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Monocyte chemoattractant proteins (MCPs) are involved in monocyte trafficking during severe inflammation by modulating the chemokine-glycosaminoglycan-receptor signaling axis. MCPs comprise a family of four chemokines (CCL2, CCL7, CCL8, and CCL13/12) that exhibit differential expression patterns in mammals, functional diversity, and receptor/glycosaminoglycan (GAG) binding promiscuity. In this context, the evolution-structure–function paradigm of MCP chemokines in mammals was established by assessing phylogeny, functional divergence, selection pressure, and coevolution in correlation with structural and surface characteristics. Comprehensive analyses were performed using an array of evolutionary and structural bioinformatic methods including molecular dynamics simulations. Our findings demonstrate that substitutions in receptor/GAG-interacting residues mediate episodic diversification and functional diversity in MCP chemokines. Additionally, a balanced interplay of selection pressures has driven the functional changes observed among MCP paralogs, with positive selection at various receptor/GAG-binding sites contributing to their promiscuous receptor/GAG interactions. Meanwhile, processes like purifying selection and coevolution maintain the classical chemokine structure and preserve the ancestral functions of MCP chemokines. Overall, this study suggests that selection pressure on sites within the N-terminal region [N-loop and 3 10 -helix] and 40S loop of MCP chemokines alters surface properties to fine-tune the molecular interactions and functional characteristics without altering the overall chemokine structure. Graphical Abstract

Interleukin-1β (IL-1β) is abundant in the tumor microenvironment, where this cytokine can promote tumor growth, but also antitumor activities. We studied IL-1β during early tumor progression using a model of orthotopically introduced 4T1 breast cancer cells. Whereas there is tumor progression and spontaneous metastasis in wild-type (WT) mice, in IL-1β–deficient mice, tumors begin to grow but subsequently regress. This change is due to recruitment and differentiation of inflammatory monocytes in the tumor microenvironment. In WT mice, macrophages heavily infiltrate tumors, but in IL-1β–deficient mice, low levels of the chemokine CCL2 hamper recruitment of monocytes and, together with low levels of colony-stimulating factor-1 (CSF-1), inhibit their differentiation into macrophages. The low levels of macrophages in IL-1β–deficient mice result in a relatively high percentage of CD11b⁺ dendritic cells (DCs) in the tumors. In WT mice, IL-10 secretion from macrophages is dominant and induces immunosuppression and tumor progression; in contrast, in IL-1β–deficient mice, IL-12 secretion by CD11b⁺ DCs prevails and supports antitumor immunity. The antitumor immunity in IL-1β–deficient mice includes activated CD8⁺ lymphocytes expressing IFN-γ, TNF-α, and granzyme B; these cells infiltrate tumors and induce regression. WT mice with 4T1 tumors were treated with either anti–IL-1β or anti–PD-1 Abs, each of which resulted in partial growth inhibition. However, treating mice first with anti–IL-1β Abs followed by anti–PD-1 Abs completely abrogated tumor progression. These data define microenvironmental IL-1β as a master cytokine in tumor progression. In addition to reducing tumor progression, blocking IL-1β facilitates checkpoint inhibition.

In a nomenclature proposal published in 2010 monocytes were subdivided into classical and non-classical cells and in addition an intermediate monocyte subset was proposed. Over the last couple of years many studies have analyzed these intermediate cells, their characteristics have been described, and their expansion has been documented in many clinical settings. While these cells appear to be in transition from classical to non-classical monocytes and hence may not form a distinct cell population in a strict sense, their separate analysis and enumeration is warranted in health and disease.

