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
{"title":"胸腔积液中的干样衰竭 CD8 T 细胞预示着非小细胞肺癌（NSCLC）和间皮瘤患者的生存率会提高。","authors":"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","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Anti-tumor CD8 T cells are important for immunity but can become 'exhausted' and hence ineffective. Tumor-infiltrating exhausted CD8<sup>+</sup> T cells include less differentiated stem-like exhausted T (Tex<sup>stem</sup>) cells and terminally exhausted T (Tex<sup>term</sup>) 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.</p><p><strong>Methods: </strong>Pre-treatment malignant pleural effusions (PEs) from 43 NSCLC (41 non-squamous, 2 squamous) patients were analyzed by flow cytometry. The percentages of Tex<sup>stem</sup> and Tex<sup>term</sup> 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.</p><p><strong>Results: </strong>Higher frequency of Tex<sup>stem</sup> was associated with significantly increased OS [median 9.9 <i>vs.</i> 3.4 months, hazard ratio (HR) 0.36, 95% CI: 0.16-0.79, P=0.01]. The frequency of Tex<sup>term</sup> was not associated with OS. These findings were validated in the mesothelioma cohort (high <i>vs.</i> low Tex<sup>stem</sup>, median OS 32.1 <i>vs.</i> 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<sup>stem</sup> cells also contained 'bystander' virus-specific T cells.</p><p><strong>Conclusions: </strong>This study demonstrates that PE CD8 Tex<sup>stem</sup> cell abundance is associated with better survival outcomes, and thus may be a useful prognostic biomarker.</p>","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":null,"pages":null},"PeriodicalIF":4.0000,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11484714/pdf/","citationCount":"0","resultStr":"{\"title\":\"Stem-like exhausted CD8 T cells in pleural effusions predict improved survival in non-small cell lung cancer (NSCLC) and mesothelioma.\",\"authors\":\"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\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Anti-tumor CD8 T cells are important for immunity but can become 'exhausted' and hence ineffective. Tumor-infiltrating exhausted CD8<sup>+</sup> T cells include less differentiated stem-like exhausted T (Tex<sup>stem</sup>) cells and terminally exhausted T (Tex<sup>term</sup>) 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.</p><p><strong>Methods: </strong>Pre-treatment malignant pleural effusions (PEs) from 43 NSCLC (41 non-squamous, 2 squamous) patients were analyzed by flow cytometry. The percentages of Tex<sup>stem</sup> and Tex<sup>term</sup> 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.</p><p><strong>Results: </strong>Higher frequency of Tex<sup>stem</sup> was associated with significantly increased OS [median 9.9 <i>vs.</i> 3.4 months, hazard ratio (HR) 0.36, 95% CI: 0.16-0.79, P=0.01]. The frequency of Tex<sup>term</sup> was not associated with OS. These findings were validated in the mesothelioma cohort (high <i>vs.</i> low Tex<sup>stem</sup>, median OS 32.1 <i>vs.</i> 19.8 months, HR 0.31, 95% CI: 0.10-0.96, P=0.04). 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引用次数: 0
摘要
背景：抗肿瘤 CD8 T 细胞对免疫非常重要，但也会 "衰竭"，从而失去作用。肿瘤浸润的衰竭 CD8+ T 细胞包括分化程度较低的干样衰竭 T 细胞（Texstem）和终末衰竭 T 细胞（Texterm）。这两个亚群被认为是癌症患者的预后生物标志物。在这项研究中，我们回顾性地调查了它们在转移性非小细胞肺癌（NSCLC）患者中的预后意义，并在间皮瘤队列中验证了我们的发现：方法：采用流式细胞术分析了43例NSCLC患者（41例非鳞癌，2例鳞癌）治疗前的恶性胸腔积液（PE）。在调整临床病理变量后，Texstem 和 Texterm CD8 T 细胞的百分比与总生存率（OS）相关。研究结果通过间皮瘤队列（n=49）进行了验证。对来自 5 名间皮瘤患者和 3 名 NSCLC 患者的 16 份治疗前 PE 样本进行了 T 细胞表型分析，并使用了质谱细胞计数法。对来自 2 名 NSCLC 患者和 2 名间皮瘤患者的 4 份治疗前 PE 样本进行了单细胞多组学分析，以分析转录组图谱、表面标记和 T 细胞受体（TCR）谱系：Texstem频率越高，OS显著增加[中位数9.9个月对3.4个月，危险比（HR）0.36，95% CI：0.16-0.79，P=0.01]。Texterm的频率与OS无关。这些发现在间皮瘤队列中得到了验证（高Texterm与低Texterm，中位OS为32.1个月与19.8个月，HR为0.31，95% CI：0.10-0.96，P=0.04）。详细的单细胞测序和质谱分析显示，与间皮瘤的T细胞相比，NSCLC的衰竭T细胞表达了更多的干相似性和更少的抑制性标记，Texstem细胞还包含 "旁观者 "病毒特异性T细胞：这项研究表明，PE CD8 Texstem 细胞的丰度与较好的生存结果相关，因此可能是一种有用的预后生物标志物。
Stem-like exhausted CD8 T cells in pleural effusions predict improved survival in non-small cell lung cancer (NSCLC) and mesothelioma.
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.
期刊介绍：
Translational Lung Cancer Research(TLCR, Transl Lung Cancer Res, Print ISSN 2218-6751; Online ISSN 2226-4477) is an international, peer-reviewed, open-access journal, which was founded in March 2012. TLCR is indexed by PubMed/PubMed Central and the Chemical Abstracts Service (CAS) Databases. It is published quarterly the first year, and published bimonthly since February 2013. It provides practical up-to-date information on prevention, early detection, diagnosis, and treatment of lung cancer. Specific areas of its interest include, but not limited to, multimodality therapy, markers, imaging, tumor biology, pathology, chemoprevention, and technical advances related to lung cancer.
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