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Somatic Mutations in Lung Cancer Patients With HLA Supertype B44 Influence Immunotherapy Response

NEW YORK – Researchers at the University of California, Los Angeles David Geffen School of Medicine have found that the mutational landscape of non-small cell lung cancer (NSCLC) can affect the efficacy of immune checkpoint blockade (ICB) therapy in patients with the human leukocyte antigen (HLA) B44 supertype.

In a paper published on Monday in Nature Cancer, the researchers noted that HLA-B has been shown to be a major determinant of disease outcome differences and can play a role in ICB efficacy. HLA supertypes comprise HLA alleles that share structural features of binding pocket residues that interact with peptide anchors, which generate most HLA-peptide binding energy. The B44 supertype features an electropositive binding pocket that preferentially displays peptides with negatively charged amino acid anchors. It has been associated with improved survival in ICB-treated melanoma, but the same hasn't been seen in ICB-treated NSCLC patients, the researchers wrote.

In their study, they found that tumor mutations leading to negatively charged glutamic acid substitutions occured more often in melanoma than in NSCLC, and that stratifying B44 supertype patients based on the presence of such mutations identified those patients with an ICB benefit similar to that seen in melanoma.

"We anticipate these findings could improve assessment of HLA-related outcomes and prediction of ICB benefit in those with B44, representing approximately half of the world's population," the authors wrote.

The researchers began by evaluating the impact of B44 in an NSCLC cohort of 65 people treated with single-agent pembrolizumab (Merck's Keytruda) with more than five years of follow-up and tissue samples available. Additionally, they evaluated the mechanistic underpinnings of divergent ICB response in this group, which they validated in publicly available NSCLC and melanoma cohorts.

Indeed, they found that patients with the B44 supertype had worse outcomes than those without. The median overall survival of patients with B44 in the NSCLC cohort was 9.3 months compared to 18.8 months for patients without it. Median progression-free survival was 2.1 months for patients with B44 compared to 10.2 months for those without it.

The researchers hypothesized that negatively charged glutamic acid substitutions in the anchor position were beneficial for immune presentation due to enhanced binding to B44's positively charged binding pocket. They further proposed that radical glutamic acid substitutions, or those that replace an uncharged or positively charged wildtype amino acid with glutamic acid, may be distributed unevenly in melanoma and NSCLC, decreasing the likelihood of substitutions that could act as new B44 anchors in NSCLC tumors.

In order to test this hypothesis, they used whole-exome sequencing and neoepitope prediction on 38 tumor tissue samples from their NSCLC cohort and found that radical glutamic acid substitutions occur more commonly in melanoma than NSCLC. An average of 2.8 percent of somatic substitutions were to glutamic acid in NSCLC compared to 5.9 percent in melanoma mutations. NSCLC also had relatively more transversion mutations, particularly cytosine to adenine, caused by bulky adducts from smoking.

In further experiments, the researchers also identified certain motif neoepitopes in patients with B44 and noted that their presence could be associated with ICB outcomes. However, they added, further validation with other HLA supertypes, such as B27, would be required. In the study, they found that B27 had significant survival benefits based on the presence of motif neoepitopes, but this couldn't be further defined because of the small number of available tumor samples.