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. 2025 Nov 30;14(11):5074-5081.
doi: 10.21037/tlcr-2025-509. Epub 2025 Nov 27.

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

Linda Ye  1   2 , Ian Dick  1   3 , Tina Firth  1   4 , Bruce W Robinson  1   3   5 , Jenette Creaney  1   4   5 , Alec Redwood  1   3   4
Affiliations

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

Linda Ye et al. Transl Lung Cancer Res. .

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).

Keywords: T cell; exhaustion; lung cancer.

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Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-509/coif). L.Y. received a Charlies Foundation for Research (grant No. MRGP22-23_15) for funding of this project. B.W.R. received funding for this project from the NHMRC (grant No. 2029268) and the US Department of Defense (grant No. CA190450). J.C. received a Sir Charles Gairdner Hospital Charlies Foundation for Research grant (grant No. MRGP22-23_15), a fellowship from the Cancer Council of Western Australia (CCWA) and a US Department of Defense (grant No. CA190450). A.R. received funding for this project from the NHMRC (grant No. 2029268) and the US Department of Defense (grant No. CA190450). The other authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Characterization of exhausted CD8 T cell subsets in PBMC of metastatic NSCLC patients (n=30). (A) Identification of exhausted CD8 T cell subsets in PBMC of NSCLC patients. Representative flow cytometry plot of Texstem and Texterm CD8 T cell subsets according to PD-1, CD39 and CD28 expression in a NSCLC patient. Gated on live CD3+CD4–CD8+ PBMC T cells. (B) Percentages of Texstem and Texterm within CD8 T cells from PBMC of NSCLC patients. The median value is presented. Comparisons made between groups were performed using Wilcoxon matched-pairs signed-rank test. ****, P<0.0001. NSCLC, non-small cell lung cancer; PBMC, peripheral blood mononuclear cells; PD-1, programmed death-1; Texstem, stem like exhausted T cells; Texterm, terminally exhausted T cells.
Figure 2
Figure 2
Comparing the frequencies of T-cell subsets between pleural effusion and PBMC (n=15). (A) PBMC had higher proportions of CD8 and lower proportions of CD4 T cells compared to PE. The median value is presented. Comparisons made between groups were performed using Wilcoxon matched-pairs signed-rank test. (B) PBMC and PE CD8 and CD4 T cells show positive correlation. Pearson’s correlation. (C) PBMC contained significantly lower frequencies of Texstem and Texterm compared to PE. (D) PBMC and PE Texstem and Texterm show positive correlation. *, P<0.05; **, P<0.01; ***, P<0.001; ****, P<0.0001. PBMC, peripheral blood mononuclear cells; PE, pleural effusion; Texstem, stem like exhausted T cells; Texterm, terminally exhausted T cells.
Figure 3
Figure 3
Correlating PBMC Tex subsets with overall survival in patients with advanced NSCLC (n=30). (A) Texstem, but not (B) Texterm or (C) PD-1+ cells correlate with improved survival in NSCLC patients (n=30). Multivariate Cox regression analysis of overall survival plotted according to abundance of PBMC exhausted CD8 T cell subsets dichotomized at the median. HR, hazard ratio; NSCLC, non-small cell lung cancer; PD-1, programmed death-1; PBMC, peripheral blood mononuclear cells; Texstem, stem like exhausted T cells; Texterm, terminally exhausted T cells.
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