The paradoxical prognostic effects of T-cell-derived circulating DNA in EGFR-mutated advanced non-small-cell lung cancer involve the crosstalk between heme biosynthesis and immune microenvironment
Issued Date
2025-12-01
Resource Type
eISSN
20452322
Scopus ID
2-s2.0-105019103999
Journal Title
Scientific Reports
Volume
15
Issue
1
Rights Holder(s)
SCOPUS
Bibliographic Citation
Scientific Reports Vol.15 No.1 (2025)
Suggested Citation
Zungsontiporn N., Ngamchokwathana C., Santisukwongchote S., Sitthideatphaiboon P., Leelayuwatanakul N., Korphaisarn K., Chantranuwat P., Sriuranpong V., Aporntewan C., Hirankarn N., Vinayanuwattikun C. The paradoxical prognostic effects of T-cell-derived circulating DNA in EGFR-mutated advanced non-small-cell lung cancer involve the crosstalk between heme biosynthesis and immune microenvironment. Scientific Reports Vol.15 No.1 (2025). doi:10.1038/s41598-025-20307-z Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/112759
Title
The paradoxical prognostic effects of T-cell-derived circulating DNA in EGFR-mutated advanced non-small-cell lung cancer involve the crosstalk between heme biosynthesis and immune microenvironment
Corresponding Author(s)
Other Contributor(s)
Abstract
The paradoxical impact of T-cell-derived circulating DNA (T-cirDNA) and prognostication in advanced non-small cell lung cancer (NSCLC) has been reported. Further exploration was conducted in 158 EGFR-mutated NSCLC participants who received EGFR inhibitors, correlated with tumor PD-L1 score, CD8 tumor-infiltrating lymphocytes (TILs), and bulk RNA sequencing. We categorized T-cirDNA levels into three groups based on a previous study: undetectable (26.8%), low (≤ 1% ratio; 36.6%), and high (> 1% ratio; 36.6%). Undetectable and high T-cirDNA groups were independent factors correlated with favorable outcomes. The presence of intra-tumoral CD8 TILs (≥ 1%) was also an independent unfavorable prognostic factor; however, it had the lowest proportion in the low T-cirDNA group (16%). Tumor-immune microenvironment (TIME)-related gene set enrichment analysis revealed an overlapped significant heme biosynthesis signature correlated with poor outcome and diverse T-cirDNA group. Despite a high heme biosynthesis signature score in the undetectable T-cirDNA group, inverse correlation with CIBERSORT-activated CD4 memory T-cells was found (R − 0.79, p-value 0.019). Those findings were contrary to the low and high T-cirDNA groups. The significant contribution of heme biosynthesis was the overexpression of CPOX. Crosstalk of EGFR and COPX function prohibits the activation of CD4 + memory T-cells or the spatial intra-tumoral CD8 + T-cells. Undetectable T-cirDNA represents inactivated naïve T-cells and solely active downstream EGFR signaling.