Heparanase: A New Metastasis-Associated Antigen Recognized in Breast Cancer Patients by Spontaneously Induced Memory T Lymphocytes

Sommerfeldt, Nora; Beckhove, Philipp; Ge, Yingzi; Schütz, Florian; Choi, Carmen; Bucur, Mariana; Domschke, Christoph; Sohn, Christof; Schneeweis, A; Rom, Joachim; Pollmann, D.; Leucht, D.; Vlodavsky, Israël; Schirrmacher, Volker

doi:10.1158/0008-5472.can-05-2363

Cited by 43 publications

(41 citation statements)

References 32 publications

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“…Sommerfeldt and colleagues first proved that heparanase could serve as a universal TAA for tumor immunotherapy, and several CTL epitopes of human heparanase were identified in 2006 (12). Since then, several other epitopes have been reported for both murine and human heparanase and tested for their antitumor activity on various tumor cells in vitro and in vivo (13)(14)(15).…”

Section: Discussionmentioning

confidence: 99%

“…The first group of immunogenic epitopes in heparanase was discovered by Sommerfeldt and colleagues using the SYFPEITHI algorithm to identify nonapeptides of the heparanase amino acid sequence (12). By using HLA-A2-restricted epitope prediction algorithms based on supermotif and quantitative motif methods, we successfully predicted and identified another 3 HLA-A2-restricted CTL epitopes, Hpa277 (277-285, KMLKSFLKA), Hpa405 (405-413, WLSLLFKKL) and hHpa525 (525-533, PAF-SYSFFV), in human heparanase and 2 H-2Kb-restricted CTL epitopes, mHpa398 (398-405, LSLLFKKL) and mHpa519 (519-526, FSYGFFVI), in mice.…”

Section: Introductionmentioning

confidence: 99%

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

Wang

Tang

Lü

et al. 2011

Cancer Prevention Research

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Peptide vaccination for cancer immunotherapy requires an ideal immune response induced by epitope peptides derived from tumor-associated antigens (TAA). Heparanase is broadly expressed in various advanced tumors. Accumulating evidence suggests that heparanase can serve as a universal TAA for tumor immunotherapy. However, due to the low immunogenicity of peptide vaccines, an ideal immune response against tumors usually cannot be elicited in patients. To increase the immunogenicity of peptide vaccines, we designed three 4-branched multiple antigenic peptides (MAP) on the basis of the human leukocyte antigen (HLA)-A2-restricted cytotoxic T lymphocyte (CTL) epitopes of human heparanase that we identified previously as antigen carriers. Our results show that MAP vaccines based on the HLA-A2-restricted CLT epitopes of human heparanase were capable of inducing HLA-A2-restricted and heparanasespecific CTL in vitro and in mice. Moreover, compared with their corresponding linear peptides, heparanase MAP vaccines elicited much stronger lysis of tumor cells by activating CD8þ T lymphocytes and increasing the releasing of IFN-g. However, these heparanase-specific CTLs did not lyse heparanase-expressing autologous lymphocytes and dendritic cells, which confirm the safety of these MAP vaccines. Therefore, our findings indicate that MAP vaccines based on CTL epitopes of human heparanase can be used as potent immunogens for tumor immunotherapy because of advantages such as broad spectrum, high effectiveness, high specificity, and safety. Cancer Prev Res; 4(8); 1285-95. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Wang

Tang

Lü

et al. 2011

Cancer Prevention Research

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“…2,21–25 This polyvalent T cell pool consists of effector and central T mem cells, which produce IFN-γ upon Ag re-encounter and can eliminate autologous tumor cells. 26–28 However, there is increasing evidence that tumor-associated immune suppression can be mediated in an Ag-specific manner, too.…”

