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

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

Linda Ye1,2 ORCID logo, Ian Dick1,3, Tina Firth1,4, Bruce W. Robinson1,3,5, Jenette Creaney1,4,5, Alec Redwood1,3,4

1National Centre for Asbestos Related Diseases, Medical School, University of Western Australia, Nedlands, Australia; 2Department of Medical Oncology, Royal Perth Hospital, Perth, Australia; 3School of Biomedical Sciences, University of Western Australia, Nedlands, Australia; 4Institute for Respiratory Health, University of Western Australia, Nedlands, Australia; 5Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Australia

Correspondence to: Dr. Linda Ye, MBBS, FRACP. National Centre for Asbestos Related Diseases, Medical School, University of Western Australia, Level 5 QQ building, QEII Medical Centre, Nedlands 6009, WA, Australia; Department of Medical Oncology, Royal Perth Hospital, Perth 6000, Australia. Email: yang.ye@health.wa.gov.au.

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

Submitted May 04, 2025. Accepted for publication Aug 05, 2025. Published online Nov 27, 2025.

doi: 10.21037/tlcr-2025-509

The anti-cancer immune response is achieved in part by CD8 T cells recognizing cancer-associated epitopes (1). However, sustained T-cell receptor (TCR) stimulation of tumor-specific T cells results in suppression of their effector functions and eventually a numerical decline, a phenomenon often described as exhaustion. This dysfunction contributes to tumor immune escape and metastasis (2,3).

Exhausted T cells (Tex) are recognized as a dynamic population that progress through a spectrum of exhaustion states, from stem-like to terminally exhausted phenotypes, resulting in a heterogenous population of Tex. Broadly, Tex comprise of precursor exhausted or stem-like Tex (Texstem), that retain effector function and reinvigoration potential, that progressively differentiate into terminally Tex (Texterm) that lose effector and proliferative function (4,5). Texstem have been described as a source of effector-like T cells in chronic viral infections (6) and cancer, and are suggested to be the primary T-cell subset responding to programmed death-1 (PD-1)/ligand-1 (PD-L1) blockade therapy (7,8).

T-cell exhaustion, as assessed by PD-1 expression on intratumoral lymphocytes, has been associated with poor patient survival across a number of different cancer types (9-14). However, less is known about the role of specific subsets of these cells. In our recent study we demonstrated that Texstem and Texterm in malignant pleural effusions (PEs) of patients with non-small cell lung cancer (NSCLC) and mesothelioma are distinct in their prognostic significance (15). Specifically, a higher frequency of Texstem cells was significantly associated with improved overall survival (OS) in both cancer types, whereas Texterm cells showed no correlation with survival outcomes.

PE are a feature of advanced NSCLC and are common in mesothelioma, offering a unique tumor microenvironment where immune and tumor cells interact. PE is frequently lymphocyte-rich, making it a valuable source for studying tumor-associated immune responses, particularly Tex populations. However, only 15–40% of patients with advanced thoracic malignancies develop PE (2,16-18) and pleural fluid sampling requires invasive procedures such as thoracentesis or indwelling pleural catheter insertion which carry inherent risks of morbidity and mortality. We therefore investigated whether blood-based Texstem cell measurements could serve as a viable alternative, offering the advantage of greater accessibility and broader clinical applicability. However, prior studies indicate that peripheral blood contains fewer Tex compared to PE (19-21), raising the question of whether Texstem levels in blood accurately reflect those in the tumor microenvironment. To address this, we assessed the feasibility of using blood-based Texstem measurements as a potential prognostic biomarker. We present this article in accordance with the MDAR reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-509/rc).

Clinical samples were obtained through the National Centre for Asbestos Related Diseases (NCARD) Biobank, which collects specimens under standardized protocols from consecutive patients attending Sir Charles Gairdner Hospital, Perth, Australia. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Sir Charles Gairdner Osbourne Park Health Care Group Human Research Ethics Committee EC00271 (PRN 0000001516) and informed consent was obtained from all individual participants.

For this study, we selected NSCLC cases with a confirmed pathological diagnosis, no prior pleurodesis or treatment, and sufficient samples for flow cytometry analysis collected within three months of diagnosis. A total of 30 patients met these criteria and were included. Peripheral blood mononuclear cells (PBMCs) were analyzed from all 30 patients, with matched PBMC and PE samples available for 15 cases.

