Regulation of myeloid-cell activation

Greene, Joseph T.; Brian, Ben F; Senevirathne, S Erandika; Freedman, Tanya S.

doi:10.1016/j.coi.2021.09.004

Cited by 12 publications

(7 citation statements)

References 76 publications

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“…Meanwhile, our analysis in tumors with positive correlation between SPP1 and immune infiltration found that most of the SPP1 expression was present with macrophages or monocytes, so in our subsequent analyses, we roughly considered that SPP1 expression in tumors was mainly contributed by macrophages. Macrophages promote immune cell infiltration and release inflammatory cytokines but abnormal production or reactive deleterious activation of macrophages to pro-inflammatory or anti-inflammatory stimuli disrupts tissue homeostasis and promotes disease [ 47 ]. Therefore, high expression of SPP1 in macrophages may induce immune responses in tumors and thus affect prognosis.…”

Section: Discussionmentioning

confidence: 99%

Tumor-associated macrophage subtypes on cancer immunity along with prognostic analysis and SPP1-mediated interactions between tumor cells and macrophages

Xu,

Chen,

Liu

et al. 2024

PLoS Genet

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Tumor-associated macrophages (TAM) subtypes have been shown to impact cancer prognosis and resistance to immunotherapy. However, there is still a lack of systematic investigation into their molecular characteristics and clinical relevance in different cancer types. Single-cell RNA sequencing data from three different tumor types were used to cluster and type macrophages. Functional analysis and communication of TAM subpopulations were performed by Gene Ontology-Biological Process and CellChat respectively. Differential expression of characteristic genes in subpopulations was calculated using zscore as well as edgeR and Wilcoxon rank sum tests, and subsequently gene enrichment analysis of characteristic genes and anti-PD-1 resistance was performed by the REACTOME database. We revealed the heterogeneity of TAM, and identified eleven subtypes and their impact on prognosis. These subtypes expressed different molecular functions respectively, such as being involved in T cell activation, apoptosis and differentiation, or regulating viral bioprocesses or responses to viruses. The SPP1 pathway was identified as a critical mediator of communication between TAM subpopulations, as well as between TAM and epithelial cells. Macrophages with high expression of SPP1 resulted in poorer survival. By in vitro study, we showed SPP1 mediated the interactions between TAM clusters and between TAM and tumor cells. SPP1 promoted the tumor-promoting ability of TAM, and increased PDL1 expression and stemness of tumor cells. Inhibition of SPP1 attenuated N-cadherin and β-catenin expression and the activation of AKT and STAT3 pathway in tumor cells. Additionally, we found that several subpopulations could decrease the sensitivity of anti-PD-1 therapy in melanoma. SPP1 signal was a critical pathway of communication between macrophage subtypes. Some specific macrophage subtypes were associated with immunotherapy resistance and prognosis in some cancer types.

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Section: Discussionmentioning

confidence: 99%

Tumor-associated macrophage subtypes on cancer immunity along with prognostic analysis and SPP1-mediated interactions between tumor cells and macrophages

Xu,

Chen,

Liu

et al. 2024

PLoS Genet

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“…For example, the activation of mammalian target of rapamycin complex 1 (mTORC1) on myeloid cells promotes anabolic metabolism and shift from glycolysis towards lactic fermentation as a faster energetic source to induce and sustain the functional adaptations required under a pro-inflammatory scenario ( 6 ). Under certain pathological conditions, the chronic or uncontrolled activation of myeloid cells significantly contributes to perpetuate inflammation and tissue damage, which leads to the main clinical manifestations associated to such diseases ( 2 , 7 ). Although current immunosuppressive therapies represent the mainstay of treatment for many inflammatory conditions, their clinical efficacy is still limited for many patients and their overuse is associated with significant adverse effects ( 8 ).…”

Section: Introductionmentioning

confidence: 99%

Cannabinoid WIN55,212-2 reprograms monocytes and macrophages to inhibit LPS-induced inflammation

