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 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.

Automated summary

This study systematically characterized the HLA-I status in triple-negative breast cancers (TNBCs) and found that HLA-I loss of heterozygosity (LOH) is an independent prognostic biomarker, especially for patients with non-immune-inflamed tumors. HLA-I LOH tumors had upregulated mutational signature 3 scores and homologous recombination deficiency scores, indicating DNA repair failure, higher mutation and neoantigen loads, and more subclones, contributing to poor immune selection pressure.