Zhao Jiaqi, Liu Maolin, Zhu Chongmei, Li Zhuolin, Liu Zuhui, Abulizi Dilimulati, Liu Siqing, Wang Xin, Yang Haoxian X, Hou Xue
Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, No. 651, Dongfeng East Road, Guangzhou City, Guangdong Province, 510060, PR China.
Department of Pathology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, PR China.
Cell Oncol (Dordr). 2025 May 13. doi: 10.1007/s13402-025-01067-4.
Immunotherapy has transformed the neoadjuvant treatment landscape for patients with resectable locally advanced non-small cell lung cancer (NSCLC). However, a population of patients cannot obtain major pathologic response (MPR) and thus benefit less from neoadjuvant immunotherapy, highlighting the need to uncover the underlying mechanisms driving resistance to immunotherapy.
Two published single-cell RNA sequencing (scRNA-seq) datasets were used to analyze the subsets of cancer-associated fibroblasts (CAFs) and T cells and functional alterations after neoadjuvant immunotherapy. The stromal signature predicting ICI response was identified and validated using our local cohort with stage III NSCLC receiving neoadjuvant immunotherapy and other 4 public ICI transcriptomic cohorts.
Non-MPR tumors showed higher enrichment of CAFs and increased extracellular matrix deposition than MPR tumors, as suggested by bioinformatic analysis. Further, CAF-mediated immune suppression may involve reciprocal interactions with T cells in addition to a physical barrier mechanism. In contrast, MPR tumors demonstrated therapy-induced activation of memory CD8 T cells into an effector phenotype. Additionally, neoadjuvant immunotherapy resulted in expansion of precursor exhausted T (Texp) cells, which were remodeled into an anti-tumor phenotype. Notably, we identified metabolic heterogeneity within distinct T cell clusters during immunotherapy. Methionine recycling emerged as a predictive factor for T-cell differentiation and a favorable pathological response. The stromal signature was associated with ICI response, and this association was validated in five independent ICI transcriptomic cohorts.
These discoveries underscore the distinct tumor microenvironments in MPR and non-MPR patients and may elucidate resistance mechanisms to immunotherapy in NSCLC.
免疫疗法已经改变了可切除的局部晚期非小细胞肺癌（NSCLC）患者的新辅助治疗格局。然而，有一部分患者无法获得主要病理缓解（MPR），因此从新辅助免疫疗法中获益较少，这凸显了揭示免疫疗法耐药潜在机制的必要性。
使用两个已发表的单细胞RNA测序（scRNA-seq）数据集来分析癌症相关成纤维细胞（CAF）和T细胞的亚群以及新辅助免疫疗法后的功能改变。使用我们当地接受新辅助免疫疗法的III期NSCLC队列以及其他4个公开的免疫检查点抑制剂（ICI）转录组队列来鉴定和验证预测ICI反应的基质特征。
生物信息学分析表明，与MPR肿瘤相比，非MPR肿瘤显示出更高的CAF富集和细胞外基质沉积增加。此外，CAF介导的免疫抑制可能除了物理屏障机制外，还涉及与T细胞的相互作用。相比之下，MPR肿瘤表现出治疗诱导的记忆性CD8 T细胞激活为效应表型。此外，新辅助免疫疗法导致前体耗竭T（Texp）细胞扩增，这些细胞被重塑为抗肿瘤表型。值得注意的是，我们在免疫治疗期间不同T细胞簇中发现了代谢异质性。甲硫氨酸循环成为T细胞分化和良好病理反应的预测因素。基质特征与ICI反应相关，并且这种关联在五个独立的ICI转录组队列中得到验证。
这些发现强调了MPR和非MPR患者中不同的肿瘤微环境，并可能阐明NSCLC中免疫疗法的耐药机制。