Cellular immunotherapies represent a promising approach for the treatment of cancer. Engineered adoptive cell therapies redirect and augment a leukocyte’s inherent ability to mount an immune response by introducing novel anti-tumor capabilities and targeting moieties. A prominent example of this approach is the use of T cells engineered to express chimeric antigen receptors (CARs), which have demonstrated significant efficacy against some hematologic malignancies. Despite increasingly sophisticated strategies to harness immune cell function, efficacy against solid tumors has remained elusive for adoptive cell therapies. Amongst cell types used in immunotherapies, however, macrophages have recently emerged as prominent candidates for the treatment of solid tumors. In this review, we discuss the use of monocytes and macrophages as adoptive cell therapies. Macrophages are innate immune cells that are intrinsically equipped with broad therapeutic effector functions, including active trafficking to tumor sites, direct tumor phagocytosis, activation of the tumor microenvironment and professional antigen presentation. We focus on engineering strategies for manipulating macrophages, with a specific focus on CAR macrophages (CAR-M). We highlight CAR design for macrophages, the production of CAR-M for adoptive cell transfer, and clinical considerations for their use in treating solid malignancies. We then outline recent progress and results in applying CAR-M as immunotherapies. The recent development of engineered macrophage-based therapies holds promise as a key weapon in the immune cell therapy armamentarium.

Classical and non-classical monocytes, and the macrophages and monocyte-derived dendritic cells they produce, play key roles in host defense against pathogens, immune regulation, tissue repair and many other processes throughout the body. Recent studies have revealed previously unappreciated heterogeneity among monocytes that may explain this functional diversity, but our understanding of mechanisms controlling the functional programming of distinct monocyte subsets remains incomplete. Resolving monocyte heterogeneity and understanding how their functional identity is determined holds great promise for therapeutic immune modulation. In this review, we examine how monocyte origins and developmental influences shape the phenotypic and functional characteristics of monocyte subsets during homeostasis and in the context of infection, inflammation, and cancer. We consider how extrinsic signals and transcriptional regulators impact monocyte production and functional programming, as well as the influence of epigenetic and metabolic mechanisms. We also examine the evidence that functionally distinct monocyte subsets are produced via different developmental pathways during homeostasis and that inflammatory stimuli differentially target progenitors during an emergency response. We highlight the need for a more comprehensive understanding of the relationship between monocyte ontogeny and heterogeneity, including multiparametric single-cell profiling and functional analyses. Studies definingmechanismsofmonocytesubsetproductionandmaintenanceofunique monocyte identities have the potential to facilitate the design of therapeutic interventions to target specific monocyte subsets in a variety of disease contexts, including infectious and inflammatory diseases, cancer, and aging.

In contrast to the past reliance on morphology, the identification and enumeration of blood monocytes are nowadays done with monoclonal antibodies and flow cytometry and this allows for subdivision into classical, intermediate, and non-classical monocytes. Using specific cell surface markers, dendritic cells in blood can be segregated from these monocytes. While in the past, changes in monocyte numbers as determined in standard hematology counters have not had any relevant clinical impact, the subset analysis now has uncovered informative changes that may be used in management of disease.

In lung cancer, tumor‐associated macrophages (TAMs), especially M2‐like TAMs, represent the main tumor progression components in the tumor microenvironment (TME). Therefore, M2‐like TAMs may serve as a therapeutic target. The purpose of this study was to investigate the effect of M2‐like TAM depletion in the TME on tumor growth and chemotherapy response in lung cancer. The levels of secreted monocyte chemoattractant protein (MCP‐1) and prostaglandin E2 (PGE2) in the supernatants of lung cancer cell lines A549 and LLC were evaluated via ELISA. Cell migration assays were performed to assess the recruitment ability of macrophage cell lines THP‐1 and J774‐1 cells. Differentiation of macrophages was assessed via flow cytometry. Immunohistochemical staining was performed to visualize M2‐like TAMs in transplanted lung cancer in mouse. We used the COX‐2 inhibitor nimesulide to inhibit the secretion of MCP‐1 and PGE2, which promotes macrophage migration and M2‐like differentiation. Nimesulide treatment decreased the secretion of MCP‐1 and PGE2 from lung cancer cells. Nimesulide treatment suppressed the migration of macrophages by blocking MCP‐1. Lung cancer supernatant induced the differentiation of macrophages toward the M2‐like phenotype, and nimesulide treatment inhibited M2‐like differentiation by blocking MCP‐1 and PGE2. In the lung cancer mouse model, treatment with nimesulide depleted M2‐like TAMs in the TME and enhanced the tumor inhibitory effect of cisplatin. Our results indicated that blocking the secretion of MCP‐1 and PGE2 from tumor cells depleted M2‐like TAMs in the TME and the combination therapy with cisplatin considerably suppressed tumor growth in the LLC mouse model. Nimesulide blocked the secretion of MCP‐1 and PGE2 from tumor cells, resulting in the depletion of M2 tumor‐associated macrophages (TAMs) in the tumor microenvironment (TME). Combination therapy of nimesulide with cisplatin considerably suppressed tumor growth in the LLC mouse model.

