新抗原免疫编辑可提高免疫检查点阻断功效，但新抗原的分子特征以及新抗原免疫原性如何影响治疗反应仍知之甚少。为了解决这些问题，80 名非小细胞肺癌患者被纳入 CheckMate 153 (CA209-153) 生物标志物队列，该队列在治疗前和纳武单抗治疗期间收集放射学引导活检样本。治疗期间突变和新抗原的早期丧失都与临床获益相关。我们检测了 1,453 种候选新抗原，其中许多在纳武单抗治疗后癌细胞分数降低，并鉴定出 196 种可被 T 细胞识别的新肽。将这些新抗原映射到克隆动力学、进化轨迹和临床反应，揭示了对携带免疫原性新抗原的克隆的强烈选择。我们鉴定了与免疫原性相关的位置特异性氨基酸和理化特征，并制定了免疫原性评分。纳武单抗诱导的非小细胞肺癌微环境演变与黑色素瘤有一些相似之处，但也存在明显的关键差异。这项研究提供了纳武单抗作用机制背后的新抗原景观的前所未有的分子肖像。© 2024。作者，获得 Springer Nature America, Inc. 的独家许可。

Neoantigen immunoediting drives immune checkpoint blockade efficacy, yet the molecular features of neoantigens and how neoantigen immunogenicity shapes treatment response remain poorly understood. To address these questions, 80 patients with non-small cell lung cancer were enrolled in the biomarker cohort of CheckMate 153 (CA209-153), which collected radiographic guided biopsy samples before treatment and during treatment with nivolumab. Early loss of mutations and neoantigens during therapy are both associated with clinical benefit. We examined 1,453 candidate neoantigens, including many of which that had reduced cancer cell fraction after treatment with nivolumab, and identified 196 neopeptides that were recognized by T cells. Mapping these neoantigens to clonal dynamics, evolutionary trajectories and clinical response revealed a strong selection against immunogenic neoantigen-harboring clones. We identified position-specific amino acid and physiochemical features related to immunogenicity and developed an immunogenicity score. Nivolumab-induced microenvironmental evolution in non-small cell lung cancer shared some similarities with melanoma, yet critical differences were apparent. This study provides unprecedented molecular portraits of neoantigen landscapes underlying nivolumab's mechanism of action.© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.