Blood-based molecular and cellular biomarkers of early response to neoadjuvant PD-1 blockade in patients with non-small cell lung cancer

• Published in: Cancer cell international Vol. 24; no. 1; pp. 225 - 16
• Main Authors: Zhang, Xi, Chen, Rui, Huo, Zirong, Li, Wenqing, Jiang, Mengju, Su, Guodong, Liu, Yuru, Cai, Yu, Huang, Wuhao, Xiong, Yuyan, Wang, Shengguang
• Format: Journal Article
• Language: English
• Published: England BioMed Central 29.06.2024; BMC
• Subjects: Anti-PD-1 blockade; Biomarkers; Cancer therapies; CD4 antigen; Chemotherapy; Early therapy response; Gene expression; Genetic testing; Germline mutations; Hypotheses; Immune cell subsets; Immunological memory; Immunotherapy; Ligands; Lung cancer; Lymphocytes; Lymphocytes T; Memory cells; Mutation; Non-small cell lung cancer; Non-small cell lung carcinoma; Patients; PD-1 protein; PD-L1 protein; Peripheral blood; Predictive biomarker; Response rates; Small cell lung carcinoma; Transcriptomics; Tumor cell lines; Anti-PD-1 blockade; Early therapy response; Germline mutations; Immune cell subsets; Predictive biomarker; Non-small cell lung cancer
• ISSN: 1475-2867; 1475-2867
• DOI: 10.1186/s12935-024-03412-3

Despite the improved survival observed in PD-1/PD-L1 blockade therapy, a substantial proportion of cancer patients, including those with non-small cell lung cancer (NSCLC), still lack a response. Transcriptomic profiling was conducted on a discovery cohort comprising 100 whole blood samples, as collected multiple times from 48 healthy controls (including 43 published data) and 31 NSCLC patients that under treatment with a combination of anti-PD-1 Tislelizumab and chemotherapy. Differentially expressed genes (DEGs), simulated immune cell subsets, and germline DNA mutational markers were identified from patients achieved a pathological complete response during the early treatment cycles. The predictive values of mutational markers were further validated in an independent immunotherapy cohort of 1661 subjects, and then confirmed in genetically matched lung cancer cell lines by a co-culturing model. The gene expression of hundreds of DEGs (FDR p < 0.05, fold change < -2 or > 2) distinguished responders from healthy controls, indicating the potential to stratify patients utilizing early on-treatment features from blood. PD-1-mediated cell abundance changes in memory CD4 + and regulatory T cell subset were more significant or exclusively observed in responders. A panel of top-ranked genetic alterations showed significant associations with improved survival (p < 0.05) and heightened responsiveness to anti-PD-1 treatment in patient cohort and co-cultured cell lines. This study discovered and validated peripheral blood-based biomarkers with evident predictive efficacy for early therapy response and patient stratification before treatment for neoadjuvant PD-1 blockade in NSCLC patients.