The median age of the cohort was 66 years (50–86 years) and there were 17 males (57%). Most patients were former or current smokers (83%). The majority of patients had non-squamous carcinoma (87%), all of which were adenocarcinomas (ADCs) and four patients had squamous cell carcinomas (SCCs) (13%). Molecular testing in patients with ADC showed 8 (31%) had a Kirsten rat sarcoma virus (KRAS) mutation and 5 (19%) had an epidermal growth factor receptor (EGFR) mutation. Tumor PD-L1 tumor proportion score (TPS) was only available for 22 patients and twelve patients received at least one line of systemic therapy (Table 1).

Table 1

Clinicopathological characteristics of patients with advanced non-small cell lung cancer (n=30)

Variable Subgroup Value
Age (years) – 66 [50–86]
Sex Female 13 [43]
Male 17 [57]
Histopathology Squamous 4 [13]
Non-squamous 26 [87]
EGFR† Mutant 5 [19]
Wildtype 21 [81]
KRAS† Mutant 8 [31]
Wildtype 18 [69]
PD-L1‡ 0 5 [23]
1–49 8 [36]
≥50 9 [41]
Smoking Never 5 [17]
Ex/current 25 [83]
ECOG 0–1 18 [60]
2–4 12 [40]
Charlson Comorbidities Index 7–9 17 [57]
10–13 13 [43]
Lines of systemic therapy 0 12 [40]
1 7 [23]
2 or more 11 [37]
First line systemic therapy agent Chemotherapy 8 [44]
Immunotherapy 5 [28]
Targeted therapy 3 [17]
Chemoimmunotherapy 2 [11]

Data are presented as median [range] or n [%]. †, EGFR and KRAS testing only performed in non-squamous carcinomas (n=26); ‡, PD-L1 results available for 22 patients. ECOG, Eastern Cooperative Oncology Group; PD-L1, programmed death ligand-1.

PBMC had been isolated using Ficoll-Paque density gradient separation from blood and cryopreserved in RPMI-1640 media, 50% newborn calf serum (NCS) and 10% dimethyl sulfoxide (DMSO) until use. For this study, PE and PBMCs were thawed, washed, and stained for flow cytometry, as previously described (15). Briefly, cells were first stained with a fixable viability dye, followed by surface marker staining using fluorochrome-conjugated antibodies targeting CD3 (BioLegend, San Diego, USA, UCHT1), CD4 (BD Biosciences, San Jose, USA, SK3 or RPA-T4), CD8 (BD Biosciences, RPA-T8), PD-1 (BD Biosciences, EH12.1), CD39 (BD Biosciences, Tu66), and CD28 (BioLegend, CD28.2). Samples were acquired using LSR Fortessa, and data were analyzed with FlowJo (v10.6).

Tex subsets were detected in peripheral blood using flow cytometry (Figure 1A). Texstem cells were defined as PD-1mid CD39⁻ CD28⁺ CD8+ and Texterm as PD-1hi CD39⁺ CD8⁺ T cells, based on established Tex subset definitions (15,22). PD-1 is an inhibitory receptor upregulated upon TCR-mediated activation, marking Tex in chronic stimulation settings (23). CD39, an ectoenzyme in the ATP-adenosine pathway, has been linked to terminal exhaustion, poor effector function, neoantigen specificity, and tumor growth (24-26). In contrast CD28 is a co-stimulatory molecular that is a marker of functional stem-like CD8 T cells (22,27).

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.

Texstem cells were detected in all 30 patient PBMC samples, with frequencies ranging from 0.1% to 18.0% of CD8⁺ T cells (mean 5.1%±4.8%, median 4.3%). Texterm cells were detected in 27 patients, while three patients lacked detectable Texterm populations. Texterm frequencies ranged from 0% to 2.5% of CD8⁺ T cells (mean 0.4%±0.5%, median 0.3%). All Tex subsets were gated on live CD3+ CD8+ CD4− T cells following the gating strategy shown in Figure S1. Consistent with previous observations in PE samples (15), Texstem frequencies were significantly higher than Texterm (P<0.001) (Figure 1B).

Fifteen patients had paired PE available for comparison. Compared to PE, PBMC samples contained higher proportions of CD8 and lower proportions of CD4 T cells (Figure 2A) and both showed strong positive correlation between the two sites (Figure 2B). Texstem and Texterm frequencies were significantly lower in PBMC compared to PE (3.8% vs. 9.4%, P=0.006 and 0.3% vs. 1.1%, P=0.002, respectively) (Figure 2C). Despite these differences, Texstem and Texterm frequencies remained significantly correlated between PBMC and PE (Texstem: r=0.82, P<0.001; Texterm: r=0.63, P=0.01) (Figure 2D).

