Circulating stem-like exhausted CD8 T cells point to better outcomes in lung cancer: a brief report

Our plain-English summary of Circulating stem-like exhausted CD8 T cells point to better outcomes in lung cancer: a brief report, by L. Ye, I. Dick, T. Firth, et al (Translational Lung Cancer Research, 2025).

The study

• Authors: L. Ye, I. Dick, T. Firth, B.W. Robinson, J. Creaney, A. Redwood
• Journal: Translational Lung Cancer Research
• Published: 2025;14(11):5074-5081
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Anti-cancer T cells exhibit a spectrum of functional abilities and exhaustion levels and can be broadly categorized as stem-like exhausted T cells (Texstem) that retain cancer-killing capacity, and terminally exhausted T cells (Texterm) with limited function. Previously, we identified CD8 Texstem and Texterm cells in malignant pleural effusions (PEs) of non-small cell lung cancer (NSCLC) and mesothelioma patients. In both cancers, increased frequency of Texstem cells was associated with improved overall survival (OS). However, not all cancer patients develop PE, and sampling of PE is invasive, with associated risks. In this study we sought to determine if Texstem and Texterm cells in the blood of patients with NSCLC also associated with survival. Using flow cytometry, we quantified Texstem and Texterm in blood samples from 30 patients with advanced NSCLC and assessed their correlation with OS. In half of these cases, we also analyzed matched PE samples for comparison. Compared to PE, peripheral blood had a lower frequency of Texstem (3.8% vs. 9.4% of CD8 T cells, P=0.006) and Texterm (0.3% vs. 1.1%, P=0.002). However, both subsets were significantly correlated between the two sites (Texstem r=0.82, P<0.001; Texterm r=0.63, P=0.01). Higher Texstem cell frequency in the blood was associated with improved survival after adjusting for potentially prognostic patient and tumor related factors. When stratified into high and low groups based on the median, higher Texstem cells levels correlated with better OS [hazard ratio (HR) 0.16, 95% confidence interval (CI): 0.03-0.10, P=0.048]. As shown previously in PE, Texterm cells in the blood did not correlate with OS. Our results further support the importance of Texstem in the anti-cancer immune response and provide useful evidence for the utility of peripheral blood sampling for future studies examining exhausted T cells (Tex).

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In plain English

This brief report studied 30 patients with advanced non-small cell lung cancer (NSCLC) whose samples came from the National Centre for Asbestos Related Diseases Biobank in Perth, Australia. The article did not examine asbestos exposure. The authors used flow cytometry to measure two kinds of 'exhausted' CD8 immune cells in blood: stem-like exhausted cells (Texstem) and terminally exhausted cells (Texterm). Fifteen patients also had matching pleural fluid. In those patients, both cell types made up a smaller share of CD8 T cells in blood than in fluid (Texstem 3.8% vs. 9.4%; Texterm 0.3% vs. 1.1%), but blood and fluid levels were significantly correlated. By the end of follow-up, 24 of the 30 patients had died. After adjusting for patient and tumor factors, patients with above-median blood Texstem levels had better overall survival (hazard ratio 0.16, 95% CI 0.03 to 0.99, P=0.048). This association was not statistically significant in the unadjusted analysis. Texterm levels were not associated with survival. The authors concluded that Texstem cells warrant further study as a prognostic marker. They noted that the sample was small, retrospective and mostly adenocarcinomas.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective study of stored biobank samples (brief report), with a preliminary survival analysis
• Who was studied: 30 patients with pathologically confirmed advanced NSCLC, untreated and with no prior pleurodesis. They came from consecutive patients at Sir Charles Gairdner Hospital, Perth, Australia, and were sampled through the NCARD Biobank within three months of diagnosis. Median age 66 (range 50 to 86), 17 males, 83% former or current smokers, 26 adenocarcinomas and 4 squamous cell carcinomas. 15 had matched pleural effusion samples.
• Exposure: No asbestos exposure was assessed. The factor studied was the frequency of stem-like exhausted (Texstem) and terminally exhausted (Texterm) CD8 T cells in blood, and in pleural effusion for 15 patients, measured by flow cytometry.
• Main results:
  • In the 15 patients with paired samples, Texstem and Texterm frequencies, as percentages of CD8 T cells, were lower in blood than in pleural effusion: Texstem 3.8% vs. 9.4% (P=0.006) and Texterm 0.3% vs. 1.1% (P=0.002).
  • In the same 15 patients, blood and pleural effusion levels were correlated for Texstem (r=0.82, P<0.001) and for Texterm (r=0.63, P=0.01).
  • Among the 30 patients, 24 had died by the census date, all from lung cancer.
  • In the 30 patients, high (above-median) blood Texstem levels were associated with improved overall survival in the adjusted (multivariable) analysis: HR 0.16, 95% CI 0.03 to 0.99, P=0.048.
  • The Texstem association was statistically significant only in the adjusted analysis, not in the unadjusted one (Table 2 unadjusted HR 1.16, 95% CI 0.52 to 2.60, P=0.72).
  • Analysed as a continuous measure, Texstem predicted improved survival when controlling for sex, KRAS mutation and lines of systemic therapy (HR 0.85 per unit increase, P=0.02).
  • In the adjusted analysis, high blood Texterm was not associated with overall survival (HR 0.60, 95% CI 0.14 to 2.62, P=0.50). High PD-1+ CD8 T cell levels were not associated with it either (HR 1.24, 95% CI 0.19 to 8.12, P=0.83).
• The authors' conclusion: The authors concluded that Texstem cells warrant further study as a prognostic biomarker. They also concluded that blood analysis of circulating exhausted T cell subsets can provide insight into prognosis in advanced NSCLC.
• Limitations the authors state:
  • Small number of patients and retrospective data collection.
  • The cohort was mostly adenocarcinomas, so it is unclear whether the findings apply to squamous cell carcinomas.
  • Only seven patients received immune checkpoint blockade as first-line treatment, so the authors could not examine whether Texstem relates to response to immunotherapy.

Topics

Medical terms in this study, explained in our Lexicon: STEM, Lung Cancer, Pleural Effusion, Non-Small Cell Lung Cancer, Mesothelioma, Overall Survival, Hazard Ratio, confidence interval.

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• Integrated Analysis of Clinical Outcome of Mesenchymal Stem Cell-related Genes in Pan-cancer — M. Jiang, D. Zhu, et al. (2024)

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