The HLA-I landscape confers prognosis and antitumor immunity in breast cancer.

Breast cancer is a highly heterogeneous disease with varied subtypes, prognoses and therapeutic responsiveness. Human leukocyte antigen class I (HLA-I) shapes the immunity and thereby influences the outcome of breast cancer. However, the implications of HLA-I variations in breast cancer remain poorly understood. In this study, we established a multiomics cohort of 1156 Chinese breast cancer patients for HLA-I investigation. We calculated four important HLA-I indicators in each individual, including HLA-I expression level, somatic HLA-I loss of heterozygosity (LOH), HLA-I evolutionary divergence (HED) and peptide-binding promiscuity (Pr). Then, we evaluated their distribution and prognostic significance in breast cancer subtypes. We found that the four breast cancer subtypes had distinct features of HLA-I indicators. Increased expression of HLA-I and LOH were enriched in triple-negative breast cancer (TNBC), while Pr was relatively higher in hot tumors within TNBCs. In particular, a higher Pr indicated a better prognosis in TNBCs by regulating the infiltration of immune cells and the expression of immune molecules. Using the matched genomic and transcriptomic data, we found that mismatch repair deficiency-related mutational signature and pathways were enriched in low-Pr TNBCs, suggesting that targeting mismatch repair deficiency for synthetic lethality might be promising therapy for these patients. In conclusion, we presented an overview of HLA-I indicators in breast cancer and provided hints for precision treatment for low-Pr TNBCs.