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CD200R signaling regulates myeloid cell production of chemokines in tumor microenvironment

ABSTRACT: CD200R signaling regulates myeloid cell production of chemokines in tumor microenvironment

PROVIDER: PRJNA873063 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21228618_1.fastq.gz	Fastqsanger.gz
	SRR21228618_2.fastq.gz	Fastqsanger.gz
	SRR21228619_1.fastq.gz	Fastqsanger.gz
	SRR21228619_2.fastq.gz	Fastqsanger.gz
	SRR21228620_1.fastq.gz	Fastqsanger.gz

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CD200R signaling regulates myeloid cell production of chemokines in tumor microenvironment

Project description:CD200 is overexpressed in human solid tumors such as neuroblastoma and melanoma and considered to be a checkpoint molecule to be targeted for cancer immunotherapy. However, its role in tumor microenvironment (TME) is not well understood. In this study, we evaluated the role of CD200-CD200R pathway in TME using two human relevant, CD200-positive murine tumor models, i.e. the mouse neuroblastoma NB9464D, and melanoma Yummer1.7 models. We found that in CD200R-/- mice, both tumor types grew significantly slower than in wild type mice. TME analyses using scRNAseq and flow cytometry revealed that tumors from CD200R-/- mice overall recruited more CD45+ immune cells including CD4+ and CD8+ T cells and NK cells but less neutrophils into tumors. Antibody depletion experiments revealed that immune effectors including CD4+ and CD8+ T cells, and NK cells are crucial in inhibiting tumor growth in CD200R-/- mice. Mechanistically, we found that CD200R signaling differentially regulates the expression of chemokines in TAMs. In the absence of CD200R, TAMs upregulate CCL24 and CCL8 and downregulate CXCL3, CXCL2 and CCL3 via activation of Erk and/or P38 MAP kinases. Increased expression of CCL24 in TAMs resulted in increased recruitment of eosinophils, which contributes to anti-tumor activity. Thus, CD200R signaling regulates myeloid cell production of chemokines in TME, which explains the differential recruitment of immune effectors and downregulation of neutrophils.

2023-05-30 | GSE211963 | GEO

The CD200-CD200R axis promotes squamous cell carcinoma metastasis via regulation of Cathepsin K

Project description:The CD200-CD200R immunoregulatory signaling axis plays an etiological role in the survival and spread of numerous cancers primarily through suppression of anti-tumor immune surveillance. Our previous work outlined a pro-metastatic role for the CD200-CD200R axis in cutaneous squamous cell carcinoma (cSCC) that is independent of direct T cell suppression but modulates the function of infiltrating myeloid cells. To identify effectors of the CD200-CD200R axis important for cSCC metastasis, we conducted RNA-Seq profiling of infiltrating CD11b+Cd200r+ cells isolated from Cd200+ versus Cd200 null cSCCs and identified the cysteine protease Cathepsin K (Ctsk) to be highly upregulated in Cd200+ cSCCs. CD11b+Cd200r+ cells, which expressed phenotypic markers associated with myeloid-derived suppressor cell-like cells and tumor-associated macrophages, were the primary source of Ctsk expression in cSCC. Using a Cd200r+ myeloid cell-cSCC co-culture system, we observed that induction of Ctsk in Cd200r+ tumor-infiltrating cells was dependent on engagement of the CD200-CD200R axis, indicating that Ctsk is a target gene of this pathway in the cSCC tumor microenvironment. Inhibition of Ctsk, but not matrix metalloproteinases (MMPs), significantly blocked cSCC cell migration through collagen gels in vitro. Finally, both targeted Cd200 disruption in tumor cells and Ctsk pharmacological inhibition dramatically reduced cSCC metastasis in vivo. Collectively, our findings identify a novel direct role for Cd200r+ infiltrating myeloid lineages in tumor metastasis and support the conclusion that CD200 stimulates cSCC invasion and metastasis via induction of Ctsk in CD200r+ infiltrating cells.

2021-06-19 | GSE178496 | GEO

CD200R signaling contributes to unfavorable tumor microenvironment through regulating production of chemokines by tumor-associated myeloid cells.

Project description:CD200 is overexpressed in many solid tumors and considered as an immune checkpoint molecule dampening cancer immunity. In this study, we found that CD200R-/- mice were significantly more potent in rejecting these CD200+ tumors. scRNA sequencing demonstrated that tumors from CD200R-/- mice had more infiltration of CD4+ and CD8+ T cells, and NK cells but less infiltration of neutrophils. Antibody depletion experiments revealed that immune effector cells are crucial in inhibiting tumor growth in CD200R-/- mice. Mechanistically, we found that CD200R signaling regulates the expression of chemokines in tumor-associated myeloid cells (TAMCs). In the absence of CD200R, TAMCs increased expression of CCL24 and resulted in increased infiltration of eosinophils, which contributes to anti-tumor activity. Overall, we conclude that CD200R signaling contributes to unfavorable TME through chemokine-dependent recruitment of immune suppressive neutrophils and exclusion of anti-cancer immune effectors. Our study has implications in developing CD200-CD200R targeted immunotherapy of solid tumors.

