PO.CL01.02 · 临床研究
MORPHEUS-lung：转移性非小细胞肺癌患者接受atezolizumab+bevacizumab+立体定向体部放疗的生物标志物与临床应答
MORPHEUS-lung: Biomarkers and clinical response to atezolizumab + bevacizumab + stereotactic body radiotherapy in patients with metastatic non-small cell lung cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
目的：MORPHEUS-Lung（NCT03337698）研究的结果提示，在既往接受过免疫检查点抑制剂治疗的转移性非小细胞肺癌患者中，atezolizumab+bevacizumab+立体定向体部放疗（SBRT）相比多西他赛（对照）在数值上改善了疗效结局。我们报告探索性分析，以识别与该临床应答相关的潜在生物标志物。
实验设计：通过单细胞RNA测序对肿瘤样本进行差异基因表达和通路/免疫亚群基因特征分析，并进一步用bulk RNA测序验证。
结果：共58例患者纳入生物标志物可评估人群（atezolizumab+bevacizumab+SBRT（Atezo+Bev+Radio），n=26；多西他赛对照，n=32）。在比较基线时有临床获益（CB）与无临床获益（non-CB）患者的发现性分析中，肿瘤驻留记忆CD8⁺ T细胞（CD8 T RM）在CB组显著富集（P=0.027），并伴有T细胞受体克隆性增加，提示肿瘤反应性T细胞的克隆扩增（Gini指数P=0.018）。免疫检查点治疗的靶分子PDCD1在CD8 T EX中高表达，支持其对atezolizumab治疗的应答性。此外，CB组显示CXCL10⁺和FOLR2⁺巨噬细胞丰度增加，提示髓系-T细胞串扰增强。具有高肿瘤识别潜能的CD8 T RM通过与CXCL10⁺巨噬细胞（其PD-L1表达水平最高）的CXCL介导相互作用增强了抗肿瘤活性。在Atezo+Bev+Radio治疗后，被识别为预测性生物标志物的CD8 T RM维持持续的肿瘤反应状态，而CD8 TEMRA细胞则表现出细胞毒功能增强，可能由放射暴露驱动。Atezo+Bev+Radio治疗还诱导治疗后组中FOLR2⁺和FABP4⁺巨噬细胞显著增加。FOLR2⁺巨噬细胞通过ICOS-ICOSL信号通路与表达ICOS的CD8 T细胞相互作用，促进T细胞介导的抗肿瘤免疫。相反，FABP4⁺巨噬细胞通过PVR-TIGIT信号轴与表达TIGIT的Treg细胞相互作用，从而促成免疫抑制。数据整合揭示了T细胞和巨噬细胞相关的基因特征，在一个独立队列中得到验证，并与atezolizumab+bevacizumab+SBRT治疗后的生存获益相关。
结论：这些结果提示T细胞和巨噬细胞的激活与Atezo+Bev+Radio的良好临床应答相关。此外，CD8 T RM、CD8 T EX和CXCL10+巨噬细胞可作为对Atezo+Bev+Radio治疗应答的潜在生物标志物，并可能有助于为个体患者量身定制精准医疗。
查看英文原文 English abstract
Purpose: Results from the MORPHEUS-Lung (NCT03337698) study suggest that atezolizumab+bevacizumab+stereotactic body radiotherapy (SBRT) was associated with numerically improved efficacy outcomes vs docetaxel (control) in immune checkpoint inhibitor-exposed patients with metastatic non-small cell lung cancer. We report exploratory analyses to identify potential biomarkers associated with this clinical response.
Experimental Design: Tumor samples were analyzed for differential gene expression and pathway/immune subset gene signatures by single cell RNA-sequencing and further validated with bulk RNA-sequencing.
Results: A total of 58 patients were included in the biomarker-evaluable population (atezolizumab + bevacizumab + SBRT (Atezo+Bev+Radio), n = 26; docetaxel control, n = 32). In the discovery analysis comparing patients with clinical benefit (CB) versus non-clinical benefit (non-CB) at baseline, tumor-resident memory CD8⁺ T cells (CD8 T RM ) were significantly enriched in the CB group (P = 0.027) accompanied by an increased T-cell receptor clonality, indicating clonal expansion of tumor-reactive T cells (Gini index P = 0.018). PDCD1, the target molecule of immune checkpoint therapy, was highly expressed in CD8 T EX , supporting their responsiveness to atezolizumab treatment. Furthermore, the CB group showed increased abundance of CXCL10⁺ and FOLR2⁺ macrophages, suggesting enhanced myeloid-T cell crosstalk. CD8 T RM with high tumor-recognition potential exhibited strengthened antitumor activity through CXCL-mediated interactions with CXCL10⁺ macrophages, which expressed PD-L1 at the highest level. Following Atezo+Bev+Radio treatment, CD8 T RM -identified as predictive biomarkers-maintained a persistent tumor-reactive state, whereas CD8 TEMRA cells showed increased cytotoxic function likely driven by radiation exposure. Atezo+Bev+Radio treatment also induced a marked increase in FOLR2⁺ and FABP4⁺ macrophages in the post-treatment group. FOLR2⁺ macrophages interacted with CD8 T cells expressing ICOS via the ICOS-ICOSL signaling pathway, promoting T cell-mediated antitumor immunity. In contrast, FABP4⁺ macrophages engaged Treg cells expressing TIGIT through the PVR-TIGIT signaling axis, thereby contributing to immune suppression. Integration of the data revealed T cell- and macrophage-related gene signatures validated in an independent cohort, correlating with survival benefit after atezolizumab + bevacizumab + SBRT treatment.
Conclusions: These results suggest that activation of T cells and macrophages are associated with a favorable clinical response Atezo+Bev+Radio. Moreover, CD8 T RM , CD8 T EX , and CXCL10 + macrophages may serve as potential biomarkers of response to Atezo+Bev+Radio treatment and potentially aid in tailored, precision medicine for individual patients.
利益披露 Disclosure
S. Lim,
AstraZeneca ).
BeOne Medicines ).
Boehringer Ingelheim ).
Daiichi Sankyo ).
Eli Lilly ).
GSK ).
Jiangsu Hengrui ).
J INTS Bio ).
Johnson & Johnson ).
Roche ).
Takeda ).
Yuhan ).
S. Lee, None..
D. Kim, None.
N. Pardo,
F. Hoffmann-La Roche ).
Takeda ).
N. Al-Sakaff,
Roche Employment.
H. Helms,
Roche Employment.
G. Velimir,
genentech Employment.
B. Nabet,
Genentech Employment.
J. Pintoffl,
Roche Employment.
F. Ghiringhelli, None.