Multiple Antigenic Peptides of Human Heparanase Elicit a Much More Potent Immune Response against Tumors

Wang, Guozhen; Tang, Xu-Dong; Lü, Muhan; Gao, Jianguo; Liang, Guangping; Li, Ning; Li, Changzhu; Wu, Yingyi; Chen, Ling; Cao, Yunxia; Fang, Dian‐Chun; Yang, Shi‐Ming

doi:10.1158/1940-6207.capr-11-0083

Cited by 25 publications

(20 citation statements)

References 34 publications

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“…Thus, HS remodeling by heparanase may affect several aspects of inflammatory reactions, such as leukocyte recruitment, extravasation and migration towards inflammation sites; release of cytokines and chemokines anchored within the ECM or cell surfaces, as well as activation of innate immune cells 9, 41, 42 . Mounting evidence suggests that heparanase affects activities of several types of innate immunocytes, including neutrophils, macrophages, dendritic and mast cells 32, 43–48 . Of those, neutrophils represent the important effectors in acute inflammatory responses, including AP.…”

Section: Discussionmentioning

confidence: 99%

The Role of Heparanase in the Pathogenesis of Acute Pancreatitis: A Potential Therapeutic Target

Khamaysi

Singh

Nasser³

et al. 2017

Sci Rep

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Acute pancreatitis (AP) is one of the most common diseases in gastroenterology. However, neither the etiology nor the pathophysiology of the disease is fully understood and no specific or effective treatment has been developed. Heparanase is an endoglycosidase that cleaves heparan sulfate (HS) side chains of HS sulfate proteoglycans into shorter oligosaccharides, activity that is highly implicated in cellular invasion associated with cancer metastasis and inflammation. Given that AP involves a strong inflammatory aspect, we examined whether heparanase plays a role in AP. Here, we provide evidence that pancreatic heparanase expression and activity are significantly increased following cerulein treatment. Moreover, pancreas edema and inflammation, as well as the induction of cytokines and signaling molecules following cerulein treatment were attenuated markedly by heparanase inhibitors, implying that heparanase plays a significant role in AP. Notably, all the above features appear even more pronounced in transgenic mice over expressing heparanase, suggesting that these mice can be utilized as a sensitive model system to reveal the molecular mechanism by which heparanase functions in AP. Heparanase, therefore, emerges as a potential new target in AP, and heparanase inhibitors, now in phase I/II clinical trials in cancer patients, are hoped to prove beneficial also in AP.

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Section: Discussionmentioning

confidence: 99%

The Role of Heparanase in the Pathogenesis of Acute Pancreatitis: A Potential Therapeutic Target

Khamaysi

Singh

Nasser³

et al. 2017

Sci Rep

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“…Cumulative evidence suggests that heparanase affects the activities of several types of innate immunocytes, including neutrophils, macrophages, dendritic and mast cells (Benhamron et al, 2006; Benhamron et al, 2012; Blich et al, 2013; Lerner et al, 2011; Massena et al, 2011; Schmidt et al, 2012; Wang et al, 2011). Of those, neutrophils represent the important effectors in the acute inflammatory responses.…”

Section: Heparanase In Acute and Chronic Inflammationmentioning

confidence: 99%

Heparanase: From basic research to therapeutic applications in cancer and inflammation

