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

Autor:	Ye L; National Centre for Asbestos Related Diseases, Faculty of Health and Medical Science, University of Western Australia, Nedlands, WA, Australia., Ryu H; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Centre, Seattle, WA, USA.; School of Medicine, Sungkyunkwan University, Suwon, Republic of Korea., Granadier D; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Centre, Seattle, WA, USA.; School of Medicine, University of Washington, Seattle, WA, USA., Nguyen LT; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Centre, Seattle, WA, USA., Simoni Y; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Centre, Seattle, WA, USA., Dick I; School of Biomedical Science, University of Western Australia, Nedlands, WA, Australia., Firth T; National Centre for Asbestos Related Diseases, Faculty of Health and Medical Science, University of Western Australia, Nedlands, WA, Australia., Rouse E; National Centre for Asbestos Related Diseases, Faculty of Health and Medical Science, University of Western Australia, Nedlands, WA, Australia., Chiang P; National Centre for Asbestos Related Diseases, Faculty of Health and Medical Science, University of Western Australia, Nedlands, WA, Australia., Lee YCG; School of Biomedical Science, University of Western Australia, Nedlands, WA, Australia.; Institute for Respiratory Health, University of Western Australia, Nedlands, WA, Australia., Robinson BW; National Centre for Asbestos Related Diseases, Faculty of Health and Medical Science, University of Western Australia, Nedlands, WA, Australia.; School of Biomedical Science, University of Western Australia, Nedlands, WA, Australia.; Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, WA, Australia., Creaney J; National Centre for Asbestos Related Diseases, Faculty of Health and Medical Science, University of Western Australia, Nedlands, WA, Australia.; Institute for Respiratory Health, University of Western Australia, Nedlands, WA, Australia.; Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, WA, Australia., Newell EW; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Centre, Seattle, WA, USA., Redwood AJ; National Centre for Asbestos Related Diseases, Faculty of Health and Medical Science, University of Western Australia, Nedlands, WA, Australia.; School of Biomedical Science, University of Western Australia, Nedlands, WA, Australia.; Institute for Respiratory Health, University of Western Australia, Nedlands, WA, Australia.
Jazyk:	angličtina
Zdroj:	Translational lung cancer research [Transl Lung Cancer Res] 2024 Sep 30; Vol. 13 (9), pp. 2352-2372. Date of Electronic Publication: 2024 Sep 27.
DOI:	10.21037/tlcr-24-284
Abstrakt:	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 (Tex term ) 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 stem and Tex term 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 stem 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 Tex term 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 stem cells also contained 'bystander' virus-specific T cells. Conclusions: This study demonstrates that PE CD8 Tex stem cell abundance is associated with better survival outcomes, and thus may be a useful prognostic biomarker. Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-284/coif). H.R. reports grants from IIRC post-doctoral fellowship (No. 224990-99, to H.R.) and post-doctoral training fellowship from the National Research Foundation of Korea (NRF-2020R1A6A3A03037852, to H.R.). T.F. reports serving as the board secretary of Mind the Change Inc. Y.C.G.L. is the current NHMRC Leadership Fellow and a recipient of the Investigator Grant (Leadership 2) (since July 2023), and the recipient of the Next Generation Clinical Research Practitioner Fellowship (from 2018 to June 2023). Rocket Med (UK) has provided free pleural fluid drainage kits for patients enrolled in randomized trials that Y.C.G.L. led. B.W.R. reports funding from the NHMRC of Australia, Insurance Commission of Western Australia, The US Department of Defense, Western Australian Department of Health, iCARE Foundation, Sir Charles Gairdner Research Advisory Committee, the Future Health Research and Innovation Fund scheme through the Biobank Interim Support Program 2021 and the Cancer Council of Western Australia. J.C. reports funding from the Australian National Health and Medical Research Council; The US Department of Defense; Insurance Commission of Western Australia; Western Australian Department of Health; iCARE Foundation; Sir Charles Gairdner Research Advisory Committee; Future Health Research and Innovation Fund scheme through the Biobank Interim Support Program 2021; Cancer Council of Western Australia. E.W.N. reports funding from the National Institutes of Health (NIH, Nos. R01CA264646 and R01AI176563 to E.W.N.), US Department of Defense, and Fred Hutchinson Cancer Center. And a cofounder, advisor and shareholder of ImmunoScape; an advisor and shareholder of Neogene Therapeutics; an advisor for NanoString Technologies and InduPro, and a shareholder in Trojan Bio. A.J.R. reports funding from The Australian National Health and Medical Research Council and The US Department of Defense. The other authors have no conflicts of interest to declare. (2024 AME Publishing Company. All rights reserved.)
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