免疫检查点阻断通过扩增效应 CD8⁺ T 细胞克隆增强淋巴细胞清除性化疗诱导的抗肿瘤免疫
Immune Checkpoint Blockade Augments Lymphodepleting Chemotherapy-Induced Antitumor Immunity by Expanding Effector CD8+ T-cell Clones.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
自动化定量 CD8⁺ TIL（肿瘤浸润淋巴细胞）与肿瘤突变负荷作为接受一线抗 PD-1 免疫治疗黑色素瘤患者的独立生物标志物
英文原题：Automated Quantitative CD8+ Tumor-Infiltrating Lymphocytes and Tumor Mutation Burden as Independent Biomarkers in Melanoma Patients Receiving Front-Line Anti-PD-1 Immunotherapy.
查看英文原题
Automated Quantitative CD8+ Tumor-Infiltrating Lymphocytes and Tumor Mutation Burden as Independent Biomarkers in Melanoma Patients Receiving Front-Line Anti-PD-1 Immunotherapy.
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研究概要
一种自动化数字分析算法提供了量化 CD8⁺TIL 密度的标准化方法，该密度可预测对一线抗 PD-1 治疗的应答。
中文摘要
背景
CD8+ TIL（肿瘤浸润淋巴细胞）可预测抗 PD-(L)1 治疗应答。然而，黑色素瘤 CD8+ TIL 尚无标准化评估方法，开发特异、经济、可重复且具有临床可操作性的抗 PD-(L)1 治疗生物标志物仍具挑战。我们报告了一种全切片图像（WSI）分析方法，用于自动定量接受一线抗 PD-1 阻断治疗的晚期黑色素瘤患者 CD8+ TIL 密度，并研究其与免疫治疗应答的关系。
方法
纳入 2015 年 1 月至 2023 年 5 月期间在匹兹堡大学癌症研究所接受一线 PD-1 抑制剂治疗的 78 例患者。利用图像分析算法对数字化 WSI 进行 CD8+ TIL 密度定量。对其中 62 例患者进行靶向二代测序（NGS）以测定肿瘤突变负荷（TMB）。通过 ROC 曲线确定生物标志物阈值和治疗应答之间的关系，并研究 CD8+ TIL 密度、TMB 阈值与治疗应答的相关性。
结果
在所有评估时间点，较高的 CD8+ TIL 密度均与一线抗 PD-1 应答改善显著相关。CD8+ TIL 密度阈值为 222.9 个细胞/mm² 时，无论在何时评估应答，均可可靠地区分应答者和非应答者。多变量分析显示，超过该阈值的患者 PFS 显著改善，OS 也呈改善趋势。同样，TMB 升高与抗 PD-1 应答改善相关，14.70 Mut/Mb 的阈值与应答可能性提高相关。TMB 与 CD8+ TIL 密度相关性较低，提示二者是相互独立的应答预测标志物。
结论
自动化数字分析算法可标准化定量 CD8+ TIL 密度，并预测一线抗 PD-1 治疗应答。CD8+ TIL 密度和 TMB 是抗 PD-1 阻断治疗应答的独立预测因子。
展开英文摘要原文
BACKGROUND
CD8+ tumor-infiltrating lymphocyte (TIL) predicts response to anti-PD-(L)1 therapy. However, there remains no standardized method to assess CD8+ TIL in melanoma, and developing a specific, cost-effective, reproducible, and clinically actionable biomarker to anti-PD-(L)1 remains elusive. We report on the development of automatic CD8+ TIL density quantification via whole slide image (WSI) analysis in advanced melanoma patients treated with front-line anti-PD-1 blockade, and correlation immunotherapy response.
METHODS
Seventy-eight patients treated with PD-1 inhibitors in the front-line setting between January 2015 and May 2023 at the University of Pittsburgh Cancer Institute were included. CD8+ TIL density was quantified using an image analysis algorithm on digitized WSI. Targeted next-generation sequencing (NGS) was performed to determine tumor mutation burden (TMB) in a subset of 62 patients. ROC curves were used to determine biomarker cutoffs and response to therapy. Correlation between CD8+ TIL density and TMB cutoffs and response to therapy was studied.
RESULTS
Higher CD8+ TIL density was significantly associated with improved response to front-line anti-PD-1 across all time points measured. CD8+ TIL density 222.9 cells/mm2 reliably segregated responders and non-responders to front-line anti-PD-1 therapy regardless of when response was measured. In a multivariate analysis, patients with CD8+ TIL density exceeding cutoff had significantly improved PFS with a trend toward improved OS. Similarly, increasing TMB was associated with improved response to anti-PD-1, and a cutoff of 14.70 Mut/Mb was associated with improved odds of response. The correlation between TMB and CD8+ TIL density was low, suggesting that each represented independent predictive biomarkers of response.
CONCLUSIONS
An automatic digital analysis algorithm provides a standardized method to quantify CD8+ TIL density, which predicts response to front-line anti-PD-1 therapy. CD8+ TIL density and TMB are independent predictors of response to anti-PD-1 blockade.
论文信息
- 作者
- Fortman D、Karunamurthy A、Hartman D、Wang H、Seigh L、Abukhiran I、Najjar YG、Pantanowitz L
- 第一作者单位
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.United States
- 通讯作者单位
- Division of Hematology-Oncology, Department of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.United States
- 文献类型
- 美国 NIH 资助研究
- 期刊
- The oncologist2024 Jul 5
- 原文标识
- PubMed 38655867 · DOI 10.1093/oncolo/oyae054
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