Background Monocyte subsets differentially influence pathophysiology of heart failure and atrial fibrillation (AF) through inflammation, fibrosis, and angiogenesis. Spironolactone has antifibrotic properties. This study investigated the effect spironolactone on monocyte subsets and monocyte effects for peak oxygen consumption (peakVO2), diastolic function and brain natriuretic peptide (BNP) in the IMPRESS-AF randomised controlled trial population (2-year treatment with spironolactone 25 mg vs placebo). Methods CD14++CD16-CCR2+(Mon1), CD14++CD16+CCR2+(Mon2) and CD14+CD16++CCR2-(Mon3) monocyte subsets were analysed by flow cytometry and compared between spironolactone and placebo groups at 12 months and 24 months after randomisation. PeakVO2, diastolic function (echocardiographic E/'e) and BNP were measured at baseline and 24 months. Linear regression was used to assess the effects of monocytes on the outcomes (Python 3.10 modules). Results Monocyte data were available in 225 (90%) IMPRESS-AF patients (age 72[67-77], 78% male). At 12-month the spironolactone group had fewer Mon3 (50[36-74] vs 60[44-90] cells/microL, p =0.02), and lower CD14 expression on Mon1 (1.37[1.17-1.59] vs 1.48[1.24-1.70], p =0.04); no difference remained by 24 months ( p >0.05). A high 12-month Mon1 count independently predicted lower E/e’ at 24 months ( p =0.02). Conclusions Spironolactone temporarily reduced proinflammatory monocyte markers (Mon3 count and CD14 expression on Mon1). Mon1 may have a positive effect on diastolic dysfunction in AF.

Background Neuronal and glial cell interaction is essential for synaptic homeostasis and may be affected in Alzheimer’s disease (AD). We measured cerebrospinal fluid (CSF) neuronal and glia markers along the AD continuum, to reveal putative protective or harmful stage-dependent patterns of activation. Methods We included healthy controls ( n  = 36) and Aβ-positive (Aβ+) cases (as defined by pathological CSF amyloid beta 1-42 (Aβ42)) with either subjective cognitive decline (SCD, n  = 19), mild cognitive impairment (MCI, n  = 39), or AD dementia ( n  = 27). The following CSF markers were measured: a microglial activation marker—soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a marker of microglial inflammatory reaction—monocyte chemoattractant protein-1 (MCP-1), two astroglial activation markers—chitinase-3-like protein 1 (YKL-40) and clusterin, a neuron-microglia communication marker—fractalkine, and the CSF AD biomarkers (Aβ42, phosphorylated tau (P-tau), total tau (T-tau)). Using ANOVA with planned comparisons, or Kruskal-Wallis tests with Dunn’s pairwise comparisons, CSF levels were compared between clinical groups and between stages of biomarker severity using CSF biomarkers for classification based on amyloid pathology (A), tau pathology (T), and neurodegeneration (N) giving rise to the A/T/N score. Results Compared to healthy controls, sTREM2 was increased in SCD ( p  < .01), MCI ( p  < .05), and AD dementia cases ( p  < .001) and increased in AD dementia compared to MCI cases ( p  < .05). MCP-1 was increased in MCI ( p  < .05) and AD dementia compared to both healthy controls ( p  < .001) and SCD cases ( p  < .01). YKL-40 was increased in dementia compared to healthy controls ( p  < .01) and MCI ( p  < .05). All of the CSF activation markers were increased in subjects with pathological CSF T-tau (A+T−N+ and A+T+N+), compared to subjects without neurodegeneration (A−T−N− and A+T−N−). Discussion Microglial activation as indicated by increased sTREM2 is present already at the preclinical SCD stage; increased MCP-1 and astroglial activation markers (YKL-40 and clusterin) were noted only at the MCI and AD dementia stages, respectively, and in Aβ+ cases (A+) with pathological T-tau (N+). Possible different effects of early and later glial activation need to be explored.