is a potential approach against impairments in HSC function with aging.

The diagnosis of sepsis, and especially its differentiation from sterile inflammation, may be challenging. The triggering receptor expressed on myeloid cells-1 is an amplifier of the innate immune response. Its soluble form is detectable in various biological fluids and can be used as a surrogate marker of triggering receptor expressed on myeloid cells-1 activation. In this article, we review the abundant literature evaluating the usefulness of soluble triggering receptor expressed on myeloid cells-1 for the diagnosis and the prognosis evaluation of sepsis or localized infections.

Angiotensin-converting enzyme (ACE) affects blood pressure. In addition, ACE overexpression in myeloid cells increases their immune function. Using MS and chemical analysis, we identified marked changes of intermediate metabolites in ACE-overexpressing macrophages and neutrophils, with increased cellular ATP (1.7–3.0-fold) and Krebs cycle intermediates, including citrate, isocitrate, succinate, and malate (1.4–3.9-fold). Increased ATP is due to ACE C-domain catalytic activity; it is reversed by an ACE inhibitor but not by an angiotensin II AT1 receptor antagonist. In contrast, macrophages from ACE knockout (null) mice averaged only 28% of the ATP levels found in WT mice. ACE overexpression does not change cell or mitochondrial size or number. However, expression levels of the electron transport chain proteins NDUFB8 (complex I), ATP5A, and ATP5β (complex V) are significantly increased in macrophages and neutrophils, and COX1 and COX2 (complex IV) are increased in macrophages overexpressing ACE. Macrophages overexpressing ACE have increased mitochondrial membrane potential (24% higher), ATP production rates (29% higher), and maximal respiratory rates (37% higher) compared with WT cells. Increased cellular ATP underpins increased myeloid cell superoxide production and phagocytosis associated with increased ACE expression. Myeloid cells overexpressing ACE indicate the existence of a novel pathway in which myeloid cell function can be enhanced, with a key feature being increased cellular ATP.

International audience; Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature hematopoietic precursors known to suppress immune responses. Interaction of SIRP alpha (SIRPα), expressed by myeloid cells, with the ubiquitous receptor CD47 is an important immune checkpoint of the innate response regulating macrophages and dendritic cells functions. We previously described that MDSC expressing SIRPα accumulated after transplantation and maintained kidney allograft tolerance. However, the role of the SIRPα/CD47 axis on MDSC function remained unknown. Here, we found that blocking SIRPα or CD47 with monoclonal antibodies (mAbs) induced differentiation of MDSC into myeloid cells overexpressing MHC class II, CD86 costimulatory molecule and increased secretion of macrophage-recruiting chemokines (eg, MCP-1). Using a model of long-term kidney allograft tolerance sustained by MDSC, we observed that administration of blocking anti-SIRPα or CD47 mAbs induced graft dysfunction and rejection. Loss of tolerance came along with significant decrease of MDSC and increase in MCP-1 concentration in the periphery. Graft histological and transcriptomic analyses revealed an inflammatory (M1) macrophagic signature at rejection associated with overexpression of MCP-1 mRNA and protein in the graft. These findings indicate that the SIRPα-CD47 axis regulates the immature phenotype and chemokine secretion of MDSC and contributes to the induction and the active maintenance of peripheral acquired immune tolerance.

Despite the advances in immunotherapy for cancer treatment, patients still obtain limited benefits, mostly owing to unrestrained tumour self-expansion and immune evasion that exploits immunoregulatory mechanisms. Traditionally, myeloid cells have a dominantly immunosuppressive role. However, the complicated populations of the myeloid cells and their multilateral interactions with tumour/stromal/lymphoid cells and physical abnormalities in the tumour microenvironment (TME) determine their heterogeneous functions in tumour development and immune response. Tumour-associated myeloid cells (TAMCs) include monocytes, tumour-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), and granulocytes. Single-cell profiling revealed heterogeneous TAMCs composition, sub-types, and transcriptomic signatures across 15 human cancer types. We systematically reviewed the biophysical heterogeneity of TAMC composition and pro/anti-tumoral and immuno-suppressive/stimulating properties of myeloid-derived microenvironments. We also summarised comprehensive clinical strategies to overcome resistance to immunotherapy from three dimensions: targeting TAMCs, reversing physical abnormalities, utilising nanomedicines, and finally, put forward futuristic perspectives for scientific and clinical research.