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Cell Sep 2023Natural killer (NK) cells play indispensable roles in innate immune responses against tumor progression. To depict their phenotypic and functional diversities in the...
Natural killer (NK) cells play indispensable roles in innate immune responses against tumor progression. To depict their phenotypic and functional diversities in the tumor microenvironment, we perform integrative single-cell RNA sequencing analyses on NK cells from 716 patients with cancer, covering 24 cancer types. We observed heterogeneity in NK cell composition in a tumor-type-specific manner. Notably, we have identified a group of tumor-associated NK cells that are enriched in tumors, show impaired anti-tumor functions, and are associated with unfavorable prognosis and resistance to immunotherapy. Specific myeloid cell subpopulations, in particular LAMP3 dendritic cells, appear to mediate the regulation of NK cell anti-tumor immunity. Our study provides insights into NK-cell-based cancer immunity and highlights potential clinical utilities of NK cell subsets as therapeutic targets.
Topics: Humans; Immunity, Innate; Immunotherapy; Killer Cells, Natural; Myeloid Cells; Neoplasms; Tumor Microenvironment; Dendritic Cells; Single-Cell Gene Expression Analysis
PubMed: 37607536
DOI: 10.1016/j.cell.2023.07.034 -
Nature Apr 2024Ageing of the immune system is characterized by decreased lymphopoiesis and adaptive immunity, and increased inflammation and myeloid pathologies. Age-related changes in...
Ageing of the immune system is characterized by decreased lymphopoiesis and adaptive immunity, and increased inflammation and myeloid pathologies. Age-related changes in populations of self-renewing haematopoietic stem cells (HSCs) are thought to underlie these phenomena. During youth, HSCs with balanced output of lymphoid and myeloid cells (bal-HSCs) predominate over HSCs with myeloid-biased output (my-HSCs), thereby promoting the lymphopoiesis required for initiating adaptive immune responses, while limiting the production of myeloid cells, which can be pro-inflammatory. Ageing is associated with increased proportions of my-HSCs, resulting in decreased lymphopoiesis and increased myelopoiesis. Transfer of bal-HSCs results in abundant lymphoid and myeloid cells, a stable phenotype that is retained after secondary transfer; my-HSCs also retain their patterns of production after secondary transfer. The origin and potential interconversion of these two subsets is still unclear. If they are separate subsets postnatally, it might be possible to reverse the ageing phenotype by eliminating my-HSCs in aged mice. Here we demonstrate that antibody-mediated depletion of my-HSCs in aged mice restores characteristic features of a more youthful immune system, including increasing common lymphocyte progenitors, naive T cells and B cells, while decreasing age-related markers of immune decline. Depletion of my-HSCs in aged mice improves primary and secondary adaptive immune responses to viral infection. These findings may have relevance to the understanding and intervention of diseases exacerbated or caused by dominance of the haematopoietic system by my-HSCs.
Topics: Animals; Female; Male; Mice; Adaptive Immunity; Aging; B-Lymphocytes; Cell Lineage; Hematopoietic Stem Cells; Inflammation; Lymphocytes; Lymphopoiesis; Myeloid Cells; Myelopoiesis; Phenotype; Rejuvenation; T-Lymphocytes; Viruses
PubMed: 38538791
DOI: 10.1038/s41586-024-07238-x -
Nature Sep 2023The immune-suppressive tumour microenvironment represents a major obstacle to effective immunotherapy. Pathologically activated neutrophils, also known as...
The immune-suppressive tumour microenvironment represents a major obstacle to effective immunotherapy. Pathologically activated neutrophils, also known as polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), are a critical component of the tumour microenvironment and have crucial roles in tumour progression and therapy resistance. Identification of the key molecules on PMN-MDSCs is required to selectively target these cells for tumour treatment. Here, we performed an in vivo CRISPR-Cas9 screen in a tumour mouse model and identified CD300ld as a top candidate of tumour-favouring receptors. CD300ld is specifically expressed in normal neutrophils and is upregulated in PMN-MDSCs upon tumour-bearing. CD300ld knockout inhibits the development of multiple tumour types in a PMN-MDSC-dependent manner. CD300ld is required for the recruitment of PMN-MDSCs into tumours and their function to suppress T cell activation. CD300ld acts via the STAT3-S100A8/A9 axis, and knockout of Cd300ld reverses the tumour immune-suppressive microenvironment. CD300ld is upregulated in human cancers and shows an unfavourable correlation with patient survival. Blocking CD300ld activity inhibits tumour development and has synergistic effects with anti-PD1. Our study identifies CD300ld as a critical immune suppressor present on PMN-MDSCs, being required for tumour immune resistance and providing a potential target for cancer immunotherapy.