| S-EPMC10239067 | biostudies-literature

The inhibitory receptor CD200R educates ILC1s for optimal cytotoxicity

Project description:Conventional natural killer (cNK) cells are educated through inhibitory receptor engagement with MHC-Ⅰ ligands, ensuring functional competence and self-tolerance. However, as a population likewise exhibiting cytotoxicity, whether type 1 innate lymphoid cells (ILC1s) undergo education and the underlying mechanisms remain unclear. Our study reveals that, CD200R, an inhibitory receptor specifically expressed by ILC1s, selectively suppresses ILC1 cytotoxicity upon CD200 engagement. Surprisingly, CD200R deficiency impairs ILC1 degranulation and cytotoxic activity without affecting inflammatory cytokine production. This defect is accompanied by compromised metabolic fitness in ILC1s. Analogous to cNK cell education, we demonstrate that CD200R educates ILC1 cytotoxicity primarily through the WNT/β-catenin pathway. Importantly, the impaired effector functions of uneducated ILC1s could be restored by exposure to certain cytokines. Collectively, our study defines a critical role for the inhibitory receptor CD200R in educating ILC1s to achieve cytotoxic maturity, revealing a parallel yet distinct mechanism from cNK cell education.

2025-12-01 | GSE307477 | GEO

Next Generation Sequencing Facilitates Quantitative Analysis of the effects of CD200R engagment on sorted mouse pulmonary ILC2 Transcriptomes.

Project description:The prevalence of asthma and airway hyperreactivity (AHR) is increasing at an alarming rate. Group 2 innate lymphoid cells (ILC2s) are copious producers of type 2 cytokines, which leads to AHR and lung inflammation. In this study, we demonstrate murine ILC2s express CD200 receptor (CD200R), and this expression is inducible. We ascertain CD200R engagement inhibits activation, proliferation, and type 2 cytokine production, revealing a potent immunoregulatory role for CD200–CD200R axis on ILC2s. Furthermore, we demonstrate that CD200R engagement inhibits both canonical and non-canonical NF-B signaling pathways in activated ILC2s. Importantly, we herein design both preventative and therapeutic approaches utilizing CD200R engagement on ILC2s, which lead to improved airway resistance, dynamic compliance, and eosinophilia. Finally, our results reveal CD200R is expressed on human ILC2s, and its engagement ameliorates AHR in humanized ILC2 models, further emphasizing the translational applications of our findings for treatment of ILC2-related diseases such as allergic asthma.

2021-02-17 | GSE166889 | GEO

Secretory MPP3 reinforce myeloid differentiation trajectory and amplify myeloid cell production

Project description:Secretory MPP3 reinforce myeloid differentiation trajectory and amplify myeloid cell production

| PRJNA753832 | ENA

Secretory MPP3 reinforce myeloid differentiation trajectory and amplify myeloid cell production

Project description:Hematopoietic stem cells (HSC) and downstream lineage-biased multipotent progenitors (MPP) tailor blood production and control myelopoiesis on demand. However, a precise resolution of myeloid differentiation trajectories and cellular heterogeneity in various MPP populations and understanding of their role in controlling myeloid cell production remains largely lacking. Here, we analyze that myeloid-biased MPP3 are functionally and molecularly heterogenous, with a distinct subset of myeloid-primed secretory cells with high endoplasmic reticulum (ER) volume.

2021-08-18 | GSE181902 | GEO

Influence of CD200R-deficiency on gene expression in primary murine neutrophils

Project description:RNA-seq analysis at steady state of primary bone marrow neutrophils isolated from WT and CD200R-/- C57BL6 mice. Of the 323 genes that were significantly differentially expressed, one of the major pathways that differed included genes related to reactive oxygen species (ROS) clearance and scavenging.

2019-04-04 | GSE129287 | GEO

p38α activation-mediated IFNAR1 downregulation by tumor derived factors induced neutrophil-attracting chemokines production

Project description:p38α activation-mediated IFNAR1 downregulation by tumor derived factors induced neutrophil-attracting chemokines production

| PRJNA552538 | ENA

p38α activation-mediated IFNAR1 downregulation by tumor derived factors induced neutrophil-attracting chemokines production

Project description:Tumor derived factors induced type I interferon receptor (IFNAR1) downregulation both in vivo and in vitro. IFNAR1 was shown to be phosphorylated, ubiquitinated and downregulated in response to soluble or vesicular tumor derived factors in a p38-dependent manner. Upon administration of B16F10 tumor derived factors, lungs of Ifnar1S526A knock-in mice (termed "SA"), where mutation in a phospho-acceptor site within the IFNAR1 phospho-degron renders IFNAR1 insensitive to p38-driven phosphorylation, ubiquitination and degradation, retained IFNAR1 and sustained the expression of the IFN stimulated genes. Futuremore, careful examination and validation of gene expression profiles revealed an increased expression of several chemokines known to attract neutrophils (including Cxcl1, Cxcl3 and Cxcl5) in the lungs of WT mice treated with tumor derived factors. This increase was notably less pronounced in the SA mice, suggesting that IFNAR1 downregulation by tumor derived factors induced neutrophil-attracting chemokines production.

2021-06-15 | GSE133781 | GEO

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