Paradoxical prognostic phenomenon of plasma T-cell-derived circulating DNA level in advanced non-small cell lung cancer
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Non-tumor-derived circulating DNA (nt-cirDNA) of advanced non-small cell lung cancer (NSCLC), with unclear origination, is associated with prognosis. We hypothesized that a part of nt-cirDNA release from CD3 or CD8 tumor-infiltrating lymphocytes (TILs) could have clinical implications.
To investigate the feasibility of T-cell-derived circulating DNA (T-cirDNA) detection, real-time PCR with Taqman assay-specific rearranged TCRβ CDR3 region was conducted in plasma of 103 advanced NSCLC. CD3 and CD8-specific immunohistochemistry from biopsy specimen, was reviewed by one blinded pathologist to the T-cirDNA results. Prognostic impact including demographic characteristics was integrated into the model.
Circulating DNA was detectable in 100 patients with median of 4 ng ml−1, while median of plasma T-cirDNA was 1.71 pg ml−1. Median %ratio of T-cirDNA/cirDNA was 0.02%. T-cirDNA was categorized by %ratio of T-cirDNA/cirDNA as undetectable, low (≤ 1%) and high (> 1%). Paradoxical prognostic impact of T-cirDNA/cirDNA was observed. Undetectable and high T-cirDNA/cirDNA translated to independent favorable prognostic outcome, HR of 0.54 [95% CI 0.30–0.96] and 0.41 [95% CI 0.21–0.80], respectively. 43 patients were assessed for CD3/CD8 TILs and PD-L1. High intratumoral CD3/CD8 TILs but not stromal CD3 TILs was correlated with high T-cirDNA/cirDNA representing active T-lymphocyte activity to eliminate cancer cells. While the prognosis of undetectable T-cirDNA/cirDNA, represents inactivated naïve T-cell, was determined by the presence of EGFR mutation and had long durable response of EGFR inhibitors.
T-cirDNA could be a novel biomarker representing adaptive immune resistance in NSCLC patients. Further exploration as a predictive biomarker for EGFR inhibitors in setting of EGFR mutation might be warranted.
KeywordsNon-tumor-derived circulating DNA Non-small cell lung cancer Tumor-infiltrating lymphocytes T-cell-derived circulating nucleic acid
Epidermal growth factor receptor
Epidermal growth factor inhibitor
T-cell-receptor beta chain loci
Complementarity determining regions 3
Cluster of differentiation 3
Cluster of differentiation 8
Polymerase chain reaction
This project was financially supported by The Ratchadapiseksompotch Endowment Fund [RA60/087], Faculty of Medicine, Chulalongkorn University to CV and Chulalongkorn Academic Advancement into Its 2nd Century Project to VS and CV. The authors thank the nursing staff and laboratory technicians; Ms. Chatcha Phromma, Ms. Donlaya martman of the Medical Oncology Unit for completing, processing blood sample collection from advanced non-small cell lung cancer patients and coordinated with pathologists. We would also like to thank Dr. Bowon Weerasubpong for help with recruitment of some participants and preparation of documents for Ethics Committee and Ratchadapiseksompotch Endowment Fund consideration.
PS: methodology, investigation, data curation, writing-review and editing. SS: methodology, investigation, writing-review and editing. SK: data curation, investigation. CS: data curation, investigation. PC: supervision. VS: supervision and funding acquisition. CV: methodology, investigation, conceptualization, funding acquisition, writing-original draft, writing-review and editing.
Compliance with ethical standards
Conflict of interest
We declare that we have no conflict of interest.
The Institutional Review Board of the Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand, has approvd the following study which is to be carried out in compliance with the International guideline for human research protection as Declaration of Helsinki, The Belmont Report, CIOMS Guideline and International Conference on Harmonization in Good Clinical Practice (ICH-GCP).
Written informed was obtained from all participants.
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