Topics: Animals; Humans; Mice; CRISPR-Cas Systems; Disease Progression; Gene Editing; Immunotherapy; Myeloid-Derived Suppressor Cells; Neoplasms; Neutrophils; Receptors, Immunologic; Survival Analysis; T-Lymphocytes; Tumor Microenvironment; Lymphocyte Activation
PubMed: 37674079
DOI: 10.1038/s41586-023-06511-9 -
Science (New York, N.Y.) Aug 2023The intestinal microbiota regulates mammalian lipid absorption, metabolism, and storage. We report that the microbiota reprograms intestinal lipid metabolism in mice by...
The intestinal microbiota regulates mammalian lipid absorption, metabolism, and storage. We report that the microbiota reprograms intestinal lipid metabolism in mice by repressing the expression of long noncoding RNA (lncRNA) (small nucleolar RNA host gene 9) in small intestinal epithelial cells. suppressed the activity of peroxisome proliferator-activated receptor γ (PPARγ)-a central regulator of lipid metabolism-by dissociating the PPARγ inhibitor sirtuin 1 from cell cycle and apoptosis protein 2 (CCAR2). Forced expression of in the intestinal epithelium of conventional mice impaired lipid absorption, reduced body fat, and protected against diet-induced obesity. The microbiota repressed expression through an immune relay encompassing myeloid cells and group 3 innate lymphoid cells. Our findings thus identify an unanticipated role for a lncRNA in microbial control of host metabolism.
Topics: Animals; Mice; Gastrointestinal Microbiome; Immunity, Innate; Lipid Metabolism; Lymphocytes; PPAR gamma; RNA, Long Noncoding; Sirtuin 1; Cell Cycle Proteins; Apoptosis Regulatory Proteins; Myeloid Cells; Intestines; Adipose Tissue; Humans
PubMed: 37616368
DOI: 10.1126/science.ade0522 -
Cancer Cell Jul 2023RNA N-methyladenosine (mA) modification is implicated in cancer progression. However, the impact of mA on the antitumor effects of radiotherapy and the related...
RNA N-methyladenosine (mA) modification is implicated in cancer progression. However, the impact of mA on the antitumor effects of radiotherapy and the related mechanisms are unknown. Here we show that ionizing radiation (IR) induces immunosuppressive myeloid-derived suppressor cell (MDSC) expansion and YTHDF2 expression in both murine models and humans. Following IR, loss of Ythdf2 in myeloid cells augments antitumor immunity and overcomes tumor radioresistance by altering MDSC differentiation and inhibiting MDSC infiltration and suppressive function. The remodeling of the landscape of MDSC populations by local IR is reversed by Ythdf2 deficiency. IR-induced YTHDF2 expression relies on NF-κB signaling; YTHDF2 in turn leads to NF-κB activation by directly binding and degrading transcripts encoding negative regulators of NF-κB signaling, resulting in an IR-YTHDF2-NF-κB circuit. Pharmacological inhibition of YTHDF2 overcomes MDSC-induced immunosuppression and improves combined IR and/or anti-PD-L1 treatment. Thus, YTHDF2 is a promising target to improve radiotherapy (RT) and RT/immunotherapy combinations.
Topics: Animals; Humans; Mice; Gene Expression Regulation; Myeloid Cells; Neoplasms; NF-kappa B; RNA-Binding Proteins; Signal Transduction
PubMed: 37236197
DOI: 10.1016/j.ccell.2023.04.019 -
Targeting MS4A4A on tumour-associated macrophages restores CD8+ T-cell-mediated antitumour immunity.Gut Nov 2023Checkpoint immunotherapy unleashes T-cell control of tumours but is suppressed by immunosuppressive myeloid cells. The transmembrane protein MS4A4A is selectively highly...