Section: Introductionmentioning

confidence: 99%

Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses

et al. 2018

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Mutated proteins arising from somatic mutations in tumors are promising targets for cancer immunotherapy. They represent true tumor-specific antigens (TSAs) as they are exclusively expressed in tumors, reduce the risk of autoimmunity and are more likely to overcome tolerance compared to wild-type (wt) sequences. Hence, we designed a panel of long peptides (LPs, 28–35 aa) comprising driver gene mutations in TP35 and KRAS frequently found in gastrointestinal tumors to test their combined immunotherapeutic potential. We found increased numbers of T cells responsive against respective mutated and wt peptides in colorectal cancer patients that carry the tested mutations in their tumors than patients with other mutations. Further, active immunization of HLA(-A2/DR1)-humanized mice with mixes of the same mutated LPs yielded simultaneous, polyvalent CD8+/CD4+ T cell responses against the majority of peptides. Peptide-specific T cells possessed a multifunctional cytokine profile with CD4+ T cells showing a TH1-like phenotype. Two mutated peptides (Kras[G12V], p53[R248W]) induced significantly higher T cell responses than corresponding wt sequences and comprised HLA-A2/DR1-restricted mutated epitopes. However, vaccination with the same highly immunogenic LPs strongly increased systemic regulatory T cells (Treg) numbers in a syngeneic sarcoma model over-expressing these mutated protein variants and resulted in accelerated tumor outgrowth. In contrast, tumor outgrowth was delayed when vaccination was directed against tumor-intrinsic Kras/Tp53 mutations of lower immunogenicity. Conclusively, we show that LP vaccination targeting multiple mutated TSAs elicits polyvalent, multifunctional, and mutation-specific effector T cells capable of targeting tumors. However, the success of this therapeutic approach can be hampered by vaccination-induced, TSA-specific Tregs.

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“…A major advance in tumor immunology in the last 20 years was marked by the verification that CTL or B-cell epitopes rather than integral TAAs induce immunoreactivity (8). The first group of immunogenic epitopes in Hpa was identified by Sommerfeldt et al using the SYFPEITHI algorithm to identify nonapeptides of the Hpa amino acid sequence (9). In our previous study, according to the primary structure of Hpa and on the basis of predicting the Hpa B-cell epitopes via bioinformatics, we designed and synthesized multiple antigenic peptides (MAPs) using the eight-branched polypeptide modus (10,11).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of heparanase multiple antigenic peptide 2 is associated with poor prognosis in gastric cancer: Potential for therapy

et al. 2012

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Abstract. Tumor-associated antigens (TAAs) trigger a TAA-specific immune response, thus they are the crux of antitumor immunosurveillance. A major advance in tumor immunology in the last 20 years was marked by the verification that CTL or B-cell epitopes rather than integral TAAs induce immunoreactivity. Previous studies on the correlation between heparanase (Hpa) expression and clinical or pathological features have generally used commercial antibodies against full-length Hpa protein rather than the functional epitopes, and the antigen determinants of such antibodies have not yet been defined. In our investigation of Hpa peptide expression in gastric cancer tissues and its association with tumor invasion, metastasis and prognosis, we analyzed Hpa expression in the tissues of 132 patients with gastric cancer using tissue microarray (TMA) technology and immunohistochemical staining.Three self-developed rabbit polyclonal antibodies against Hpa multiple antigenic peptides (MAP) and one commercial polyclonal rabbit antibody against the 50-8 kDa Hpa heterodimer were used. Clinical and pathological significance was evaluated using the Chi-square test and Kaplan-Meier survival curve analysis. The results demonstrated that the positivity rates using the antibody against MAP2 and the commercial antibody were 60.6% (80/132) and 65.2% (86/132), respectively. No expression of either MAP1 or MAP3 was noted in the cancer tissues of the 132 cases. MAP2 behaved in a similar manner to the commercial antibody in that a higher Hpa expression was observed in the cancer tissues with vessel invasion, serosal involvement, distant metastasis, poor differentiation and TNM stages Ⅲ and Ⅳ. Moreover, the patients with a positive Hpa expression had a far poorer prognosis, with lower one-year and five-year survival rates. Our results demonstrate that in a similar manner to full-length Hpa proteins, MAP2 expression is closely associated with the invasion, metastasis and prognosis of gastric cancer. This finding may be of potential use in clinical therapy and in estimating the prognosis of a tumor.

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Heparanase: A New Metastasis-Associated Antigen Recognized in Breast Cancer Patients by Spontaneously Induced Memory T Lymphocytes

Cited by 43 publications

References 32 publications

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

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

Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses

Overexpression of heparanase multiple antigenic peptide 2 is associated with poor prognosis in gastric cancer: Potential for therapy

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