PMID- 34615706 OWN - NLM STAT- MEDLINE DCOM- 20220112 LR - 20220112 IS - 2051-1426 (Electronic) IS - 2051-1426 (Linking) VI - 9 IP - 10 DP - 2021 Oct TI - Integrated analysis reveals prognostic value of HLA-I LOH in triple-negative breast cancer. LID - 10.1136/jitc-2021-003371 [doi] LID - e003371 AB - 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. CI - (c) Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. FAU - Zhou, Yi-Fan AU - Zhou YF AUID- ORCID: 0000-0003-3134-0174 AD - Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China. FAU - Xiao, Yi AU - Xiao Y AD - Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China. FAU - Jin, Xi AU - Jin X AD - Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China. FAU - Di, Gen-Hong AU - Di GH AD - Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China zhimingshao@yahoo.com yizhoujiang@fudan.edu.cn genhongdi@163.com. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China. FAU - Jiang, Yi-Zhou AU - Jiang YZ AD - Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China zhimingshao@yahoo.com yizhoujiang@fudan.edu.cn genhongdi@163.com. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China. FAU - Shao, Zhi-Ming AU - Shao ZM AD - Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China zhimingshao@yahoo.com yizhoujiang@fudan.edu.cn genhongdi@163.com. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China. AD - Institutes of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - J Immunother Cancer JT - Journal for immunotherapy of cancer JID - 101620585 RN - 0 (HLA Antigens) SB - IM MH - Female MH - HLA Antigens/*genetics MH - Humans MH - Loss of Heterozygosity/*genetics MH - Prognosis MH - Survival Analysis MH - Triple Negative Breast Neoplasms/*genetics/mortality PMC - PMC8496394 OTO - NOTNLM OT - antigen presentation OT - breast neoplasms COIS- Competing interests: None declared. EDAT- 2021/10/08 06:00 MHDA- 2022/01/13 06:00 PMCR- 2021/10/05 CRDT- 2021/10/07 06:00 PHST- 2021/08/29 00:00 [accepted] PHST- 2021/10/07 06:00 [entrez] PHST- 2021/10/08 06:00 [pubmed] PHST- 2022/01/13 06:00 [medline] PHST- 2021/10/05 00:00 [pmc-release] AID - jitc-2021-003371 [pii] AID - 10.1136/jitc-2021-003371 [doi] PST - ppublish SO - J Immunother Cancer. 2021 Oct;9(10):e003371. doi: 10.1136/jitc-2021-003371.