Lee Lang Ho, Xu Xin, Mourikis Thanos, Tang Fanying, Fairchild Lauren, Ji Lexiang, Grauel Angelo L, Wagner Joel P, Szpakowski Sebastian, Pelletier Marc R, Kattenhorn Lisa, Sansregret Laurent, Costa Carlotta, Bossen Claudia, Burks Heather, Farago Anna F, Wu Jincheng
Novartis Pharmaceuticals Corporation, Cambridge, Massachusetts.
Novartis Pharmaceuticals Corporation, Basel, Switzerland.
Cancer Res Commun. 2025 Jun 1;5(6):1049-1059. doi: 10.1158/2767-9764.CRC-24-0605.
Immune checkpoint inhibitors (ICI) have demonstrated clinical efficacy in non-small cell lung cancer (NSCLC), and extensive research has been conducted to explore biomarkers predictive of ICI response. However, the impact of ICI on the tumor and tumor microenvironment at primary and acquired resistance states is understudied due to the difficulty of collecting tissue biopsies at disease progression. In this study, we leveraged clinical and real-world data to study ICI resistance. Data used in this work consist of treatment outcome information and tissue RNA sequencing data from advanced-stage NSCLC cohorts from three sources: the Tempus real-world evidence database; CANOPY-1 (NCT03631199), a phase III clinical trial in first-line NSCLC; and Stand Up To Cancer (SU2C) publication. Our results indicate higher IFNγ and T-cell exhaustion in patients' tumors at acquired resistance and low levels of B-cell and dendritic cell expression at primary resistance. The lower B-cell and dendritic cell levels may be primarily driven by prior treatment with a platinum-based chemotherapy regimen. Baseline transcriptomics data additionally suggest that innate immune cells may play an antitumor role in PD-L1<1% patients, whereas IFNγ and T-cell inflammation are more predictive of ICI treatment outcomes in PD-L1≥1% patients. Our study suggests a clear divergence of the tumor microenvironment in patients with primary versus acquired resistance and a potential role of myeloid cells in the PD-L1<1% population. These findings shed light on potential next-generation therapies to overcome ICI resistance.
ICI benefits patients with NSCLC, but resistance remains common. Our research highlights differences in tumor environments between primary and acquired resistance after ICI treatment, emphasizing distinct post-therapy approaches. Findings also suggest myeloid cells as key players in PD-L1-negative cases, guiding future treatment strategies to overcome resistance and improve outcomes.
免疫检查点抑制剂（ICI）已在非小细胞肺癌（NSCLC）中显示出临床疗效，并且已经进行了广泛的研究以探索预测ICI反应的生物标志物。然而，由于在疾病进展时收集组织活检存在困难，ICI对原发性和获得性耐药状态下肿瘤及肿瘤微环境的影响研究不足。在本研究中，我们利用临床和真实世界数据来研究ICI耐药性。本研究中使用的数据包括来自三个来源的晚期NSCLC队列的治疗结果信息和组织RNA测序数据：Tempus真实世界证据数据库；CANOPY-1（NCT03631199），一项一线NSCLC的III期临床试验；以及“挺身抗癌”（SU2C）出版物。我们的结果表明，在获得性耐药时患者肿瘤中的IFNγ和T细胞耗竭增加，而在原发性耐药时B细胞和树突状细胞表达水平较低。较低的B细胞和树突状细胞水平可能主要由先前使用铂类化疗方案治疗所驱动。基线转录组学数据还表明，先天性免疫细胞可能在PD-L1<1%的患者中发挥抗肿瘤作用，而IFNγ和T细胞炎症在PD-L1≥1%的患者中更能预测ICI治疗结果。我们的研究表明，原发性耐药与获得性耐药患者的肿瘤微环境存在明显差异，并且髓样细胞在PD-L1<1%的人群中可能发挥潜在作用。这些发现为克服ICI耐药性的潜在下一代疗法提供了线索。
ICI使NSCLC患者受益，但耐药仍然常见。我们的研究突出了ICI治疗后原发性耐药与获得性耐药之间肿瘤环境的差异，强调了不同的治疗后方法。研究结果还表明髓样细胞是PD-L1阴性病例中的关键因素，指导未来克服耐药性并改善治疗结果的治疗策略。