OBJECTIVE
Checkpoint immunotherapy unleashes T-cell control of tumours but is suppressed by immunosuppressive myeloid cells. The transmembrane protein MS4A4A is selectively highly expressed in tumour-associated macrophages (TAMs). Here, we aimed to reveal the role of MS4A4A TAMs in regulating the immune escape of tumour cells and to develop novel therapeutic strategies targeting TAMs to enhance the efficacy of immune checkpoint inhibitor (ICI) in colorectal cancer.
DESIGN
The inhibitory effect of MS4A4A blockade alone or combined with ICI treatment on tumour growth was assessed using murine subcutaneous tumour or orthotopic transplanted models. The effect of MS4A4A blockade on the tumour immune microenvironment was assessed by flow cytometry and mass cytometry. RNA sequencing and western blot analysis were used to further explore the molecular mechanism by which MS4A4A promoted macrophages M2 polarisation.
RESULTS
MS4A4A is selectively expressed by TAMs in different types of tumours, and was associated with adverse clinical outcome in patients with cancer. In vivo inhibition of MS4A4A and anti-MS4A4A monoclonal antibody treatment both curb tumour growth and improve the effect of ICI therapy. MS4A4A blockade treatment reshaped the tumour immune microenvironment, resulting in reducing the infiltration of M2-TAMs and exhausted T cells, and increasing the infiltration of effector CD8 T cells. Anti-MS4A4A plus anti-programmed cell death protein 1 (PD-1) therapy remained effective in large, treatment-resistant tumours and could induce complete regression when further combined with radiotherapy. Mechanistically, MS4A4A promoted M2 polarisation of macrophages by activating PI3K/AKT pathway and JAK/STAT6 pathway.
CONCLUSION
Targeting MS4A4A could enhance the ICI efficacy and represent a new anticancer immunotherapy.
Topics: Humans; Animals; Mice; Tumor-Associated Macrophages; CD8-Positive T-Lymphocytes; Phosphatidylinositol 3-Kinases; Neoplasms; Macrophages; Tumor Microenvironment; Membrane Proteins
PubMed: 37507218
DOI: 10.1136/gutjnl-2022-329147 -
Nature Reviews. Immunology Sep 2023Triggering receptors expressed on myeloid cells (TREMs) encompass a family of cell-surface receptors chiefly expressed by granulocytes, monocytes and tissue macrophages.... (Review)
Review
Triggering receptors expressed on myeloid cells (TREMs) encompass a family of cell-surface receptors chiefly expressed by granulocytes, monocytes and tissue macrophages. These receptors have been implicated in inflammation, neurodegenerative diseases, bone remodelling, metabolic syndrome, atherosclerosis and cancer. Here, I review the structure, ligands, signalling modes and functions of TREMs in humans and mice and discuss the challenges that remain in understanding TREM biology.
Topics: Humans; Animals; Mice; Triggering Receptor Expressed on Myeloid Cells-1; Receptors, Immunologic; Membrane Glycoproteins; Myeloid Cells; Biology
PubMed: 36750615
DOI: 10.1038/s41577-023-00837-1 -
Immunity Aug 2023Glioblastoma (GBM), a highly lethal brain cancer, is notorious for immunosuppression, but the mechanisms remain unclear. Here, we documented a temporospatial patterning...
Glioblastoma (GBM), a highly lethal brain cancer, is notorious for immunosuppression, but the mechanisms remain unclear. Here, we documented a temporospatial patterning of tumor-associated myeloid cells (TAMs) corresponding to vascular changes during GBM progression. As tumor vessels transitioned from the initial dense regular network to later scant and engorged vasculature, TAMs shifted away from perivascular regions and trafficked to vascular-poor areas. This process was heavily influenced by the immunocompetence state of the host. Utilizing a sensitive fluorescent UnaG reporter to track tumor hypoxia, coupled with single-cell transcriptomics, we revealed that hypoxic niches attracted and sequestered TAMs and cytotoxic T lymphocytes (CTLs), where they were reprogrammed toward an immunosuppressive state. Mechanistically, we identified chemokine CCL8 and cytokine IL-1β as two hypoxic-niche factors critical for TAM trafficking and co-evolution of hypoxic zones into pseudopalisading patterns. Therefore, perturbation of TAM patterning in hypoxic zones may improve tumor control.
