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Identification of tumor rejection antigens and the immunologic landscape of medulloblastoma. | LitMetric

Identification of tumor rejection antigens and the immunologic landscape of medulloblastoma.

Genome Med

UF Brain Tumor Immunotherapy Program, Preston A. Wells Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, University of Florida, 1333 Center Drive, BSB B1-118, Gainesville, FL, 32610, USA.

Published: August 2024

AI Article Synopsis

  • Current treatments for high-risk medulloblastoma are ineffective due to tumor heterogeneity, highlighting the need for personalized immunotherapy approaches.
  • A study analyzed the genetic profiles of 170 medulloblastoma tumors to identify potential tumor rejection antigens that could enhance the effectiveness of immune responses.
  • The results indicated that patients expressed various immunogenic antigens, with higher proportions of tumor-associated antigens compared to neoantigens, particularly noting the presence of cancer-testis and new neurodevelopmental antigens across most molecular subgroups.

Article Abstract

Background: The current standard of care treatments for medulloblastoma are insufficient as these do not take tumor heterogeneity into account. Newer, safer, patient-specific treatment approaches are required to treat high-risk medulloblastoma patients who are not cured by the standard therapies. Immunotherapy is a promising treatment modality that could be key to improving survival and avoiding morbidity. For an effective immune response, appropriate tumor antigens must be targeted. While medulloblastoma patients with subgroup-specific genetic substitutions have been previously reported, the immunogenicity of these genetic alterations remains unknown. The aim of this study is to identify potential tumor rejection antigens for the development of antigen-directed cellular therapies for medulloblastoma.

Methods: We developed a cancer immunogenomics pipeline and performed a comprehensive analysis of medulloblastoma subgroup-specific transcription profiles (n = 170, 18 WNT, 46 SHH, 41 Group 3, and 65 Group 4 patient tumors) available through International Cancer Genome Consortium (ICGC) and European Genome-Phenome Archive (EGA). We performed in silico antigen prediction across a broad array of antigen classes including neoantigens, tumor-associated antigens (TAAs), and fusion proteins. Furthermore, we evaluated the antigen processing and presentation pathway in tumor cells and the immune infiltrating cell landscape using the latest computational deconvolution methods.

Results: Medulloblastoma patients were found to express multiple private and shared immunogenic antigens. The proportion of predicted TAAs was higher than neoantigens and gene fusions for all molecular subgroups, except for sonic hedgehog (SHH), which had a higher neoantigen burden. Importantly, cancer-testis antigens, as well as previously unappreciated neurodevelopmental antigens, were found to be expressed by most patients across all medulloblastoma subgroups. Despite being immunologically cold, medulloblastoma subgroups were found to have distinct immune cell gene signatures.

Conclusions: Using a custom antigen prediction pipeline, we identified potential tumor rejection antigens with important implications for the development of immunotherapy for medulloblastoma.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11331754PMC
http://dx.doi.org/10.1186/s13073-024-01363-yDOI Listing

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