Association of CD47 with Natural Killer Cell-Mediated Cytotoxicity of Head-and-Neck Squamous Cell Carcinoma Lines

Kim, Min Jung; Lee, June-Chul; Lee, Jaejung; Kim, Soyeon; Lee, Sang Goo; Park, Seok-Woo; Sung, Myung Whun; Heo, Dae Seog

doi:10.1159/000132568

Cited by 90 publications

(80 citation statements)

References 20 publications

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“…Rather, emerging evidence underlies on the contrary a tolerogenic role for TSP-1:CD47 interaction on tumor immunoadaptative b Fig. 3 surveillance, through direct inhibition of T cell activation [39] and regulation of natural killer and dendritic cells functions [40,41]. Together with these data that strengthen the relevance of targeting TSP-1:CD47 interaction, our results are in line with a central role of TSP-1 in tumor progression and reinforce evidence that has been provided Fig.…”

Section: Discussionsupporting

confidence: 89%

Matricellular TSP-1 as a target of interest for impeding melanoma spreading: towards a therapeutic use for TAX2 peptide

Jeanne

Boulagnon‐Rombi

Devy

et al. 2016

Clin Exp Metastasis

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Thrombospondin-1 (TSP-1) is a matricellular glycoprotein known for being highly expressed within a tumor microenvironment, where it promotes an aggressive phenotype particularly by interacting with the CD47 cell-surface receptor. While it originates from the stromal compartment in many malignancies, melanoma is an exception as invasive and metastatic melanoma cells overexpress TSP-1. We recently demonstrated that a new molecular agent that selectively prevents TSP-1 binding to CD47, called TAX2, exhibits anti-cancer properties when administered systemically by decreasing viable tumor tissue within subcutaneous B16 melanoma allografts. At the same time, emerging evidence was published suggesting a contribution of TSP-1 in melanoma metastatic dissemination and resistance to treatment. Through a comprehensive systems biology approach based on multiple genomics and proteomics databases analyses, we first identified a TSP-1-centered interaction network that is overexpressed in metastatic melanoma. Then, we investigated the effects of disrupting TSP-1:CD47 interaction in A375 human malignant melanoma xenografts. In this model, TAX2 systemic administrations induce tumor necrosis by decreasing intra-tumoral blood flow, while concomitantly making tumors less infiltrative. Besides, TAX2 treatment also drastically inhibits B16F10 murine melanoma cells metastatic dissemination and growth in a syngeneic experimental model of lung metastasis, as demonstrated by histopathological analyses as well as longitudinal and quantitative µCT follow-up of metastatic progression. Altogether, the results obtained by combining bioinformatics and preclinical studies strongly suggest that targeting TSP-1/CD47 axis may represent a valuable therapeutic alternative for hampering melanoma spreading.

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Section: Discussionsupporting

confidence: 89%

Matricellular TSP-1 as a target of interest for impeding melanoma spreading: towards a therapeutic use for TAX2 peptide

Jeanne

Boulagnon‐Rombi

Devy

et al. 2016

Clin Exp Metastasis

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“…CTC are therefore under evolutionary pressure to develop a phenotype that can protect or hide them from the immune system. In line with this hypothesis, we found CTC to exhibit a distinct nonimmunogenic phenotype by overexpressing CD47, a protein inhibiting the cytotoxic and phagocytic activity of activated immune cells (43)(44)(45). CD47 binds to SIRPa (46), an inhibitory receptor on macrophages and T cells (47)(48)(49) and is notably the only gene we found to be overexpressed in otherwise mostly dormant CTC.…”

