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

Linda Ye; Heeju Ryu; David Granadier; Long T. Nguyen; Yannick Simoni; Ian Dick; Tina Firth; Ebony Rouse; Peter Chiang; Y. C. Gary Lee; Bruce W. Robinson; Jenette Creaney; Evan W. Newell; Alec J. Redwood

doi:10.21037/tlcr-24-284

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

Linda Ye, Heeju Ryu, David Granadier, Long T. Nguyen, Yannick Simoni, Ian Dick, Tina Firth, Ebony Rouse, Peter Chiang, Y. C. Gary Lee, Bruce W. Robinson, Jenette Creaney, Evan W. Newell, Alec J. Redwood

Research output: Contribution to journal › Article › peer-review

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 (Tex^stem) 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 Tex^stemand 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 Tex^stemwas 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 Tex^stem, 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 Tex^stemcells also contained 'bystander' virus-specific T cells. Conclusions: This study demonstrates that PE CD8 Tex^stemcell abundance is associated with better survival outcomes, and thus may be a useful prognostic biomarker.

Original language	English
Pages (from-to)	2352-2372
Number of pages	21
Journal	Translational Lung Cancer Research
Volume	13
Issue number	9
DOIs	https://doi.org/10.21037/tlcr-24-284
Publication status	Published - 30 Sept 2024

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Ye, L., Ryu, H., Granadier, D., Nguyen, L. T., Simoni, Y., Dick, I., Firth, T., Rouse, E., Chiang, P., Gary Lee, Y. C., Robinson, B. W., Creaney, J., Newell, E. W., & Redwood, A. J. (2024). Stem-like exhausted CD8 T cells in pleural effusions predict improved survival in non-small cell lung cancer (NSCLC) and mesothelioma. Translational Lung Cancer Research, 13(9), 2352-2372. https://doi.org/10.21037/tlcr-24-284

@article{66edc55fa8d240b089c79d1da8c0821a,

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

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 Texstemand 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 Texstemwas 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 Texstemcells also contained 'bystander' virus-specific T cells. Conclusions: This study demonstrates that PE CD8 Texstemcell abundance is associated with better survival outcomes, and thus may be a useful prognostic biomarker.",

keywords = "mesothelioma, Non-small cell lung cancer (NSCLC), T cell exhaustion",

author = "Linda Ye and Heeju Ryu and David Granadier and Nguyen, {Long T.} and Yannick Simoni and Ian Dick and Tina Firth and Ebony Rouse and Peter Chiang and {Gary Lee}, {Y. C.} and Robinson, {Bruce W.} and Jenette Creaney and Newell, {Evan W.} and Redwood, {Alec J.}",

year = "2024",

month = sep,

day = "30",

doi = "10.21037/tlcr-24-284",

language = "English",

volume = "13",

pages = "2352--2372",

journal = "Translational Lung Cancer Research",

issn = "2218-6751",

publisher = "Society for Translational Medicine (STM)",

number = "9",

}

Ye, L, Ryu, H, Granadier, D, Nguyen, LT, Simoni, Y, Dick, I, Firth, T, Rouse, E, Chiang, P, Gary Lee, YC , Robinson, BW , Creaney, J, Newell, EW & Redwood, AJ 2024, 'Stem-like exhausted CD8 T cells in pleural effusions predict improved survival in non-small cell lung cancer (NSCLC) and mesothelioma', Translational Lung Cancer Research, vol. 13, no. 9, pp. 2352-2372. https://doi.org/10.21037/tlcr-24-284

TY - JOUR

T1 - Stem-like exhausted CD8 T cells in pleural effusions predict improved survival in non-small cell lung cancer (NSCLC) and mesothelioma

AU - Ye, Linda

AU - Ryu, Heeju

AU - Granadier, David

AU - Nguyen, Long T.

AU - Simoni, Yannick

AU - Dick, Ian

AU - Firth, Tina

AU - Rouse, Ebony

AU - Chiang, Peter

AU - Gary Lee, Y. C.

AU - Robinson, Bruce W.

AU - Creaney, Jenette

AU - Newell, Evan W.

AU - Redwood, Alec J.

PY - 2024/9/30

Y1 - 2024/9/30

N2 - 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 Texstemand 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 Texstemwas 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 Texstemcells also contained 'bystander' virus-specific T cells. Conclusions: This study demonstrates that PE CD8 Texstemcell abundance is associated with better survival outcomes, and thus may be a useful prognostic biomarker.

AB - 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 Texstemand 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 Texstemwas 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 Texstemcells also contained 'bystander' virus-specific T cells. Conclusions: This study demonstrates that PE CD8 Texstemcell abundance is associated with better survival outcomes, and thus may be a useful prognostic biomarker.

KW - mesothelioma

KW - Non-small cell lung cancer (NSCLC)

KW - T cell exhaustion

UR - http://www.scopus.com/inward/record.url?scp=85205766679&partnerID=8YFLogxK

U2 - 10.21037/tlcr-24-284

DO - 10.21037/tlcr-24-284

M3 - Article

AN - SCOPUS:85205766679

SN - 2218-6751

VL - 13

SP - 2352

EP - 2372

JO - Translational Lung Cancer Research

JF - Translational Lung Cancer Research

IS - 9

ER -

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

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