Longitudinal trajectories of peripheral blood lymphocyte subsets and PD-1 expression as dynamic prognostic markers in lung cancer
- 1Department of Pathology, The China-Japan Friendship Hospital
- 2National Center for Respiratory Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital
Abstract
Background: Lung cancer is characterized by strong heterogeneity and dynamic evolution. Peripheral immune subsets and checkpoint molecules reflect tumor–immune interactions, but static biomarkers cannot capture temporal changes. This study assessed whether longitudinal trajectories of lymphocyte subsets and PD-1 expression could provide real-time risk stratification for progression-free survival (PFS).
Methods: This retrospective cohort included 442 lung cancer patients with prospectively collected peripheral blood samples from an institutional biobank. Samples were obtained at baseline and multiple follow-ups. Frequencies of CD4 ⁺ T cells, CD8 ⁺ T cells, and natural killer (NK) cells, as well as PD-1 levels on CD4 ⁺ and CD8 ⁺ T cells, were measured by flow cytometry. Kaplan–Meier and time-dependent Cox models evaluated associations with PFS; discrimination was assessed via Harrell’s C-index.
Results: Mean age was 63.1 ± 8.4 years; 76% were male, 77% had non-small cell lung cancer (NSCLC), and 81% presented at late stage. Progressive disease (PD) occurred in 13.1%. Longitudinal analysis revealed distinct immune alterations in PD patients. In single-immune-variable time-dependent Cox models, time-updated CD8 ⁺ /PD-1 was an independent risk factor (HR = 9.40, 95% CI: 1.51–58.7, p = 0.017), while the other immune subsets were not significant in the overall population. Subgroup analyses showed consistent adverse effects of CD8 ⁺ /PD-1 in NSCLC (HR = 545.5, p = 0.003), SCLC (HR = 666.0, p = 0.034), early-stage (HR = 2067.7, p = 0.015), and late-stage (HR = 248.8, p = 0.005) patients. Time-updated CD4 ⁺ /PD-1 was protective in NSCLC (HR = 0.003, p = 0.009) and late-stage (HR = 0.005, p = 0.012). High baseline CD8 ⁺ /PD-1 predicted shorter median PFS (p=0.020). The time-updated model showed good discrimination (C-index 0.694).
Conclusion: Dynamic CD8 ⁺ /PD-1 trajectories provide independent, adverse prognostic value, whereas preserved CD4 ⁺ /PD-1 reflects immune competence in specific subgroups. Serial monitoring enables real-time risk assessment and personalized management in lung cancer.
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BibTeX
@article{chen2026longitudinal,
title = {{Longitudinal trajectories of peripheral blood lymphocyte subsets and PD-1 expression as dynamic prognostic markers in lung cancer}},
author = {Huang Chen and Ruiying Jiang and Yuhan Wu and Bin Tong and Lichao Jiang and Qixin Huang and Yao Liu and Qianqian Feng and Fang Yu and Rui Yang and Zhengyuan Guan and Ye Wang and Bei Wang and Dingrong Zhong and Meng Yang},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1898409},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1898409/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Longitudinal trajectories of peripheral blood lymphocyte subsets and PD-1 expression as dynamic prognostic markers in lung cancer
AU - Huang Chen
AU - Ruiying Jiang
AU - Yuhan Wu
AU - Bin Tong
AU - Lichao Jiang
AU - Qixin Huang
AU - Yao Liu
AU - Qianqian Feng
AU - Fang Yu
AU - Rui Yang
AU - Zhengyuan Guan
AU - Ye Wang
AU - Bei Wang
AU - Dingrong Zhong
AU - Meng Yang
PY - 2026
DA - 2026/10/29
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1898409
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1898409/full
AB - Background: Lung cancer is characterized by strong heterogeneity and dynamic evolution. Peripheral immune subsets and checkpoint molecules reflect tumor–immune interactions, but static biomarkers cannot capture temporal changes. This study assessed whether longitudinal trajectories of lymphocyte subsets and PD-1 expression could provide real-time risk stratification for progression-free survival (PFS). Methods: This retrospective cohort included 442 lung cancer patients with prospectively collected peripheral blood samples from an institutional biobank. Samples were obtained at baseline and multiple follow-ups. Frequencies of CD4 ⁺ T cells, CD8 ⁺ T cells, and natural killer (NK) cells, as well as PD-1 levels on CD4 ⁺ and CD8 ⁺ T cells, were measured by flow cytometry. Kaplan–Meier and time-dependent Cox models evaluated associations with PFS; discrimination was assessed via Harrell’s C-index. Results: Mean age was 63.1 ± 8.4 years; 76% were male, 77% had non-small cell lung cancer (NSCLC), and 81% presented at late stage. Progressive disease (PD) occurred in 13.1%. Longitudinal analysis revealed distinct immune alterations in PD patients. In single-immune-variable time-dependent Cox models, time-updated CD8 ⁺ /PD-1 was an independent risk factor (HR = 9.40, 95% CI: 1.51–58.7, p = 0.017), while the other immune subsets were not significant in the overall population. Subgroup analyses showed consistent adverse effects of CD8 ⁺ /PD-1 in NSCLC (HR = 545.5, p = 0.003), SCLC (HR = 666.0, p = 0.034), early-stage (HR = 2067.7, p = 0.015), and late-stage (HR = 248.8, p = 0.005) patients. Time-updated CD4 ⁺ /PD-1 was protective in NSCLC (HR = 0.003, p = 0.009) and late-stage (HR = 0.005, p = 0.012). High baseline CD8 ⁺ /PD-1 predicted shorter median PFS (p=0.020). The time-updated model showed good discrimination (C-index 0.694). Conclusion: Dynamic CD8 ⁺ /PD-1 trajectories provide independent, adverse prognostic value, whereas preserved CD4 ⁺ /PD-1 reflects immune competence in specific subgroups. Serial monitoring enables real-time risk assessment and personalized management in lung cancer.
SN - 1664-3224
ER -