Benchmarking HLA genotyping and clarifying HLA impact on survival in tumor immunotherapy

Human leukocyte antigen (HLA) genotyping gains intensive attention due to its critical role in cancer immunotherapy. It is still a challenging issue to generate reliable HLA genotyping results through in silico tools. In addition, the survival impact of HLA alleles in tumor prognosis and immunotherapy remains controversial. In this study, the benchmarking of HLA genotyping on TCGA is performed and a ‘Gun‐Bullet’ model which helps to clarify the survival impact of HLA allele is presented. The performance of HLA class I genotyping is generally better than class II. POLYSOLVER, OptiType, and xHLA perform generally better at HLA class I calling with an accuracy of 0.954, 0.949, and 0.937, respectively. HLA‐HD obtained the highest accuracy of 0.904 on HLA class II alleles calling. Each HLA genotyping tool displayed specific error patterns. The ensemble HLA calling from the top‐3 tools is superior to any individual one. HLA alleles show distinct survival impact among cancers. Cytolytic activity (CYT) was proposed as the underlying mechanism to interpret the survival impact of HLA alleles in the ‘Gun‐Bullet’ model for fighting cancer. A strong HLA allele plus a high tumor mutation burden (TMB) could stimulate intensive immune CYT, leading to extended survival. We established an up to now most reliable TCGA HLA benchmark dataset, composing of concordance alleles generated from eight prevalently used HLA genotyping tools. Our findings indicate that reliable HLA genotyping should be performed based on concordance alleles integrating multiple tools and incorporating TMB background with HLA genotype, which helps to improve the survival prediction compared to HLA genotyping alone.