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.

Previously we have found that higher Texstem frequencies in PE samples were associated with improved OS in patients with advanced NSCLC and mesothelioma (15). Based on these findings, we conducted a preliminary analysis of the PBMC results from the 30 patients to assess potential associations with OS. OS was defined as the time from histological diagnosis until death or date of census. At the time of censor, 24 of the 30 patients had died, all secondary to lung cancer. Consistent with our previous findings in PE samples, multivariable analysis showed that high Texstem levels in PBMC were associated with improved OS when categorized as high versus low, dichotomized by the median [hazard ratio (HR) 0.16, 95% confidence interval (CI): 0.03–0.99, P=0.048] (Figure 3A, Table 2). In contrast, Texterm and PD-1+ CD8 T cells were not associated with OS (Texterm HR 0.60, 95% CI: 0.14–2.62, P=0.50, PD-1+ HR 1.24, 95% CI: 0.19–8.12, P=0.83) (Figure 3B,3C, Table 2). As Texstem levels demonstrated a statically significant association with OS only in multivariate and not univariate analysis, we performed regression modelling using individual and various combinations of covariates and found that Texstem becomes a significant predictor of OS when controlled for patient sex, ECOG status, smoking history, EGFR and KRAS mutation status, and the number of lines of systemic therapies received. When analysed as a continuous variable, Texstem predicted for improved OS when controlling for patient sex, KRAS mutation and the number of lines of systemic therapy (per unit increase HR 0.85, P=0.02), suggesting that these covariates are key confounders in this analysis.

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.

Table 2

Cox regression model showing hazard ratios for overall survival conferred by variables in NSCLC patients (n=30)

Variable Subgroup Univariate Multivariate†,‡
HR 95% CI P HR 95% CI P
Age Per unit increase 1.03 0.99–1.07 0.11
Sex M vs. F 0.87 0.39–1.95 0.74
Smoking Former/current vs. never 2.08 0.61–7.09 0.24
ECOG 2–4 vs. 0–1 1.43 0.61–3.38 0.41
Charlson Comorbidities Index 10–13 vs. 7–9 1.43 0.64–3.21 0.38
Histology SCC vs. ADC 0.41 0.09–1.81 0.24
EGFR Mutant vs. WT 0.68 0.22–2.04 0.21
KRAS Mutant vs. WT 1.01 0.40–2.56 0.98
Lines of therapy 0 –
1 0.51 0.19–1.38 0.51
≥2 0.10 0.02–0.52 0.006
Texstem High vs. low§ 1.16 0.52–2.60 0.72 0.16 0.03–0.99 0.048
Texterm High vs. low§ 1.42 0.61–3.30 0.41 0.60 0.14–2.62 0.50
Texstem: Texterm ratio Per unit increase 1.00 0.99–1.00 0.74 1.00 1.00–1.01 0.19
PD-1+ High vs. low§ 1.11 0.49–2.53 0.80 1.24 0.19–8.12 0.83

†, multivariate cox regression analysis adjusted for age, sex, smoking status, ECOG, Charlson Comorbidities Index, histology, EGFR and KRAS mutation status and lines of systemic therapy; ‡, each immune cell group (Texstem, Texterm, PD-1+) and Texstem: Texterm ratio were modelled independently in multivariate analysis; §, high and low groups dichotomized by the median value. Median Texstem 4.3%; median Texterm 0.3%, median Texstem: Texterm ratio 13.9, median PD-1+ 10.1%. ADC, adenocarcinoma; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; F, female; HR, hazard ratio; M, male; NSCLC, non-small cell lung cancer; PD-1, programmed death-1; SCC, squamous cell carcinoma; Texstem, stem-like exhausted T cells; Texterm, terminally exhausted T cells; WT, wild type.

In summary, in this study we applied the same flow cytometry approach that was used in our previous publication using PE samples (15) to define the Texstem and Texterm phenotypic populations in pre-treatment PBMC samples from advanced NSCLC patients and compared to that of PE. We show that in most patients the peripheral circulation is populated by both Texstem and Texterm. Some studies have examined the T-cell exhaustion states in either PE or peripheral blood (28-30), however, a direct comparison of Tex subsets between the two compartments has not been performed. Our findings show that the Tex subsets of NSCLC peripheral blood and PE have distinct differences. Overall, as one would expect, PE has a greater proportion of Tex compared to peripheral blood, likely due to direct exposure to tumors cells that infiltrate the pleura. There were higher proportions of both Texstem and Texterm in PE. These results are in keeping with previous studies demonstrating that inhibitory receptors PD-1/L1, T cell immunoglobulin and mucin domain containing-3 (TIM-3), lymphocyte activation gene-3 (LAG-3) and cytotoxic T-lymphocyte associated protein-4 (CTLA-4) are expressed at greater proportions on PE T cells compared to peripheral blood T cells in lung cancer patients (31-34).

