Merkel cell carcinoma expresses the immunoregulatory ligand CD200 and induces immunosuppressive macrophages and regulatory T cells

Gaiser, Maria Rita; Weis, Cleo–Aron; Gaiser, Timo; Jiang, Hong; Buder‐Bakhaya, Kristina; Herpel, Esther; Warth, Arne; Xiao, Ying; Miao, Lijing; Brownell, Isaac

doi:10.1080/2162402x.2018.1426517

Cited by 24 publications

(20 citation statements)

References 25 publications

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“…CD200R is principally expressed on immune cells of monocyte-macrophage lineage, with an emphasis on myeloid-derived suppressor cells (MDSCs) [ 19 , 24 ]. Additionally, Gaiser et al found evidence of CD200R-expressing macrophages in Merkel cell carcinoma and suggested a role for the induction of an immunosuppressive M2 phenotype [ 25 ]. This is supported, diagonally, by the fact that we detected immune cells staining double positive for both CD200R and PD-L1.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Assessment of CD200 and CD200R Expression in Lung Cancer

Vathiotis

MacNeil

Zugazagoitia

et al. 2021

Cancers

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CD200/CD200R is an immune checkpoint with broad expression patterns and a potential target for immune therapy. In this study, we assess both CD200 and CD200R expression in solid tumors, with a focus on lung cancer, and evaluate their association with clinicopathologic characteristics, mutation status, outcome, and programmed death-ligand 1 (PD-L1) expression. We used multiplexed quantitative immunofluorescence (QIF) to measure the expression of CD200 and CD200R in a total of 455 patients from three lung cancer cohorts. Using carefully validated antibodies, we performed target measurement with tyramide-based QIF panels and analyzed the data using the PM2000 microscope and AQUA software. CD200 tumor positivity was found in 29.7% of non-small cell lung cancer (NSCLC) patients and 33.3% of lung large cell neuroendocrine carcinoma (LCNEC) patients. CD200 demonstrated notable intratumoral heterogeneity. CD200R was expressed in immune cells in 25% of NSCLC and 41.3% of LCNEC patients. While CD200R is predominantly expressed in immune cells, rare tumor cell staining was seen in a highly heterogeneous pattern. CD200R expression in the stromal compartment was significantly higher in patients with squamous differentiation (p < 0.0001). Neither CD200 nor CD200R were associated with other clinicopathologic characteristics or mutation status. Both biomarkers were not prognostic for disease-free or overall survival in NSCLC. CD200 showed moderate correlation with PD-L1. CD200/CD200R pathway is frequently expressed in lung cancer patients. Differential expression patterns of CD200 and CD200R with PD-L1 suggest a potential role for targeting this pathway alone in patients with NSCLC.

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Section: Discussionmentioning

confidence: 99%

Quantitative Assessment of CD200 and CD200R Expression in Lung Cancer

Vathiotis

MacNeil

Zugazagoitia

et al. 2021

Cancers

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“…In BCCs, recruited Tregs build an immunosuppressive niche by locally synthesizing TGF-β (Omland et al, 2016). In MCC, M2 macrophages and Tregs present in the tumor maintain an immunosuppressive state contributing to a pro-tumorigenic microenvironment (Gaiser et al, 2018). Interestingly, increased recruitment of CD8 + T cells to the skin is associated with better prognosis in MCCs (Touzé et al, 2011).…”

Section: Skin Diseasesmentioning

confidence: 99%

Unraveling the ECM-Immune Cell Crosstalk in Skin Diseases

Bhattacharjee

Ayyangar

Kurbet

et al. 2019

Front. Cell Dev. Biol.

