Human leukocyte antigen (HLA)-B has been recognized as a major determinant of discrepancies in disease outcomes, and recent evidence indicates a role in immune checkpoint blockade (ICB) efficacy. The B44 supertype, which features an electropositive binding pocket that preferentially displays peptides with negatively charged amino acid anchors, is associated with improved survival in ICB-treated melanoma. Yet this effect was not seen in ICB-treated non-small-cell lung cancer (NSCLC). Here we show that mutations leading to glutamic acid substitutions occur more often in melanoma than NSCLC based on mutational landscape. We additionally show stratifying B44 based on the presence of somatic mutations that lead to negatively charged glutamic acid anchors identifies patients with NSCLC 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.

人类白细胞抗原 (HLA)-B 已被认为是疾病结果差异的主要决定因素，最近的证据表明在免疫检查点阻断 (ICB) 功效中的作用。B44 超型具有一个正电结合口袋，优先展示带有负电荷氨基酸锚的肽，与 ICB 治疗的黑色素瘤的存活率提高有关。然而，在 ICB 治疗的非小细胞肺癌 (NSCLC) 中并未观察到这种效果。在这里，我们根据突变情况表明，导致谷氨酸取代的突变在黑色素瘤中比在 NSCLC 中更常见。我们还根据导致带负电荷的谷氨酸锚的体细胞突变的存在对 B44 进行分层，从而识别出具有与黑色素瘤相似的 ICB 益处的 NSCLC 患者。