Our cohort of matched PE and peripheral blood samples show that despite differences in the frequencies of Tex, Tex subsets (especially Texstem) in blood show a moderate to strong correlative relationship with those in PE, and therefore peripheral blood samples, to a degree, can reflect the T-cell exhaustion milieu more proximal to the tumor. Naïve tumor-specific T cells are thought to encounter tumor antigens, expand and differentiate in tumor-draining lymph nodes, then traffic through blood to the tumor. Therefore, increased T-cell expansion and migration through the blood can result in higher number of T cells with the same antigenicity and exhaustion phenotype at a tumor site such as PE. Our results support the utility of peripheral blood in studying tumor-host T-cell interactions and as a resource for translational medicine in metastatic NSCLC patients. Compared to tumor tissue and tumor associated fluids such as PE, peripheral blood can be readily and repeatedly accessible and represent an opportunity to widely and longitudinally examine Tex for biomarker analysis and future translational research.

Our finding that an increased Texstem frequency in the blood correlates with improved survival in patients with advanced NSCLC is congruent with our previous findings using PE samples (15). Also consistent with our observations in PE, the survival analysis of Texterm and PD-1+ CD8 T cells did not reveal clinical significance. This provides further evidence for the clinical relevance of Texstem, not only in the tumor microenvironment but also in the peripheral circulation. Most of the evidence for the functionality and importance of Texstem in anti-cancer immunity are based on work conducted using tumor tissue in the setting of immune checkpoint blockade (ICPB). For example, in melanoma patients, stem-like exhausted CD8 tumor infiltrating lymphocytes (defined in this study as PD-1+ TCF1+) mediated proliferative response to immunotherapy, and ablation of this cell subset restricted response to immunotherapy (35), suggesting that immune checkpoint inhibitor efficacy and anti-tumor T-cell immunity is dependent on stem-like exhausted CD8 T cells (36). Due to the timeframe in which our study samples were collected, only seven patients in our study received ICPB as first line treatment. Therefore, we could not investigate whether Texstem is associated with improved response to immunotherapy and a larger more contemporary patient cohort will be required to answer this question. Nevertheless, our data supports the notion that the frequency and maintenance of Texstem in the circulation reflects sites more proximal to the tumor, and the persistence of this population may aid in anti-cancer immunity.

Our study is limited by the small number of patients and the retrospective nature of data collection. However, the results are concordant with those found in our previous research work using PE samples from two different cancer types, strengthening the validity of our findings. Similar to our PE cohort, this cohort compromises of predominantly ADCs. Therefore, it remains unclear whether our findings also apply to SCCs.

Our findings add to the body of evidence that Texstem play a pivotal role in cancer immunity and warrant further studies as a prognostic biomarker. Reinvigorating this T-cell population may provide further therapeutic opportunities in NSCLC patients. Furthermore, peripheral blood analysis of circulating exhausted T cell subsets can provide valuable insight into the prognosis of patients with advanced NSCLC.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the MDAR reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-509/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-509/prf

Funding: This work was supported by the NHMRC of Australia (Centre of Research Excellence grant No. 1197652; grant No. 2029268 to A.R. and B.W.R.), The US Department of Defense (grant No. CA190450 to B.W.R., J.C. and A.R.), Sir Charles Gairdner Hospital Charlies Foundation for Research (grant No. MRGP22-23_15 to J.C. and L.Y.) and the Cancer Council of Western Australia (fellowship to J.C.). The funding sources had no role in the preparation of the manuscript or the decision to submit the article for publication.

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.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Sir Charles Gairdner Osbourne Park Health Care Group Human Research Ethics Committee EC00271 (PRN 0000001516) and informed consent was obtained from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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Cite this article as: Ye L, Dick I, Firth T, Robinson BW, Creaney J, Redwood A. Circulating stem-like exhausted CD8 T cells point to better outcomes in lung cancer: a brief report. Transl Lung Cancer Res 2025;14(11):5074-5081. doi: 10.21037/tlcr-2025-509

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