抗肿瘤 CD8 T 细胞对于免疫很重要，但可能会“耗尽”，从而失效。肿瘤浸润耗竭 CD8 T 细胞包括分化程度较低的干细胞样耗竭 T (Texstem) 细胞和终末耗竭 T (Texterm) 细胞。这两个子集都被提议作为癌症患者的预后生物标志物。在这项研究中，我们回顾性研究了它们对转移性非小细胞肺癌 (NSCLC) 患者的预后意义，并在间皮瘤队列中验证了我们的研究结果。 43 例 NSCLC（41 例非鳞状、通过流式细胞术对 2 名鳞状细胞癌患者进行了分析。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期 (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 名间皮瘤和 3 名 NSCLC 患者的 16 份治疗前 PE 样本进行了质谱流式分析，以进行 T 细胞表型分析。对来自 2 名 NSCLC 患者和 2 名间皮瘤患者的 4 份治疗前 PE 样本进行单细胞多组学分析，以分析转录组图谱、表面标记物和 T 细胞受体 (TCR) 库。Texstem 的较高频率与显着相关OS 增加 [中位数 9.9 个月与 3.4 个月，风险比 (HR) 0.36，95% CI：0.16-0.79，P=0.01]。 Textterm 的频率与 OS 无关。这些发现在间皮瘤队列中得到了验证（高 Texstem 与低 Texstem，中位 OS 32.1 个月与 19.8 个月，HR 0.31，95% CI：0.10-0.96，P=0.04）。详细的单细胞测序和质谱流式分析显示，与间皮瘤相比，来自 NSCLC 的耗竭 T 细胞表达了更大的干细胞相似性和更少的抑制标记，并且 Texstem 细胞还含有“旁观者”病毒特异性 T 细胞。这项研究表明，PE CD8 Texstem 细胞丰度与更好的生存结果相关，因此可能是一种有用的预后生物标志物。2024 AME 出版公司。版权所有。

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.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.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.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.