Section: Discussionsupporting

confidence: 75%

Immune Escape and Survival Mechanisms in Circulating Tumor Cells of Colorectal Cancer

et al. 2014

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The prognosis of colorectal cancer is closely linked to the occurrence of distant metastases. Systemic dissemination is most likely caused by circulating tumor cells (CTC). Despite the fundamental role of CTC within the metastatic cascade, technical obstacles have so far prevented detailed genomic and, in particular, phenotypic analyses of CTC, which may provide molecular targets to delay or prevent distant metastases. We show here a detailed genomic analysis of single colorectal cancer-derived CTC by array comparative genomic hybridization (aCGH), mutational profiling, and microsatellite instability (MSI) analysis. Furthermore, we report the first gene expression analysis of manually selected colorectal cancer-derived CTC by quantitative real-time PCR (qRT-PCR) to investigate transcriptional changes, enabling CTC to survive in circulation and form distant metastases. aCGH confirmed the tumor cell identity of CellSearch-isolated colorectal cancer-derived CTC. Mutational and MSI analyses revealed mutational profiles of CTC to be similar, but not identical to the corresponding tumor tissue. Several CTC exhibited mutations in key genes such as KRAS or TP53 that could not be detected in the tumor. Gene expression analyses revealed both a pronounced upregulation of CD47 as a potential immune-escape mechanism and a significant downregulation of several other pathways, suggesting a dormant state of viable CTC. Our results suggest mutational heterogeneity between tumor tissue and CTC that should be considered in future trials on targeted therapy and monitoring of response. The finding of upregulated immune-escape pathways, which may be responsible for survival of CTC in circulation, could provide a promising target to disrupt the metastatic cascade in colorectal cancer. Cancer Res; 74(6); 1694-704. Ó2014 AACR.

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“…We do not exclude the possibility that other SIRPα + myeloid cells might contribute to the efficacy observed in our models, as granulocytes and myeloid dendritic cells respond to CD47-blocking therapies (15, 48). Moreover, CD47-blockade can initiate antigen presentation that stimulates adaptive immune responses against tumors (48-50) and targeting CD47 might directly activate T cells or NK cells (51-53). Although lymphocytes are not necessary for a therapeutic response in xenograft models, they could yield greater efficacy in immunocompetent settings and will be important to evaluate in future veterinary studies.…”

Section: Discussionmentioning

confidence: 99%

Eradication of Canine Diffuse Large B-Cell Lymphoma in a Murine Xenograft Model with CD47 Blockade and Anti-CD20

Weiskopf

Anderson

Ito

et al. 2016

Cancer Immunology Research

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Cancer immunotherapies hold much promise, but their potential in veterinary settings has not yet been fully appreciated. Canine lymphomas are among the most common tumors of dogs and bear remarkable similarity to human disease. In this study, we examined the combination of CD47 blockade with anti-CD20 passive immunotherapy for canine lymphoma. The CD47/SIRPα axis is an immune checkpoint that regulates macrophage activation. In humans, CD47 is expressed on cancer cells and enables evasion from phagocytosis. CD47-blocking therapies are now under investigation in clinical trials for a variety of human cancers. We found the canine CD47/SIRPα axis to be conserved biochemically and functionally. We identified high-affinity SIRPα variants that antagonize canine CD47 and stimulate phagocytosis of canine cancer cells in vitro. When tested as Fc fusion proteins, these therapeutic agents exhibited single-agent efficacy in a mouse xenograft model of canine lymphoma. Since robust synergy between CD47 blockade and tumor-specific antibodies has been demonstrated for human cancer, we evaluated the combination of CD47-blockade with 1E4-cIgGB, a canine-specific antibody to CD20. 1E4-cIgGB could elicit a therapeutic response against canine lymphoma in vivo as a single agent. However, augmented responses were observed when combined with CD47-blocking therapies, resulting in synergy in vitro and in vivo and eliciting cures in 100% of mice bearing canine lymphoma. Our findings support further testing of CD47-blocking therapies alone and in combination with CD20 antibodies in the veterinary setting.

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Association of CD47 with Natural Killer Cell-Mediated Cytotoxicity of Head-and-Neck Squamous Cell Carcinoma Lines

Cited by 90 publications

References 20 publications

Matricellular TSP-1 as a target of interest for impeding melanoma spreading: towards a therapeutic use for TAX2 peptide

Matricellular TSP-1 as a target of interest for impeding melanoma spreading: towards a therapeutic use for TAX2 peptide

Immune Escape and Survival Mechanisms in Circulating Tumor Cells of Colorectal Cancer

Eradication of Canine Diffuse Large B-Cell Lymphoma in a Murine Xenograft Model with CD47 Blockade and Anti-CD20

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