Pan-Cancer HLA Gene-Mediated Tumor Immunogenicity and Immune Evasion

Human leukocyte antigen (HLA) expression contributes to the activation of antitumor immunity through interactions with T-cell receptors. Pan-cancer HLA-mediated immunogenicity and immunoediting mechanisms have not been systematically studied previously. In a retrospective analysis of 33 tumor types from the Cancer Genome Atlas (TCGA), we characterized the differential expression of HLA class I and class II genes across various oncogenic pathways and immune subtypes. While HLA I genes were upregulated in all immunogenically hot tumors, HLA II genes were upregulated in an inflammatory immune subtype associated with best prognosis and were systematically downregulated in specific oncogenic pathways. A subset of immunogenically hot tumors which upregulated HLA class I but not class II genes exploited HLA-mediated escape strategies. Furthermore, with a machine learning model, we demonstrated that HLA gene expression data can be used to predict the immune subtypes of patients receiving immune checkpoint blockade and stratify patient survival. Interestingly, tumors with the highest immune infiltration did not have the best prognosis but showed significantly higher immune exhaustion.Taken together, we highlight the prognostic potential of HLA genes in immunotherapies and suggest that higher tumor immunogenicity mediated by HLA expression may sometimes lead to tumor escape under strong selective pressure.