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The extracellular matrix (ECM) is a complex network of proteins and proteoglycans secreted by keratinocytes, fibroblasts and immune cells. The function of the skin ECM has expanded from being a scaffold that provides structural integrity, to a more dynamic entity that is constantly remodeled to maintain tissue homeostasis. The ECM functions as ligands for cell surface receptors such as integrins, dystroglycans, and toll-like receptors (TLRs) and regulate cellular signaling and immune cell dynamics. The ECM also acts as a sink for growth factors and cytokines, providing critical cues during epithelial morphogenesis. Dysregulation in the organization and deposition of ECMs lead to a plethora of pathophysiological conditions that are exacerbated by aberrant ECM-immune cell interactions. In this review, we focus on the interplay between ECM and immune cells in the context of skin diseases and also discuss state of the art therapies that target the key molecular players involved.

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“…Non-melanoma skin cancers such as extramammary Paget’s disease (EMPD), cutaneous squamous cell carcinoma (cSCC) and Merkel cell carcinoma (MCC) also possess heterogeneous CD163 + TAMs that could secrete an array of cytokines and chemokines in lesional skin to regulate the tumor microenvironment [ 1 , 20 , 21 , 22 ]. For example, serum sCD163 is increased in patients with EMPD compared to healthy donors [ 23 ], suggesting that CD163 + TAMs are constitutively activated in the lesional skin of EMPD.…”

Section: Significance Of Immunosuppressive Cells In Developing Skimentioning

confidence: 99%

“…On the other hand, as Petterson et al reported [ 21 ], CD163 + TAMs in cSCC heterogeneously polarized from M1 to M2, suggesting heterogeneous activation states of TAMs. CD163 + TAMs contribute to the tumor microenvironment in MCC to promote tumor development by inducing lymphangiogenesis and immunosuppressive cells such as Tregs [ 22 , 24 ]. These reports suggested that CD163 + TAMs could represent a therapeutic target for the treatment of these non-melanoma skin cancers.…”

Section: Significance Of Immunosuppressive Cells In Developing Skimentioning

confidence: 99%

Significance of Immunosuppressive Cells as a Target for Immunotherapies in Melanoma and Non-Melanoma Skin Cancers

Fujimura

Aiba

2020

Biomolecules

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Tumor-associated macrophages (TAMs) have been detected in most skin cancers. TAMs produce various chemokines and angiogenic factors that promote tumor development, along with other immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and tumor-associated neutrophils. TAMs generated from monocytes develop into functional, fully activated macrophages, and TAMs obtain various immunosuppressive functions to maintain the tumor microenvironment. Since TAMs express PD1 to maintain the immunosuppressive M2 phenotype by PD1/PD-L1 signaling from tumor cells, and the blockade of PD1/PD-L1 signaling by anti-PD1 antibodies (Abs) activate and re-polarize TAMs into immunoreactive M1 phenotypes, TAMs represent a potential target for anti-PD1 Abs. The main population of TAMs comprises CD163+ M2 macrophages, and CD163+ TAMs release soluble (s)CD163 and several proinflammatory chemokines (CXCL5, CXCL10, CCL19, etc.) as a result of TAM activation to induce an immunosuppressive tumor microenvironment together with other immunosuppressive cells. Since direct blockade of PD1/PD-L1 signaling between tumor cells and tumor-infiltrating T cells (both effector T cells and Tregs) is mandatory for inducing an anti-immune response by anti-PD1 Abs, anti-PD1 Abs need to reach the tumor microenvironment to induce anti-immune responses in the tumor-bearing host. Taken together, TAM-related factors could offer a biomarker for anti-PD1 Ab-based immunotherapy. Understanding the crosstalk between TAMs and immunosuppressive cells is important for optimizing PD1 Ab-based immunotherapy.

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Merkel cell carcinoma expresses the immunoregulatory ligand CD200 and induces immunosuppressive macrophages and regulatory T cells

Cited by 24 publications

References 25 publications

Quantitative Assessment of CD200 and CD200R Expression in Lung Cancer

Quantitative Assessment of CD200 and CD200R Expression in Lung Cancer

Unraveling the ECM-Immune Cell Crosstalk in Skin Diseases

Significance of Immunosuppressive Cells as a Target for Immunotherapies in Melanoma and Non-Melanoma Skin Cancers

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