Institute of Molecular Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore; Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), Singapore; Division of Pathology, Singapore General Hospital, Singapore.
Division of Medical Oncology, National Cancer Centre Singapore, Singapore.
J Thorac Oncol. 2021 Aug;16(8):1349-1358. doi: 10.1016/j.jtho.2021.04.016. Epub 2021 May 8.
Programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) blockade is currently widely used in the treatment of metastatic NSCLC. Despite available biomarker stratification, clinical responses vary. Thus, the search for novel biomarkers with improved response prediction is ongoing. Previously, using mass cytometry or cytometry by time-of-flight (CyTOF), our group demonstrated that CD39CD8 immune cells represent tumor antigen-specific, cytotoxic T cells in treatment-naive NSCLC. We hypothesized that accurate quantitation of this T cell subset would predict immunotherapy outcome.
To translate this to a clinical setting, the present study compared CyTOF data with a range of clinically relevant methods, including conventional immunohistochemistry (IHC), multiplex IHC or immunofluorescence (mIHC), and gene expression assay by NanoString.
Quantification using mIHC but not conventional IHC or NanoString correlated with the CyTOF results. The specificity and sensitivity of mIHC were then evaluated in a separate retrospective NSCLC cohort. CD39CD8 T cell proportion, as determined by mIHC, successfully stratified responders and nonresponders to PD-1 or PD-L1 inhibitors (objective response rate of 63.6%, compared with 0% for the negative group). This predictive capability was independent from other confounding factors, such as total CD8 T cell proportion, CD39 lymphocyte proportion, PD-L1 positivity, EGFR mutation status, and other clinicopathologic parameters.
Our results suggest that the mIHC platform is a clinically relevant method to evaluate CD39CD8 T cell proportion and that this marker can serve as a potential biomarker that predicts response to PD-1 or PD-L1 blockade in patients with NSCLC. Further validation in additional NSCLC cohorts is warranted.
程序性死亡蛋白-1（PD-1）和程序性死亡配体 1（PD-L1）阻断目前广泛用于转移性非小细胞肺癌（NSCLC）的治疗。尽管有可用的生物标志物分层，但临床反应各不相同。因此，正在寻找具有改善反应预测能力的新型生物标志物。先前，我们小组使用质谱流式细胞术或时间飞行流式细胞术（CyTOF）证明，CD39CD8 免疫细胞代表治疗初治 NSCLC 中的肿瘤抗原特异性细胞毒性 T 细胞。我们假设，准确量化这种 T 细胞亚群将预测免疫治疗结果。
为了将其转化为临床环境，本研究比较了 CyTOF 数据与一系列临床相关方法，包括常规免疫组织化学（IHC）、多重免疫组织化学或免疫荧光（mIHC）以及 NanoString 的基因表达分析。
使用 mIHC 进行定量，但不是常规 IHC 或 NanoString 与 CyTOF 结果相关。然后，在另一个独立的回顾性 NSCLC 队列中评估了 mIHC 的特异性和敏感性。通过 mIHC 确定的 CD39CD8 T 细胞比例成功地将 PD-1 或 PD-L1 抑制剂的应答者和无应答者分层（客观缓解率为 63.6%，而阴性组为 0%）。这种预测能力独立于其他混杂因素，例如总 CD8 T 细胞比例、CD39 淋巴细胞比例、PD-L1 阳性、EGFR 突变状态和其他临床病理参数。
我们的结果表明，mIHC 平台是评估 CD39CD8 T 细胞比例的一种临床相关方法，并且该标志物可以作为预测 NSCLC 患者对 PD-1 或 PD-L1 阻断反应的潜在生物标志物。需要在其他 NSCLC 队列中进一步验证。
