Clinical and Molecular Features of Acquired Resistance to Immunotherapy in Non-Small Cell Lung Cancer

PD-(L)1 blockade has been shown to promote durable responses in non-small cell lung cancer (NSCLC) patients and has been rapidly incorporated into the treatment regimens for many with advanced disease. Despite this, mechanisms of acquired resistance (AR) to PD-(L)1 have not been well understood. To address the clinical and molecular landscape of AR to PD-(L)1 blockade in NSCLC patients, a large clinical cohort of AR to PD-(L)1 blockade in lung cancer was examined. In conjunction, a systematic genomic and transcriptomic analysis in a subset of patients (n = 29) with available tissue samples was conducted. To investigate the molecular mechanisms of AR to PD-1 blockade from pre- and/or post-treatment tumors, microarray-based whole transcriptome expression data for 29 tumor samples, and whole exome sequencing (WES) data from 34 tumor samples was generated from this subset. Microarray data was uploaded to the Gene Expression Omnibus (GEO) database. Most AR tumors showed retained or increased inflammatory characteristics with significant upregulation of IFNγ which was suggestive of persistent albeit insufficient anti-tumor immune response. This finding expounds upon the prior pre-clinical and translational data supporting the intricate role of IFNγ in sensitivity and resistance to immunotherapy. Whereas initial IFNγ exposure may be fundamental to T cell activation (a hallmark of immune response), persistent IFNγ related effects and upregulation may potentially signal immune dysfunction and IFNγ insensitivity in contrast. The inflammatory phenotypes identified have implications for future rational development of new immunotherapy strategies for patients with AR. ]]>

PD-(L)1阻断治疗（PD-(L)1 blockade）已被证实可在非小细胞肺癌（non-small cell lung cancer, NSCLC）患者中诱导持久应答，并已快速被纳入众多晚期疾病患者的治疗方案。尽管如此，针对PD-(L)1的获得性耐药（acquired resistance, AR）机制仍未被充分阐明。为阐明非小细胞肺癌患者对PD-(L)1阻断治疗产生获得性耐药的临床与分子特征，研究人员针对肺癌中PD-(L)1阻断治疗获得性耐药的大型临床队列开展了分析。同时，对其中29例具备可用组织样本的患者亚组进行了系统性基因组与转录组分析。为探究治疗前和/或治疗后肿瘤中PD-1阻断治疗获得性耐药的分子机制，该亚组生成了29份肿瘤样本的基于微阵列的全转录组表达谱数据，以及34份肿瘤样本的全外显子组测序（whole exome sequencing, WES）数据。微阵列数据已上传至基因表达综合数据库（Gene Expression Omnibus, GEO）。多数获得性耐药肿瘤呈现出炎症特征的保留或增强，且干扰素γ（IFNγ）显著上调，这提示尽管抗肿瘤免疫应答持续存在但并未发挥足够的抗肿瘤效应。这一发现进一步阐释了此前临床前与转化研究中支持干扰素γ在免疫治疗敏感性与耐药性中发挥复杂作用的相关数据。初始干扰素γ暴露或许是T细胞活化（T cell activation）的基础——这是免疫应答的标志性事件，而与之相反，持续的干扰素γ相关效应及其上调可能预示免疫功能异常与干扰素γ不敏感。本次鉴定出的炎症表型，可为未来针对获得性耐药患者的新型免疫治疗策略的合理开发提供参考依据。