DNMT3A突变的肿瘤浸润性克隆性造血可预测晚期非小细胞肺癌对免疫检查点抑制剂的应答

Introduction: Clonal hematopoiesis (CH) arises from the clonal expansion of hematopoietic stem cells and has been associated with an increased risk of hematologic malignancies, as well as adverse clinical outcomes across various solid tumors. Recent studies have shown that CH-mutated immune cells can infiltrate solid tumors, with notable enrichment in non-small cell lung cancer (NSCLC), where they may influence the local tumor microenvironment. However, the relevance of TI-CH in the context of immune checkpoint inhibitor (ICI) therapy remains poorly understood. Here, we investigated the immunologic characteristics of TI-CH and its association with ICI efficacy in patients with advanced NSCLC. Methods: We analyzed whole-exome sequencing (WES) data from 600 ICI-treated patients with advanced NSCLC. Variant assessment was restricted to the most recurrent CH driver genes DNMT3A , TET2 , and ASXL1 (DTA), using a variant allele frequency (VAF) cutoff of ≥ 2%. Analysis of high-depth panel sequencing with paired peripheral-blood samples confirmed that tumor-detected DTA mutations were of hematopoietic origin, leading to their classification as putative TI-CH. Results: The median depth of tumor WES data was 275.2× (range 145.9-469.5×). Putative TI-CH was identified in 12.5% of patients, with prevalence increasing with age ( R 2 = 0.83, P =0.011). TI-CH mutations occurred at low VAF (median VAF 0.052, range 0.021-0.320) and were predominantly single-mutation events. No significant difference in sequencing depth was observed between TI-CH positive and negative groups ( P =0.397).TI-CH-positive group showed a trend toward longer progression-free survival (PFS) (hazard ratio [HR] 0.77; 95% confidence interval [CI] 0.59-1.01; P =0.056) and had significantly better overall survival (OS) (HR 0.73; 95% CI 0.56-0.96; P =0.024). Especially, the DNMT3A -mutated TI-CH group exhibited significantly improved median PFS and OS compared with those without DNMT3A mutations (HR 0.57; 95% CI 0.40-0.83; P < 0.01; HR 0.51; 95% CI 0.35-0.75; P < 0.001). The DNMT3A -mutated group also demonstrated a higher response rate (45.0% vs 24.7%; P < 0.01). In contrast, TET2- and ASXL1 -mutated TI-CH groups showed no significant difference in survival outcomes.In multivariable analysis adjusting for relevant clinical factors, DNMT3A-mutated TI-CH remained independently associated with prolonged PFS (adjusted HR 0.65; 95% CI 0.44-0.95; P =0.027) and OS (adjusted HR 0.64; 95% CI 0.43-0.95; P =0.028). Conclusions: In this study, we characterized the landscape of TI-CH in advanced NSCLC, revealing that favorable efficacy of ICI is linked specifically to DNMT3A mutations. Collectively, these findings highlight DNMT3A -mutated TI-CH as a distinct predictive biomarker for ICI efficacy in advanced NSCLC.