Journal Article

Tumor microenvironment remodeling after neoadjuvant immunotherapy in non-small cell lung cancer revealed by single-cell RNA sequencing

Jiang, Gening, Ma, Qiang, Zhang, Peng, Xia, Haoran, Li, Dianke, Sun, Fenghuan, Wang, Chenfei, Li, Shuangyi, Chen, Yan, Yu, Huansha, Hu, Junjie, Zhang, Jing, Sun, Liangdong, Bian, Dongliang, Fan, Pengyu, Zhang, Lele, Yan, Yilv, Wang, Jin, Han, Ya, Zhu, Xinsheng

2023

Overview

Background Immunotherapy has revolutionized cancer treatment, but most patients are refractory to immunotherapy or acquire resistance, with the underlying mechanisms remaining to be explored. Methods We characterized the transcriptomes of ~92,000 single cells from 3 pre-treatment and 12 post-treatment patients with non-small cell lung cancer (NSCLC) who received neoadjuvant PD-1 blockade combined with chemotherapy. The 12 post-treatment samples were categorized into two groups based on pathologic response: major pathologic response (MPR; n = 4) and non-MPR (NMPR; n = 8). Results Distinct therapy-induced cancer cell transcriptomes were associated with clinical response. Cancer cells from MPR patients exhibited a signature of activated antigen presentation via major histocompatibility complex class II (MHC-II). Further, the transcriptional signatures of FCRL4+FCRL5+ memory B cells and CD16+CX3CR1+ monocytes were enriched in MPR patients and are predictors of immunotherapy response. Cancer cells from NMPR patients exhibited overexpression of estrogen metabolism enzymes and elevated serum estradiol. In all patients, therapy promoted expansion and activation of cytotoxic T cells and CD16+ NK cells, reduction of immunosuppressive Tregs, and activation of memory CD8+T cells into an effector phenotype. Tissue-resident macrophages were expanded after therapy, and tumor-associated macrophages (TAMs) were remodeled into a neutral instead of an anti-tumor phenotype. We revealed the heterogeneity of neutrophils during immunotherapy and identified an aged CCL3+ neutrophil subset was decreased in MPR patients. The aged CCL3+ neutrophils were predicted to interact with SPP1+ TAMs through a positive feedback loop to contribute to a poor therapy response. Conclusions Neoadjuvant PD-1 blockade combined with chemotherapy led to distinct NSCLC tumor microenvironment transcriptomes that correlated with therapy response. Although limited by a small patient sample size subjected to combination therapy, this study provides novel biomarkers to predict therapy response and suggests potential strategies to overcome immunotherapy resistance.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: 17β-Estradiol / Adjuvant treatment / Antibodies / Antigen presentation / Antigens / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Biopsy / Blood / Cancer / Cancer Research / Cancer therapies / Carcinoma, Non-Small-Cell Lung / CCL3 protein / CD16 antigen / CD8 antigen / Cell activation / Cells / Chemotherapy / CX3CR1 protein / Cytotoxicity / Drug therapy / Effector cells / Estrogen / Estrogens / Gas flow / Health aspects / Human Genetics / Humans / Immunological memory / Immunotherapy / Leukocytes (neutrophilic) / Lung cancer / Lung cancer, Non-small cell / Lung cancer, Small cell / Lung Neoplasms / Lymphocytes / Lymphocytes B / Lymphocytes T / Macrophages / Major histocompatibility complex / Medicine/Public Health / Memory cells / Metabolomics / Monocytes / Mutation / Neoadjuvant Therapy / Neutrophil / Non-small cell lung cancer / Non-small cell lung carcinoma / Patients / PD-1 protein / Phenotypes / Physiological aspects / Programmed Cell Death 1 Receptor / RNA / RNA sequencing / Scientific equipment and supplies industry / Sequence Analysis, RNA / Single cell / Surgery / Systems Biology / Tumor Microenvironment / Tumors