Topics: Humans; T-Lymphocytes, Cytotoxic; Tumor-Associated Macrophages; Macrophages; Immunosuppression Therapy; Glioblastoma; Tumor Microenvironment
PubMed: 37451265
DOI: 10.1016/j.immuni.2023.06.017 -
Nature Nov 2023Inflammation is a hallmark of cancer. In patients with cancer, peripheral blood myeloid expansion, indicated by a high neutrophil-to-lymphocyte ratio, associates with...
Inflammation is a hallmark of cancer. In patients with cancer, peripheral blood myeloid expansion, indicated by a high neutrophil-to-lymphocyte ratio, associates with shorter survival and treatment resistance across malignancies and therapeutic modalities. Whether myeloid inflammation drives progression of prostate cancer in humans remain unclear. Here we show that inhibition of myeloid chemotaxis can reduce tumour-elicited myeloid inflammation and reverse therapy resistance in a subset of patients with metastatic castration-resistant prostate cancer (CRPC). We show that a higher blood neutrophil-to-lymphocyte ratio reflects tumour myeloid infiltration and tumour expression of senescence-associated mRNA species, including those that encode myeloid-chemoattracting CXCR2 ligands. To determine whether myeloid cells fuel resistance to androgen receptor signalling inhibitors, and whether inhibiting CXCR2 to block myeloid chemotaxis reverses this, we conducted an investigator-initiated, proof-of-concept clinical trial of a CXCR2 inhibitor (AZD5069) plus enzalutamide in patients with metastatic CRPC that is resistant to androgen receptor signalling inhibitors. This combination was well tolerated without dose-limiting toxicity and it decreased circulating neutrophil levels, reduced intratumour CD11bHLA-DRCD15CD14 myeloid cell infiltration and imparted durable clinical benefit with biochemical and radiological responses in a subset of patients with metastatic CRPC. This study provides clinical evidence that senescence-associated myeloid inflammation can fuel metastatic CRPC progression and resistance to androgen receptor blockade. Targeting myeloid chemotaxis merits broader evaluation in other cancers.
Topics: Humans; Male; Chemotaxis; Disease Progression; Drug Resistance, Neoplasm; Inflammation; Lewis X Antigen; Myeloid Cells; Neoplasm Metastasis; Prostate; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Androgen Receptor Antagonists; Antineoplastic Agents
PubMed: 37844613
DOI: 10.1038/s41586-023-06696-z -
Nature Communications Nov 2023Acute inflammation can either resolve through immunosuppression or persist, leading to chronic inflammation. These transitions are driven by distinct molecular and...
Acute inflammation can either resolve through immunosuppression or persist, leading to chronic inflammation. These transitions are driven by distinct molecular and metabolic reprogramming of immune cells. The anti-diabetic drug Metformin inhibits acute and chronic inflammation through mechanisms still not fully understood. Here, we report that the anti-inflammatory and reactive-oxygen-species-inhibiting effects of Metformin depend on the expression of the plasticity factor ZEB1 in macrophages. Using mice lacking Zeb1 in their myeloid cells and human patient samples, we show that ZEB1 plays a dual role, being essential in both initiating and resolving inflammation by inducing macrophages to transition into an immunosuppressed state. ZEB1 mediates these diverging effects in inflammation and immunosuppression by modulating mitochondrial content through activation of autophagy and inhibition of mitochondrial protein translation. During the transition from inflammation to immunosuppression, Metformin mimics the metabolic reprogramming of myeloid cells induced by ZEB1. Mechanistically, in immunosuppression, ZEB1 inhibits amino acid uptake, leading to downregulation of mTORC1 signalling and a decrease in mitochondrial translation in macrophages. These results identify ZEB1 as a driver of myeloid cell metabolic plasticity, suggesting that targeting its expression and function could serve as a strategy to modulate dysregulated inflammation and immunosuppression.
Topics: Humans; Animals; Mice; Macrophages; Myeloid Cells; Inflammation; Metformin; Immunosuppression Therapy
PubMed: 37978290
DOI: 10.1038/s41467-023-42277-4