Vlodavsky¹,

Singh²,

Boyango³

et al. 2016

Drug Resistance Updates

195

229

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Heparanase, the sole heparan sulfate degrading endoglycosidase, regulates multiple biological activities that enhance tumor growth, angiogenesis and metastasis. Heparanase expression is enhanced in almost all cancers examined including various carcinomas, sarcomas and hematological malignancies. Numerous clinical association studies have consistently demonstrated that upregulation of heparanase expression correlates with increased tumor size, tumor angiogenesis, enhanced metastasis and poor prognosis. In contrast, knockdown of heparanase or treatments of tumor-bearing mice with heparanase-inhibiting compounds, markedly attenuate tumor progression further underscoring the potential of anti-heparanase therapy for multiple types of cancer. Heparanase neutralizing monoclonal antibodies block myeloma and lymphoma tumor growth and dissemination; this is attributable to a combined effect on the tumor cells and/or cells of the tumor microenvironment. In fact, much of the impact of heparanase on tumor progression is related to its function in mediating tumor-host crosstalk, priming the tumor microenvironment to better support tumor growth, metastasis and chemoresistance. The repertoire of the physiopathological activities of heparanase is expanding. Specifically, heparanase regulates gene expression, activates cells of the innate immune system, promotes the formation of exosomes and autophagosomes, and stimulates signal transduction pathways via enzymatic and non-enzymatic activities. These effects dynamically impact multiple regulatory pathways that together drive inflammatory responses, tumor survival, growth, dissemination and drug resistance; but in the same time, may fulfill some normal functions associated, for example, with vesicular traffic, lysosomal-based secretion, stress response, and heparan sulfate turnover. Heparanase is upregulated in response to chemotherapy in cancer patients and the surviving cells acquire chemoresistance, attributed, at least in part, to autophagy. Consequently, heparanase inhibitors used in tandem with chemotherapeutic drugs overcome initial chemoresistance, providing a strong rationale for applying anti-heparanase therapy in combination with conventional anti-cancer drugs. Heparin-like compounds that inhibit heparanase activity are being evaluated in clinical trials for various types of cancer. Heparanase neutralizing monoclonal antibodies are being evaluated in pre-clinical studies, and heparanase-inhibiting small molecules are being developed based on the recently resolved crystal structure of the heparanase protein. Collectively, the emerging premise is that heparanase expressed by tumor cells, innate immune cells, activated endothelial cells as well as other cells of the tumor microenvironment is a master regulator of the aggressive phenotype of cancer, an important contributor to the poor outcome of cancer patients and a prime target for therapy.

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“…Synthetic long peptides resist protease activity, prolong presentation to APCs, enhance immunogenicity, and induce both T-cytotoxic and T-helper responses. Synthetic multipeptides have greater molecular weights and immunogenicity than their corresponding peptides [18]. In the present study, we designed a peptide immunotherapy for glioblastoma using ERBB2, BIRC5 and CD99 peptides as TAAs [17].…”

Section: Discussionmentioning

confidence: 99%

“…Synthetic CTL epitope peptides such as multipeptides have greater molecular weights and immunogenicity than their corresponding peptides [10, 18]. In this study, we designed a branched multipeptide by using mini-polyethylene glycol (mini-PEG) spacers.…”

Section: Introductionmentioning

confidence: 99%

Branched multipeptide immunotherapy for glioblastoma using human leukocyte antigen-A*0201-restricted cytotoxic T-lymphocyte epitopes from ERBB2, BIRC5 and CD99

et al. 2016

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We investigated the use of cytotoxic T-lymphocyte (CTL) epitopes in peptide immunotherapy for glioblastoma. Three peptides (ERBB2, BIRC5 and CD99) were selected based on their peptide-T2 cell binding affinities and combined in a multipeptide cocktail or a branched multipeptide synthesized with mini-polyethylene glycol spacers. Dendritic cells (DCs) pulsed with the multipeptide cocktail or branched multipeptide were compared based on their immunophenotype and cytokine secretion. FACS analysis of alpha-type 1 polarized dendritic cells (αDC1s) revealed that both groups highly expressed CD80, CD83 and CD86, indicating that both treatments efficiently generated mature αDC1s with the expected phenotype. Production of IL-12p70, IL-12p40 and IL-10 also increased upon αDC1 maturation in both groups. CTLs stimulated by either αDC1 group (“DC-CTLs”) included numerous IFN-γ-secreting cells against T2 cells loaded with the corresponding multipeptides. Large numbers of IFN-γ-secreting cells were observed when human glioblastoma cell lines and primary cells were treated with multipeptide-pulsed DC-CTLs. Both multipeptide-pulsed DC-CTL groups exhibited cytotoxic activity of 40-60% against the U251 cell line and 60-80% against primary cells. Branched multipeptide from ERBB2, BIRC5 and CD99 stably bound with T2 cells, and its cytotoxicity toward target cells was similar to that of the multipeptide cocktail. Thus, branched multipeptides could be promising candidates for immunotherapeutic glioblastoma treatment.

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Multiple Antigenic Peptides of Human Heparanase Elicit a Much More Potent Immune Response against Tumors

Cited by 25 publications

References 34 publications

The Role of Heparanase in the Pathogenesis of Acute Pancreatitis: A Potential Therapeutic Target

The Role of Heparanase in the Pathogenesis of Acute Pancreatitis: A Potential Therapeutic Target

Heparanase: From basic research to therapeutic applications in cancer and inflammation

Branched multipeptide immunotherapy for glioblastoma using human leukocyte antigen-A*0201-restricted cytotoxic T-lymphocyte epitopes from ERBB2, BIRC5 and CD99

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