A Novel Cancer Therapeutic Using Thrombospondin 1 in Dendritic Cells

Weng, Tzu Yang; Huang, Shih Shien; Yen, Meng‐Chi; Lin, Chi Chen; Chen, Yi Ling; Lin, Chiu Mei; Chen, Wei Ching; Wang, Chih‐Yang; Chang, Jang Yang; Lai, Ming Derg

doi:10.1038/mt.2013.236

Cited by 29 publications

(28 citation statements)

References 49 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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“…Apart from its role in modulating tumor angiogenic response, TSP-1/CD47 signaling also leads to tolerogenic signals that allow tumor immune escape, through direct inhibition of T cell activation 29 , 60 as well as by regulating natural killers and dendritic cells functions 61 , 62 . Disruption of TSP-1:CD47 interaction under TAX2 treatment indeed promotes accumulation of infiltrating CD3+ T cells within melanoma tumors implanted in WT mice (Fig.…”

Section: Discussionmentioning

confidence: 99%

Lumican delays melanoma growth in mice and drives tumor molecular assembly as well as response to matrix-targeted TAX2 therapeutic peptide

Jeanne

Untereiner

Perreau

et al. 2017

Sci Rep

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Lumican is a small leucine-rich proteoglycan (SLRP) being known as a key regulator of collagen fibrillogenesis. However, little attention has been given so far in studying its influence on tumor-associated matrix architecture. Here, we investigate the role of host lumican on tumor matrix organization as well as on disease progression considering an immunocompetent model of melanoma implanted in Lum −/− vs. wild type syngeneic mice. Conjointly, lumican impact on tumor response to matrix-targeted therapy was evaluated considering a previously validated peptide, namely TAX2, that targets matricellular thrombospondin-1. Analysis of available genomics and proteomics databases for melanoma first established a correlation between lumican expression and patient outcome. In the B16 melanoma allograft model, endogenous lumican inhibits tumor growth and modulates response to TAX2 peptide. Indeed, IHC analyses revealed that lumican deficiency impacts intratumoral distribution of matricellular proteins, growth factor and stromal cells. Besides, innovative imaging approaches helped demonstrating that lumican host expression drives biochemical heterogeneity of s.c. tumors, while modulating intratumoral collagen deposition as well as organization. Altogether, the results obtained present lumican as a strong endogenous inhibitor of tumor growth, while identifying for the first time this proteoglycan as a major driver of tumor matrix coherent assembly.

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“…Of the functions performed by CD47, its engagement with SIRPα and thrombospondin-1 has established its role as an inhibitory receptor involved in immune evasion by cancers through inhibition of phagocytosis, antigen presentation, and T/NK cell inhibition (286)(287)(288)(289). Consequently, targeting these signaling pathways with antibodies has revealed the therapeutic candidacy of this checkpoint (283,(289)(290)(291)(292).…”

Section: Cd47mentioning

confidence: 99%

NK Cell-Based Immune Checkpoint Inhibition

Arooj²,

2020

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Immunotherapy, with an increasing number of therapeutic dimensions, is becoming an important mode of treatment for cancer patients. The inhibition of immune checkpoints, which are the source of immune escape for various cancers, is one such immunotherapeutic dimension. It has mainly been aimed at T cells in the past, but NK cells are a newly emerging target. Simultaneously, the number of checkpoints identified has been increasing in recent times. In addition to the classical NK cell receptors KIRs, LIRs, and NKG2A, several other immune checkpoints have also been shown to cause dysfunction of NK cells in various cancers and chronic infections. These checkpoints include the revolutionized CTLA-4, PD-1, and recently identified B7-H3, as well as LAG-3, TIGIT & CD96, TIM-3, and the most recently acknowledged checkpoint-members of the Siglecs family (Siglec-7/9), CD200 and CD47. An interesting dimension of immune checkpoints is their candidacy for dual-checkpoint inhibition, resulting in therapeutic synergism. Furthermore, the combination of immune checkpoint inhibition with other NK cell cytotoxicity restoration strategies could also strengthen its efficacy as an antitumor therapy. Here, we have undertaken a comprehensive review of the literature to date regarding NK cell-based immune checkpoints.

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A Novel Cancer Therapeutic Using Thrombospondin 1 in Dendritic Cells

Cited by 29 publications

References 49 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

Lumican delays melanoma growth in mice and drives tumor molecular assembly as well as response to matrix-targeted TAX2 therapeutic peptide

NK Cell-Based Immune Checkpoint Inhibition

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