Stem-like exhausted CD8 T cells in pleural effusions predict improved survival in non-small cell lung cancer (NSCLC) and mesothelioma

Our plain-English summary of Stem-like exhausted CD8 T cells in pleural effusions predict improved survival in non-small cell lung cancer (NSCLC) and mesothelioma, by L. Ye, H. Ryu, D. Granadier, et al (Translational Lung Cancer Research, 2024).

The study

• Authors: L. Ye, H. Ryu, D. Granadier, L.T. Nguyen, Y. Simoni, I. Dick, T. Firth, E. Rouse, P. Chiang, Y.C.G. Lee, B.W. Robinson, J. Creaney, E.W. Newell, A.J. Redwood
• Journal: Translational Lung Cancer Research
• Published: 2024;13(9):2352-2372
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Anti-tumor CD8 T cells are important for immunity but can become 'exhausted' and hence ineffective. Tumor-infiltrating exhausted CD8+ T cells include less differentiated stem-like exhausted T (Texstem) cells and terminally exhausted T (Texterm) cells. Both subsets have been proposed as prognostic biomarkers in cancer patients. In this study, we retrospectively investigated their prognostic significance in patients with metastatic non-small cell lung cancer (NSCLC) and validated our findings in a mesothelioma cohort.

Methods: Pre-treatment malignant pleural effusions (PEs) from 43 NSCLC (41 non-squamous, 2 squamous) patients were analyzed by flow cytometry. The percentages of Texstem and Texterm CD8 T cells were correlated with overall survival (OS) after adjusting for clinicopathological variables. Findings were validated using a mesothelioma cohort (n=49). Mass cytometry was performed on 16 pre-treatment PE samples from 5 mesothelioma and 3 NSCLC patients for T-cell phenotyping. Single-cell multi-omics analysis was performed on 4 pre-treatment PE samples from 2 NSCLC patients and 2 mesothelioma patients for analysis of the transcriptomic profiles, surface markers and T cell receptor (TCR) repertoire.

Results: Higher frequency of Texstem was associated with significantly increased OS [median 9.9 vs. 3.4 months, hazard ratio (HR) 0.36, 95% CI: 0.16-0.79, P=0.01]. The frequency of Texterm was not associated with OS. These findings were validated in the mesothelioma cohort (high vs. low Texstem, median OS 32.1 vs. 19.8 months, HR 0.31, 95% CI: 0.10-0.96, P=0.04). Detailed single-cell sequencing and mass cytometry profiling revealed that exhausted T cells from NSCLC expressed greater stem-likeness and less inhibitory markers than those from mesothelioma and that Texstem cells also contained 'bystander' virus-specific T cells.

Conclusions: This study demonstrates that PE CD8 Texstem cell abundance is associated with better survival outcomes, and thus may be a useful prognostic biomarker.

2024 AME Publishing Company. All rights reserved.

In plain English

This retrospective study did not examine asbestos exposure. It looked at immune cells in fluid that had collected around the lungs (malignant pleural effusions) before treatment. The authors measured two kinds of 'exhausted' CD8 T cells: stem-like (Texstem) and terminally exhausted (Texterm). In 43 patients with non-small cell lung cancer (NSCLC), after adjusting for other factors, those with above-median Texstem levels had a median overall survival of 9.9 months. Those below the median had 3.4 months (hazard ratio 0.36, 95% CI 0.16–0.79, P=0.01). In a check group of 49 mesothelioma patients, median survival was 32.1 versus 19.8 months (hazard ratio 0.31, 95% CI 0.10–0.96, P=0.04). After adjustment, Texterm levels were not linked to survival in either group. In detailed testing of a few patients, 61 of 153 Texstem T-cell receptor types matched a database of receptors with known non-cancer targets such as viruses, compared with 10 of 209 Texterm types. The authors concluded that Texstem cells may be a useful prognostic biomarker. They noted that the study was retrospective and that its detailed analyses used few patients.

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 pre-treatment pleural effusion samples, with survival analysis (Cox regression) and laboratory profiling (flow cytometry, mass cytometry, single-cell sequencing)
• Who was studied: 43 NSCLC patients (41 non-squamous, 2 squamous) and a validation cohort of 49 mesothelioma patients (41 epithelioid, 4 sarcomatoid, 4 biphasic; 91.8% male), with malignant pleural effusion samples taken before treatment at Sir Charles Gairdner Hospital, Perth, Australia; samples collected since 2012
• Exposure: Asbestos exposure was not assessed. The factor studied was the proportion of stem-like exhausted CD8 T cells (intermediate PD1, no CD39, CD28 positive) and terminally exhausted CD8 T cells (high PD1 and CD39) in pleural effusion, split into high and low at the median
• Main results:
  • NSCLC (n=43), multivariate analysis: high versus low Texstem, median overall survival 9.9 vs. 3.4 months, HR 0.36, 95% CI 0.16–0.79, P=0.01
  • NSCLC: higher Texterm was associated with worse survival in univariate analysis (HR 2.07, 95% CI 1.07–4.01, P=0.03) but not in multivariate analysis (HR 1.62, 95% CI 0.71–3.68, P=0.25)
  • Mesothelioma (n=49), multivariate analysis: high versus low Texstem, median overall survival 32.1 vs. 19.8 months, HR 0.31, 95% CI 0.10–0.96, P=0.04
  • Mesothelioma: Texterm was not associated with survival in univariate or multivariate analysis (multivariate HR 0.99, 95% CI 0.44–2.24)
  • In both cancers, PD1-positive CD8 T cells taken as a broad group did not correlate with survival
  • NSCLC: Texstem was higher in never smokers (n=6) than in former or current smokers (mean 20.2% vs. 11.9%, P=0.02)
  • In 26 epithelioid mesothelioma patients, Texterm correlated with serum mesothelin (r=0.525, P=0.006), but the authors said this was mainly driven by a single patient
  • Single-cell analysis (2 NSCLC, 2 mesothelioma patients): 61 of 153 Texstem clones, but only 10 of 209 Texterm clones, matched a database of T-cell receptors with known cancer-unrelated specificities (e.g. Epstein-Barr virus, cytomegalovirus, influenza)
  • Mass cytometry (3 NSCLC, 5 mesothelioma patients): exhausted T cells from NSCLC showed more CCR7 and CD127 and less CD57 than those from mesothelioma
• The authors' conclusion: The authors concluded that a higher proportion of stem-like exhausted CD8 T cells in pleural effusion is associated with improved overall survival in NSCLC and mesothelioma and may be a useful prognostic biomarker.
• Limitations the authors state:
  • The NSCLC cohort was almost entirely non-squamous, so the results cannot be generalised to squamous cell carcinoma
  • The retrospective design makes the study open to potential biases
  • The multi-dimensional analyses, especially single-cell sequencing, were done in only a small subset of patients
  • The analysis could not adjust for histological subtype in NSCLC (only two squamous cases)
  • The longitudinal analysis (10 patients) was too small to draw conclusions

Topics

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

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