medwireNews: Human leukocyte antigen class I (HLA-I) evolutionary divergence (HED) is associated with response to immune checkpoint inhibitor (ICI) treatment in people with cancer, show data published in Nature Medicine.
Timothy Chan (Memorial Sloan Kettering Cancer Center, New York, USA) and colleagues found that individuals with highly divergent HLA-I had significantly better overall survival following ICI treatment than those with minimally divergent HLA-I.
The researchers explain that the “HLA-I genotype consists of a pair of alleles at each of the classic class I genes—HLA-A, -B and -C,” which are highly polymorphic.
It has previously been observed in infectious diseases that heterozygous HLA-I genotypes allow for presentation of a more diverse set of antigens to T cells, a phenomenon known as heterozygote advantage.
“However, the effect of sequence divergence between HLA-I alleles – a quantifiable measure of HLA-I evolution – on the efficacy of […] ICI treatment for cancer remains unknown,” Chan et al remark.
To address this, they determined the HED at HLA-A, HLA-B, and HLA-C in seven previously published cohorts of patients with metastatic melanoma or non-small-cell lung cancer (NSCLC) treated with inhibitors of CTLA-4, PD-1, or PD-L1.
HED was calculated by measuring the Grantham distance between the peptide-binding domains of the two alleles and then stratifying this into quartiles. Patients in the top and bottom quartiles of mean HED across the three HLA genes were classed as having high and low HED, respectively.
Chan and team found that, when all of the patients were combined, those with high mean HED (n=62) has significantly lower risk for all-cause mortality than those with low mean HED (n=186), at a hazard ratio (HR) for death of 0.49.
For patients with both high mean HED and a high tumor mutational burden (TMB; n=18), the effect was even more pronounced; these patients had a HR for death of 0.30 relative to patients without either high mean HED or TMB.
This suggests that “patients with both high TMB and high HED are most likely to benefit from ICIs,” according to the investigators.
Interestingly, the researchers also found that the level of HED still impacted survival when patients were fully heterozygous. Specifically, fully heterozygous patients with high mean HED had a HR for death of 0.38 versus those with a low HED. Furthermore, the HR among fully heterozygous patients with both high HED and TMB was 0.11.
Of note, similar results were observed when the data were analyzed according to specific cancer and ICI type, but there was no association between HED and response among patients with melanoma and NSCLC who did not receive ICI therapy, indicating “that mean HED is predictive of response to ICIs, and may not be prognostic in the setting of patients with advanced cancer not treated with ICIs,” Chan et al remark.
The authors conclude that their findings “link divergent HLA allele advantage to immunotherapy efficacy and unveil how ICI response relies on the evolved efficiency of HLA-mediated immunity.”
They add that “both TMB and HED should be considered in the design of future clinical trials.”
By Laura Cowen
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