Cancer-associated fibroblasts and metabolic reprogramming predict pathologic response to neoadjuvant PD-1 blockade in resected non-small cell lung cancer.

IF 4.9 2区医学 Q2 CELL BIOLOGY

Cellular Oncology Pub Date : 2025-05-13 DOI:10.1007/s13402-025-01067-4

Jiaqi Zhao, Maolin Liu, Chongmei Zhu, Zhuolin Li, Zuhui Liu, Dilimulati Abulizi, Siqing Liu, Xin Wang, Haoxian Yang, Xue Hou

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引用次数: 0

Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: These discoveries underscore the distinct tumor microenvironments in MPR and non-MPR patients and may elucidate resistance mechanisms to immunotherapy in NSCLC.

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癌症相关成纤维细胞和代谢重编程预测切除的非小细胞肺癌对新辅助PD-1阻断的病理反应。

目的：免疫疗法已经改变了可切除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反应（MPR），因此从新辅助免疫治疗中获益较少，因此需要揭示导致免疫治疗耐药的潜在机制。方法：使用两个已发表的单细胞RNA测序（scRNA-seq）数据集分析癌症相关成纤维细胞（CAFs）和T细胞亚群以及新辅助免疫治疗后的功能改变。通过接受新辅助免疫治疗的III期NSCLC本地队列和其他4个公共ICI转录组队列，确定并验证了预测ICI反应的基质特征。结果：生物信息学分析显示，与MPR肿瘤相比，非MPR肿瘤CAFs的富集程度更高，细胞外基质沉积增加。此外，除了物理屏障机制外，caf介导的免疫抑制可能涉及与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，新辅助免疫治疗导致前体耗竭T细胞（Texp）的扩增，这些细胞被重塑为抗肿瘤表型。值得注意的是，我们在免疫治疗过程中发现了不同T细胞群的代谢异质性。蛋氨酸循环成为t细胞分化和有利病理反应的预测因素。基质特征与ICI反应相关，这种关联在五个独立的ICI转录组学队列中得到了验证。结论：这些发现强调了MPR和非MPR患者不同的肿瘤微环境，并可能阐明非小细胞肺癌免疫治疗的耐药机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cellular Oncology ONCOLOGY-CELL BIOLOGY

CiteScore

10.30

自引率

1.50%

发文量

审稿时长

12 months

期刊介绍： The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.