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  • American Association for Cancer Research (AACR)  (3)
  • 1
    Online Resource
    Online Resource
    Vaccination with Designed Neopeptides Induces Intratumoral, Cross-reactive CD4+ T-cell Responses in Glioblastoma
    American Association for Cancer Research (AACR) ; 2022
    In:  Clinical Cancer Research Vol. 28, No. 24 ( 2022-12-15), p. 5368-5382
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 28, No. 24 ( 2022-12-15), p. 5368-5382
    Abstract: The low mutational load of some cancers is considered one reason for the difficulty to develop effective tumor vaccines. To overcome this problem, we developed a strategy to design neopeptides through single amino acid mutations to enhance their immunogenicity. Experimental Design: Exome and RNA sequencing as well as in silico HLA-binding predictions to autologous HLA molecules were used to identify candidate neopeptides. Subsequently, in silico HLA-anchor placements were used to deduce putative T-cell receptor (TCR) contacts of peptides. Single amino acids of TCR contacting residues were then mutated by amino acid replacements. Overall, 175 peptides were synthesized and sets of 25 each containing both peptides designed to bind to HLA class I and II molecules applied in the vaccination. Upon development of a tumor recurrence, the tumor-infiltrating lymphocytes (TIL) were characterized in detail both at the bulk and clonal level. Results: The immune response of peripheral blood T cells to vaccine peptides, including natural peptides and designed neopeptides, gradually increased with repetitive vaccination, but remained low. In contrast, at the time of tumor recurrence, CD8+ TILs and CD4+ TILs responded to 45% and 100%, respectively, of the vaccine peptides. Furthermore, TIL-derived CD4+ T-cell clones showed strong responses and tumor cell lysis not only against the designed neopeptide but also against the unmutated natural peptides of the tumor. Conclusions: Turning tumor self-peptides into foreign antigens by introduction of designed mutations is a promising strategy to induce strong intratumoral CD4+ T-cell responses in a cold tumor like glioblastoma.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-22-1741
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
    Location Call Number Limitation Availability
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  • 2
    Online Resource
    Online Resource
    Blood-Based Diagnosis and Risk Stratification of Patients with Pancreatic Intraductal Papillary Mucinous Neoplasm (IPMN)
    American Association for Cancer Research (AACR) ; 2023
    In:  Clinical Cancer Research Vol. 29, No. 8 ( 2023-04-14), p. 1535-1545
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 29, No. 8 ( 2023-04-14), p. 1535-1545
    Abstract: Intraductal papillary mucinous neoplasm (IPMN) is a precursor of pancreatic ductal adenocarcinoma. Low-grade dysplasia has a relatively good prognosis, whereas high-grade dysplasia and IPMN invasive carcinoma require surgical intervention. However, diagnostic distinction is difficult. We aimed to identify biomarkers in peripheral blood for accurate discrimination. Experimental Design: Sera were obtained from 302 patients with IPMNs and 88 healthy donors. For protein biomarkers, serum samples were analyzed on microarrays made of 2,977 antibodies. A support vector machine (SVM) algorithm was applied to define classifiers, which were validated on a separate sample set. For microRNA biomarkers, a PCR-based screen was performed for discovery. Biomarker candidates confirmed by quantitative PCR were used to train SVM classifiers, followed by validation in a different sample set. Finally, a combined SVM classifier was established entirely independent of the earlier analyses, again using different samples for training and validation. Results: Panels of 26 proteins or seven microRNAs could distinguish high- and low-risk IPMN with an AUC value of 95% and 94%, respectively. Upon combination, a panel of five proteins and three miRNAs yielded an AUC of 97%. These values were much better than those obtained in the same patient cohort by using the guideline criteria for discrimination. In addition, accurate discrimination was achieved between other patient subgroups. Conclusions: Protein and microRNA biomarkers in blood allow precise diagnosis and risk stratification of IPMN cases, which should improve patient management and thus the prognosis of IPMN patients. See related commentary by Löhr and Pantel, p. 1387
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-22-2531
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
    Location Call Number Limitation Availability
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  • 3
    Online Resource
    Online Resource
    Abstract P5-11-03: Altered adipose-derived mesenchymal stem/stromal cells induced by obesity in the breast cancer microenvironment
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 4_Supplement ( 2022-02-15), p. P5-11-03-P5-11-03
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 4_Supplement ( 2022-02-15), p. P5-11-03-P5-11-03
    Abstract: It is well documented that obesity, characterized by an increased body mass index (BMI≥30), is an important risk factor for the development of aggressive breast cancer (BC), which is associated with a reduced overall survival rate and decreased treatment response. The tumor microenvironment (TME), a cellular network majorly constructed by adipocytes, adipose-derived mesenchymal stem/stromal cells (bASCs) and immune cells, impacts progression of breast cancer and treatment response of patients. This study aims to examine how obesity influences the functional characteristics of bASCs in comparison to lean bASCs in the TME. To address this issue, various molecular, biological and cellular methods are applied including transcriptomic profiling and functional assays to characterize at first the features of bASCs in the TME (adjacent to tumor; -aT/distant to tumor; -dT) in obese (ob-) and lean (ln-) bASCs (n=5, for each group) patients with breast cancer. Second, based on the transcriptomic data, we investigated the interaction of bASCs with triple negative as well as triple positive BC cell lines in 3D-spheroids and in standard 2D-cell culture conditions.Indicated by the gene signature the TME shifts bASCs towards a cancer supporting phenotype with a significant deregulated protein expression, cytokine/chemokine secretion, and reduced differentiation capacity. These changes affect critically the cell-cell interaction of BC cells with bASCs. bASCs isolated adjacent to the tumor increase the malignancy of BCs by stimulating the proliferation, migration, invasion and chemoresistance of these cells significantly. These observed effects are further enhanced by ob-aT bASCs. In conclusion, this study identifies over 900 genes deregulated in bASCs adjacent to breast cancer. Many of these genes are associated with pathways known for the development of malignant cells. Moreover, it clarifies differences in obese versus lean bASCs and their impacts on progression of breast cancer cells. Citation Format: Andreas Ritter, Susanne Roth, Alexandra Friemel, Nina-Naomi Kreis, Frank Louwen, Christine Solbach, Juping Yuan. Altered adipose-derived mesenchymal stem/stromal cells induced by obesity in the breast cancer microenvironment [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-11-03.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS21-P5-11-03
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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