Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Apr 17;74(6):173.
doi: 10.1007/s00262-025-03984-7.

Clinical and dynamic circulating cytokines profile features of long-term progression-free survival benefit to immune checkpoint inhibitors in advanced non-small cell lung cancer

Jia-Yi Deng  1   2 , Ming Gao  3 , Xue Fan  2 , Hong-Hong Yan  2 , Wei-Chi Luo  2 , Ming-Yi Yang  1   2 , Xiao-Rong Yang  1   2 , Zhi-Hong Chen  2 , Chong-Rui Xu  2 , Qing Zhou  4   5
Affiliations

Clinical and dynamic circulating cytokines profile features of long-term progression-free survival benefit to immune checkpoint inhibitors in advanced non-small cell lung cancer

Jia-Yi Deng et al. Cancer Immunol Immunother. .

Abstract

Background: Immune checkpoint inhibitors (ICIs) offer durable progression-free survival (PFS) benefit in a subset of patients with advanced non-small cell lung cancer (NSCLC). However, the predictors of long-term PFS (LTPFS) remain unclear.

Methods: Advanced NSCLC patients receiving first-line ICIs monotherapy at Guangdong Lung Cancer Institute between December 2017 and August 2022 were identified. Predictive value of different characteristics was evaluated in LTPFS (PFS ≥ 24 months) compared with short-term PFS (STPFS, PFS ≤ 3 months). Circulating cytokine levels were evaluated in paired peripheral blood samples collected before and after ICIs treatment.

Results: Among 202 patients identified and 171 included (median follow-up: 41.0 months), 44 (25.7%) experienced LTPFS, associated with a 5-year overall survival (OS) rate of 81.2%. Squamous NSCLC, intermediate or poor lung immune prognostic index (LIPI) score, and liver metastases, were negatively associated with LTPFS. High tumor mutational burden (TMB, ≥ 10 mutations/megabase) was enriched in LTPFS compared to STPFS (P = 0.002). Patients with both high TMB and PD-L1 demonstrated the greatest survival benefit from first-line ICIs monotherapy (median PFS: 24.5 months, median OS: 67.0 months). Thirty-eight peripheral blood samples were collected before and after ICIs treatment from 10 patients with LTPFS and 9 with STPFS, which revealed increased CCL11 (P = 0.013) and decreased IL1RA (P = 0.001) and IL17A (P = 0.003) levels in LTPFS after ICIs treatment.

Conclusion: Distinct clinical characteristics, including TMB, PD-L1, pathologic subtypes, LIPI score, number of organs involved, metastatic sites, and dynamic circulating cytokines profile features, can distinguish NSCLC patients achieving LTPFS from those with STPFS following first-line ICIs monotherapy.

Keywords: Cytokine; Immunotherapy; Long-term; Non-small cell lung cancer; Predictive; Survival.

PubMed Disclaimer

Conflict of interest statement

Declarations. Conflict of interests: Prof. Q. Zhou reports honoraria from AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Roche, and Sanofi outside the submitted work. The other authors have no competing interests to declare. Ethics approval statement and patient consent statement: The study was approved by the Ethics and Scientific Committees of Guangdong Provincial People’s Hospital [approval number: GDREC2019304H(R1)] and all the patients provided informed consent.

Figures

Fig. 1
Fig. 1
Flow diagram and grouping of the clinical analysis cohort. NSCLC: non-small cell lung cancer; PFS: progression-free survival; PD: progressive disease
Fig. 2
Fig. 2
Clinical outcomes in advanced NSCLC receiving first-line immunotherapy monotherapy. a Kaplan–Meier curves for PFS in the total population. b Kaplan–Meier curves for OS in the total population. c Percentage of patients with LTPFS, STPFS, and non-STPFS/non-LTPFS. d Kaplan–Meier curves for PFS among patients with LTPFS, STPFS, and non-STPFS/non-LTPFS. e Kaplan–Meier curves for OS among patients with LTPFS, STPFS, and non-STPFS/non-LTPFS
Fig. 3
Fig. 3
Clinical characteristics of LTPFS. a Stacked bar graphs showing the percentage of patients with PR, SD, PD, and NA as the best response in the LTPFS, STPFS, and non-STPFS/non-LTPFS groups. b Forest plots of univariate and multivariate analyses assessing the association of clinical characteristics with LTPFS compared to STPFS. PR: partly response; SD: stable disease; PD: progressive disease; NA: not available
Fig. 4
Fig. 4
Predictive value of PD-L1 and TMB in LTPFS. a Stacked bar graphs showing the percentage of patients with TMB ≥ 10 mut/Mb and < 10 mut/Mb in the LTPFS, STPFS, and non-STPFS/non-LTPFS groups. b Kaplan–Meier curves for PFS stratified by TMB. c Kaplan–Meier curves for OS stratified by TMB. d Stacked bar graphs showing the percentage of patients with different TMB and PD-L1 statuses in the LTPFS, STPFS, and non-STPFS/non-LTPFS groups. e Kaplan–Meier curves for PFS stratified by the combination of TMB and PD-L1 status. f Kaplan–Meier curves for OS stratified by the combination of TMB and PD-L1 status
Fig. 5
Fig. 5
Circulating biomarkers in predicting LTPFS. a Pre-treatment neutrophil–lymphocyte ratio in the LTPFS, STPFS, and non-STPFS/non-LTPFS groups. b Pre-treatment platelet-lymphocyte ratio in the LTPFS, STPFS, and non-STPFS/non-LTPFS groups. c Changes in circulating cytokines after ICIs treatment between STPFS and LTPFS
See this image and copyright information in PMC

References

    1. Liu SM, Zheng MM, Pan Y, Liu SY, Li Y, Wu YL (2023) Emerging evidence and treatment paradigm of non-small cell lung cancer. J Hematol Oncol 16:40. 10.1186/s13045-023-01436-2 - DOI - PMC - PubMed
    1. Reck M, Rodriguez-Abreu D, Robinson AG et al (2021) Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score >/= 50. J Clin Oncol 39:2339–2349. 10.1200/JCO.21.00174 - DOI - PMC - PubMed
    1. de Castro G, Jr., Kudaba I, Wu YL, et al (2023) Five-year outcomes with pembrolizumab versus chemotherapy as first-line therapy in patients with non-small-cell lung cancer and programmed death ligand-1 tumor proportion score >/= 1% in the KEYNOTE-042 study. J Clin Oncol 41:1986–1991. 10.1200/JCO.21.02885 - DOI - PMC - PubMed
    1. Perol M, Felip E, Dafni U et al (2022) Effectiveness of PD-(L)1 inhibitors alone or in combination with platinum-doublet chemotherapy in first-line (1L) non-squamous non-small-cell lung cancer (Nsq-NSCLC) with PD-L1-high expression using real-world data. Ann Oncol 33:511–521. 10.1016/j.annonc.2022.02.008 - DOI - PubMed
    1. Mok TSK, Wu YL, Kudaba I et al (2019) Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet 393:1819–1830. 10.1016/S0140-6736(18)32409-7 - DOI - PubMed

MeSH terms