Chowell, D. et al reported for the first time in 2017 on the study of HLA-I embryonic genotype and system LOH status in response to ICI therapy. This study analyzed over 1535 cancer patients treated with ICI and found that the presence of more diverse HLA-I molecules (i.e. HLA-I heterozygosity) in a given individual was associated with increased survival, possibly due to the presence of this diversity providing a wider range of tumor antigens to T cells. Further research has found that the impact of HLA-I heterozygosity on the increased survival rate after ICI treatment appears to be mainly related to the HLA-B and HLA-C loci, possibly because the MHC encoded by HLA-B binds more diverse peptides, and HLA-C is usually expressed at higher levels in antigen presenting cells than other cell types. In addition, when considering TMB, the association between HLA-1 heterozygosity and prolonged survival was also enhanced. Compared to anti PD-1 treatment patients who are homozygous at the HLA-I locus, patients who are heterozygous at all HLA-I loci have higher TCR treatment clonality. In other words, HLA heterozygous patients can better clone their TCR library.

The study also found that some HLA-B44 subtype alleles are associated with improved survival in melanoma patients receiving ICIs treatment. Most alleles in the HLA-B44 subtype share the polarity and hydrophobic residues of the glutamate (E) and carboxyl terminus anchored at position 2. One of the most abundant amino acid mutations in melanoma is G>E, indicating that there may be HLA-B44 restricted tumor derived mutation epitopes presenting enrichment in melanoma.