Integrated analysis reveals prognostic value of HLA-I LOH in triple-negative breast cancer
Background Triple-negative breast cancers (TNBCs), especially those non-immune-inflamed tumors, have a poor prognosis and limited therapies. Human leukocyte antigen (HLA)-I not only contributes to antitumor immune response and the phenotype of the tumor microenvironment, but also is a negative predi...
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| Language: | English |
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BMJ Publishing Group
2021-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/9/10/e003371.full |
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| author | Yi Xiao Xi Jin Yi-Zhou Jiang Zhi-Ming Shao Yi-Fan Zhou Gen-Hong Di |
| author_facet | Yi Xiao Xi Jin Yi-Zhou Jiang Zhi-Ming Shao Yi-Fan Zhou Gen-Hong Di |
| author_sort | Yi Xiao |
| collection | DOAJ |
| description | Background Triple-negative breast cancers (TNBCs), especially those non-immune-inflamed tumors, have a poor prognosis and limited therapies. Human leukocyte antigen (HLA)-I not only contributes to antitumor immune response and the phenotype of the tumor microenvironment, but also is a negative predictor of outcomes after immunotherapy. However, the importance of HLA functional status in TNBCs remains poorly understood.Methods Using the largest original multiomics datasets on TNBCs, we systematically characterized the HLA-Ⅰ status of TNBCs from the perspective of HLA-Ⅰ homogeneity and loss of heterozygosity (LOH). The prognostic significance of HLA-I status was measured. To explain the potential mechanism of prognostic value in HLA-Ⅰ status, the mutational signature, copy number alteration, neoantigen and intratumoral heterogeneity were measured. Furthermore, the correlation between HLA-Ⅰ functional status and the tumor immune microenvironment was analyzed.Results LOH and homogeneity in HLA-I accounted for 18% and 21% of TNBCs, respectively. HLA-I LOH instead of HLA-I homogeneity was an independent prognostic biomarker in TNBCs. In particular, for patients with non-immune-inflamed tumors, HLA-I LOH indicated a worse prognosis than HLA-I non-LOH. Furthermore, integrated genomic and transcriptomic analysis showed that HLA-I LOH was accompanied by upregulated scores of mutational signature 3 and homologous recombination deficiency scores, which implied the failure of DNA double-strand break repair. Moreover, HLA-I LOH had higher mutation and neoantigen loads and more subclones than HLA-I non-LOH. These results indicated that although HLA-I LOH tumors with failure of DNA double-strand break repair were prone to produce neoantigens, their limited capacity for antigen presentation finally contributed to poor immune selection pressure.Conclusion Our study illustrates the genomic landscape of HLA-I functional status and stresses the prognostic significance of HLA-I LOH in TNBCs. For “cold” tumors in TNBCs, HLA-I LOH indicated a worse prognosis than HLA-I non-LOH. |
| format | Article |
| id | doaj-art-ff34c59247e4496494f1f33a5a8d9afd |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2021-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-ff34c59247e4496494f1f33a5a8d9afd2025-08-20T01:53:00ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262021-10-0191010.1136/jitc-2021-003371Integrated analysis reveals prognostic value of HLA-I LOH in triple-negative breast cancerYi Xiao0Xi Jin1Yi-Zhou Jiang2Zhi-Ming Shao3Yi-Fan Zhou4Gen-Hong Di51 Department of Neurology, Sichuan University, Chengdu, Sichuan, ChinaKey Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, People`s Republic of ChinaKey Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, ChinaDepartment of Breast Surgery, Fudan University Shanghai Cancer and Key Laboratory of Breast Cancer in Shanghai, Shanghai, ChinaKey Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, People`s Republic of ChinaprofessorBackground Triple-negative breast cancers (TNBCs), especially those non-immune-inflamed tumors, have a poor prognosis and limited therapies. Human leukocyte antigen (HLA)-I not only contributes to antitumor immune response and the phenotype of the tumor microenvironment, but also is a negative predictor of outcomes after immunotherapy. However, the importance of HLA functional status in TNBCs remains poorly understood.Methods Using the largest original multiomics datasets on TNBCs, we systematically characterized the HLA-Ⅰ status of TNBCs from the perspective of HLA-Ⅰ homogeneity and loss of heterozygosity (LOH). The prognostic significance of HLA-I status was measured. To explain the potential mechanism of prognostic value in HLA-Ⅰ status, the mutational signature, copy number alteration, neoantigen and intratumoral heterogeneity were measured. Furthermore, the correlation between HLA-Ⅰ functional status and the tumor immune microenvironment was analyzed.Results LOH and homogeneity in HLA-I accounted for 18% and 21% of TNBCs, respectively. HLA-I LOH instead of HLA-I homogeneity was an independent prognostic biomarker in TNBCs. In particular, for patients with non-immune-inflamed tumors, HLA-I LOH indicated a worse prognosis than HLA-I non-LOH. Furthermore, integrated genomic and transcriptomic analysis showed that HLA-I LOH was accompanied by upregulated scores of mutational signature 3 and homologous recombination deficiency scores, which implied the failure of DNA double-strand break repair. Moreover, HLA-I LOH had higher mutation and neoantigen loads and more subclones than HLA-I non-LOH. These results indicated that although HLA-I LOH tumors with failure of DNA double-strand break repair were prone to produce neoantigens, their limited capacity for antigen presentation finally contributed to poor immune selection pressure.Conclusion Our study illustrates the genomic landscape of HLA-I functional status and stresses the prognostic significance of HLA-I LOH in TNBCs. For “cold” tumors in TNBCs, HLA-I LOH indicated a worse prognosis than HLA-I non-LOH.https://jitc.bmj.com/content/9/10/e003371.full |
| spellingShingle | Yi Xiao Xi Jin Yi-Zhou Jiang Zhi-Ming Shao Yi-Fan Zhou Gen-Hong Di Integrated analysis reveals prognostic value of HLA-I LOH in triple-negative breast cancer Journal for ImmunoTherapy of Cancer |
| title | Integrated analysis reveals prognostic value of HLA-I LOH in triple-negative breast cancer |
| title_full | Integrated analysis reveals prognostic value of HLA-I LOH in triple-negative breast cancer |
| title_fullStr | Integrated analysis reveals prognostic value of HLA-I LOH in triple-negative breast cancer |
| title_full_unstemmed | Integrated analysis reveals prognostic value of HLA-I LOH in triple-negative breast cancer |
| title_short | Integrated analysis reveals prognostic value of HLA-I LOH in triple-negative breast cancer |
| title_sort | integrated analysis reveals prognostic value of hla i loh in triple negative breast cancer |
| url | https://jitc.bmj.com/content/9/10/e003371.full |
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