An unbiased approach to defining bona fide cancer neoepitopes that elicit immune-mediated cancer rejection
| Autor: | Tatiana Shcheglova, Ion I. Mandoiu, Mariam M. George, Sahar Al Seesi, Cory A. Brennick, Jeremy L. Balsbaugh, Ryan P. Englander, Grant L.J. Keller, Andrea Schietinger, Pramod K. Srivastava, Adam T. Hagymasi, Marmar Moussa, Brian M. Baker |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Genetically modified mouse Bioinformatics medicine.medical_treatment Cancer Model Immunology Epitopes T-Lymphocyte Cancer immunotherapy Major histocompatibility complex Cancer Vaccines Epitope 03 medical and health sciences Mice 0302 clinical medicine Immune system Antigen Antigens Neoplasm Cell Line Tumor Neoplasms medicine Animals biology Cancer General Medicine medicine.disease 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research biology.protein Female Immunotherapy Research Article |
| Zdroj: | The Journal of Clinical Investigation |
| ISSN: | 1558-8238 0021-9738 |
| Popis: | Identification of neoepitopes that are effective in cancer therapy is a major challenge in creating cancer vaccines. Here, using an entirely unbiased approach, we queried all possible neoepitopes in a mouse cancer model and asked which of those are effective in mediating tumor rejection, and independently, in eliciting a measurable CD8 response. This analysis uncovered a large trove of effective anticancer neoepitopes which have strikingly different properties from conventional epitopes and suggested an algorithm to predict them. It also revealed that our current methods of prediction discard the overwhelming majority of true anticancer neoepitopes. These results from a single mouse model were validated in another, antigenically distinct mouse cancer model, and are consistent with data reported in human studies. Structural modeling showed how the MHC I-presented neoepitopes have an altered conformation, higher stability, or increased exposure to T cell receptors as compared to the un-mutated counterparts. T cells elicited by the active neoepitopes identified here demonstrated a stem-like early dysfunctional phenotype associated with effective responses against viruses and tumors of transgenic mice. These abundant anticancer neoepitopes, which have not been tested in human studies thus far, can be exploited for the generation of personalized human cancer vaccines. |
| Databáze: | OpenAIRE |
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