et al. 2023

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IntroductionChronic or uncontrolled activation of myeloid cells including monocytes, macrophages and dendritic cells (DCs) is a hallmark of immune-mediated inflammatory disorders. There is an urgent need for the development of novel drugs with the capacity to impair innate immune cell overactivation under inflammatory conditions. Compelling evidence pointed out cannabinoids as potential therapeutic tools with anti-inflammatory and immunomodulatory capacity. WIN55,212-2, a non-selective synthetic cannabinoid agonist, displays protective effects in several inflammatory conditions by mechanisms partially depending on the generation of tolerogenic DCs able to induce functional regulatory T cells (Tregs). However, its immunomodulatory capacity on other myeloid cells such as monocytes and macrophages remains incompletely understood.MethodsHuman monocyte-derived DCs (hmoDCs) were differentiated in the absence (conventional hmoDCs) or presence of WIN55,212-2 (WIN-hmoDCs). Cells were stimulated with LPS, cocultured with naive T lymphocytes and their cytokine production and ability to induce T cell responses were analysed by ELISA or flow cytometry. To evaluate the effect of WIN55,212-2 in macrophage polarization, human and murine macrophages were activated with LPS or LPS/IFNγ, in the presence or absence of the cannabinoid. Cytokine, costimulatory molecules and inflammasome markers were assayed. Metabolic and chromatin immunoprecipitation assays were also performed. Finally, the protective capacity of WIN55,212-2 was studied in vivo in BALB/c mice after intraperitoneal injection with LPS.ResultsWe show for the first time that the differentiation of hmoDCs in the presence of WIN55,212-2 generates tolerogenic WIN-hmoDCs that are less responsive to LPS stimulation and able to prime Tregs. WIN55,212-2 also impairs the pro-inflammatory polarization of human macrophages by inhibiting cytokine production, inflammasome activation and rescuing macrophages from pyroptotic cell death. Mechanistically, WIN55,212-2 induced a metabolic and epigenetic shift in macrophages by decreasing LPS-induced mTORC1 signaling, commitment to glycolysis and active histone marks in pro-inflammatory cytokine promoters. We confirmed these data in ex vivo LPS-stimulated peritoneal macrophages (PMΦs), which were also supported by the in vivo anti-inflammatory capacity of WIN55,212-2 in a LPS-induced sepsis mouse model.ConclusionOverall, we shed light into the molecular mechanisms by which cannabinoids exert anti-inflammatory properties in myeloid cells, which might well contribute to the future rational design of novel therapeutic strategies for inflammatory disorders.

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“…MDCs are a highly diverse and plastic population that can exhibit many cell states and thus perform a broad array of functions in the niche in which they are found (7) . In terms of ontogeny, the majority of these cells are derived from bone marrow progenitor cells and recruited into the TME.…”

Section: Introductionmentioning

confidence: 99%

Identification of novel myeloid-derived cell states with implication in cancer outcome

Maklouf

Guimarães

Teixeira

et al. 2023

Preprint

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Immunotherapies provide long-lasting responses across a wide range of cancers; however, only a fraction of patients responds to them. Multiple reasons contribute to the failure, including the existence of myeloid-derived cells (MDCs) within tumors. Due to their high plasticity, these cells display numerous cell states and, as a result, distinct pro-tumorigenic behaviors, making them interesting targets. However, the creation of cutting-edge anticancer therapies is hampered by the lack of MDC-specific markers. To fully define the MDC landscape in solid tumors, we combined single-cell RNA-Seq from 13 public datasets, including samples from seven different cancers and normal samples, yielding the largest collection of MDC subpopulations within the tumor microenvironment. We identified five major lineages subdivided into one mast cell cluster, three neutrophils, eight dendritic cells, six monocytes, and eleven macrophage states. Transcriptional profiles coupled with deconvolution estimates of cell populations in large cohorts revealed five MDC subpopulations as independent prognostic markers in different cancer types, including resident tissue interstitial macrophages and FCGR3A+ monocytes associated with an unfavorable clinical outcome in ovarian and breast cancer patients, respectively. Our work reveals that TREM2+ macrophages can be distinguished in different populations and associated with distinct prognoses. By analyzing a Brazilian cohort of ovarian cancer, we found that TREM2+ macrophages are associated with a better prognosis, indicating that their role might be dependent on the tumor niche and co-expression of immunosuppressive markers. Collectively, this atlas reveals in high-resolution the heterogeneous MDC identity as well as new avenues for understanding and manipulating their fate in cancer.

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Regulation of myeloid-cell activation

Cited by 12 publications

References 76 publications

Tumor-associated macrophage subtypes on cancer immunity along with prognostic analysis and SPP1-mediated interactions between tumor cells and macrophages

Tumor-associated macrophage subtypes on cancer immunity along with prognostic analysis and SPP1-mediated interactions between tumor cells and macrophages

Cannabinoid WIN55,212-2 reprograms monocytes and macrophages to inhibit LPS-induced inflammation

Identification of novel myeloid-derived cell states with implication in cancer outcome

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