期刊
JOURNAL FOR IMMUNOTHERAPY OF CANCER
卷 10, 期 10, 页码 -出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/jitc-2022-005535
关键词
Immunotherapy; Antigens; Neoplasm
资金
- German Research Foundation [SFB-TR36]
- Berlin Institute of Health [CRG-1]
- Deutsche Krebshilfe [111 546, 70113456]
- DKTK joint funding (NEO-ATT)
- European Union (ERC) [882963]
- Helmholtz-Gemeinschaft [ZT-0027]
- European Research Council (ERC) [882963] Funding Source: European Research Council (ERC)
The H3.3K27M mutation is unlikely to be a suitable target for cancer immunotherapy due to insufficient epitope processing and/or amount for recognition by HLA-A*02:01 restricted CD8(+) T cells.
Diffuse midline glioma is the leading cause of solid cancer-related deaths in children with very limited treatment options. A majority of the tumors carry a point mutation in the histone 3 variant (H3.3) creating a potential HLA-A*02:01 binding epitope (H3.3K27M(26-35)). Here, we isolated an H3.3K27M-specific T cell receptor (TCR) from transgenic mice expressing a diverse human TCR repertoire. Despite a high functional avidity of H3.3K27M-specific T cells, we were not able to achieve recognition of cells naturally expressing the H3.3K27M mutation, even when overexpressed as a transgene. Similar results were obtained with T cells expressing the published TCR 1H5 against the same epitope. CRISPR/Cas9 editing was used to exclude interference by endogenous TCRs in donor T cells. Overall, our data provide strong evidence that the H3.3K27M mutation is not a suitable target for cancer immunotherapy, most likely due to insufficient epitope processing and/or amount to be recognized by HLA-A*02:01 restricted CD8(+) T cells.
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