PO.CL01.13 · 临床研究
ER阳性乳腺肿瘤的空间转录组图谱揭示抗PD-1治疗后的免疫通路重塑与耐药机制
Spatial transcriptomic mapping of ER-positive breast tumors reveals immune pathway remodeling and resistance mechanisms following anti-PD-1 therapy
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
雌激素受体阳性（ER+）乳腺癌（BC）约占BC病例的70%-80%，其表现为低淋巴细胞浸润、低突变负荷及对免疫检查点阻断（ICB）适度的客观应答率，使其成为新型免疫刺激联合治疗的有吸引力的候选对象。在此，我们采用CosMx单细胞成像（SMI）技术，对9例ER+ BC患者在接受抗PD-1抗体Cemiplimab治疗前后~6000个靶标的转录景观进行空间分析，以识别空间分辨的耐药机制和潜在治疗靶点。经质量控制后，分析了18个独特组织切片中的约310万个细胞，从而能够稳健地表征免疫、基质和上皮细胞生态位，并具备以高分辨率识别罕见免疫细胞亚群的能力。比较患者治疗前后各细胞类型的相对丰度，我们发现同一患者不同组织切片之间的细胞类型高度一致。虽然8/9的患者以Luminal A/B癌上皮细胞为主导，但有一例患者为纯基底型癌上皮细胞，凸显了空间转录组平台在BC患者分子分型中的价值。为定义患者对Cemiplimab治疗应答的指标，我们量化了肿瘤内在炎症/免疫通路的变化，并利用空间信息计算了肿瘤浸润淋巴细胞（TIL）的变化。3/9的患者在肿瘤上皮中显示I/II型IFN信号水平升高，5/9无变化，1/9显示急剧下降，同时伴有独特的经由NF-κB的TNF-alpha信号升高。6/9的患者在治疗后TIL增加，TIL定义为距最近CD8 T细胞≤0.1 mm的肿瘤细胞比例。TIL下降最显著的患者正是此前显示IFN信号降低的同一患者，表明应答指标之间的一致性，并提示经由NFkB的TNFa信号上调是T细胞浸润的耐药机制。我们的早期工作提供了对ER+ BC抵抗ICB机制的全面空间分辨分析，提示空间定位的转录程序可揭示可干预的耐药通路，并指导ER+ BC下一代免疫治疗联合方案的设计。
查看英文原文 English abstract
Estrogen-receptor-positive (ER+) breast cancers (BCs) make up approximately 70%-80% of BC cases and demonstrate low lymphocyte infiltration, mutational burden, and modest objective response rates to immune checkpoint blockade (ICB), making them attractive candidates for novel immunostimulatory combination therapies. Here, we employ CosMx Single Cell Imaging (SMI) technology to spatially profile the transcriptional landscape of ~6000 targets in 9 ER+ BC patients, both pre- and post-treatment with the anti-PD-1 antibody Cemiplimab, to identify spatially resolved mechanisms of resistance and potential therapeutic targets. After quality control, ~3.1 million cells across 18 unique tissue sections were analyzed, allowing for robust characterization of immune, stromal, and epithelial cell niches with the ability to identify rare immune cell subsets at a high resolution. Comparing relative abundances of cell types of patients pre- and post-therapy, we see a high concordance of cell-types between tissue sections of the same patient. While 8/9 patients were dominated by Luminal A/B cancer epithelial cells, one patient had purely basal cancer epithelial cells, highlighting the value in spatial transcriptomic platforms for molecular subtyping in BC patients. To define metrics of patient response to Cemiplimab therapy, we quantified changes in tumor-intrinsic inflammatory/immune pathways and leveraged spatial information to calculate changes in tumor-infiltrating lymphocytes (TILs). 3/9 patients showed increased levels of type I/II IFN signaling in the tumor epithelium, 5/9 showed no change, and 1/9 showed a sharp decrease, coinciding with a unique increase in TNF-alpha signaling via NF-κB. 6/9 patients showed increases in TILs following therapy, defined as the fraction of tumor cells ≤ 0.1 mm from the nearest CD8 T-cell. The patient with the most pronounced decrease in TILs was the same patient who showed reduced IFN signaling previously, indicating agreement between response indicators, and suggesting upregulation of TNFa signaling via NFkB as a resistance mechanism to T-cell invasion. Our early work provides a comprehensive spatially resolved analysis of the mechanisms through which ER+ BCs resist ICB, suggesting that spatially mapped transcriptional programs can uncover actionable resistance pathways, and guide the design of next-generation immunotherapeutic combinations for ER+ BC.
利益披露 Disclosure
O. J. De Sa, None..
A. Arnaout, None.