LBPO.CL02 · 临床研究 · Late-Breaking

患者来源类器官-免疫细胞共培养及空间生物学支持针对成釉细胞瘤型颅咽管瘤的CD44v9癌症干细胞导向治疗策略

Patient-derived organoid-immune cell co-cultures and spatial biology support a CD44v9 cancer stem cell-directed therapeutic strategy for adamantinomatous craniopharyngioma

编号 LB124 展板 11 时间 4/20 09:00–12:00 区域 Section 52 主讲 Abby Branch

分会场 Late-Breaking Research: Clinical Research 2

查看 PDF 下载 PDF 🔒 查看 / 下载完整 PDF 需登录并开通下载套餐 · 查看套餐 / 开通 AACR 官方页面

作者与单位 Authors & Affiliations

Abigail G. Branch¹, Xi Sun¹, Arturo A. Lujan², Jia-Ren Lin³, Yi-Chien Wu⁴, Jennifer Eschbacher⁵, Beth Hermes⁶, Andrew S. Little⁷, Yoshie Umemura⁸, Sandro Santagata⁴, Yana Zavros¹

¹University of Georgia, Athens, GA,²University of Arizona College of Medicine, Tucson, AZ,³Brigham and Women's Hospital, Harvard Medical School Department of Pathology, Boston, MA,⁴Brigham and Women's Hospital, Harvard Medical School Department of Pa-thology, Boston, MA,⁵Department of Neuropathology, Barrow Neurological Institute, Pheonix, AZ,⁶Department of Neuropathology, Barrow Neurological Institute, Phoenix, AZ,⁷Department of Neurosurgery, Barrow Neurological Institute, Phoenix, AZ,⁸Department of Neuro-oncology, Barrow Neurological Institute, Phoenix, AZ

摘要 Abstract

中文摘要

背景：颅咽管瘤是罕见的上皮性肿瘤，可分为成釉细胞瘤型颅咽管瘤（ACP）或乳头状颅咽管瘤（PCP）亚型，二者在组织学、病理学和遗传学上存在明显差异。颅咽管瘤的治疗仍是一项医学挑战，并与其独特且未明确的肿瘤生物学相关的复杂临床结局相关联。PCP的治疗已取得显著进展。虽然PCP患者通常对BRAF-MEK抑制剂应答良好，但ACP中缺乏BRAF V600E突变构成了挑战。分化簇（CD）44跨膜糖蛋白（CD44）的可变mRNA剪接产生变异异构体CD44v9。CD44v9在包括颅咽管瘤在内的多种肿瘤中表达，是一种已知的癌症干细胞（CSC）标志物，可调控肿瘤细胞增殖、转移和化疗耐药。早期研究还提出了在ACP中靶向PD-L1和/或PD-1的潜在治疗益处。目的：确定了针对ACP治疗靶向PD-L1和/或PD-1以及CD44v9的潜在治疗益处。方法：使用采集自ACP和PCP患者的肿瘤组织进行Rarecyte Orion™多重免疫荧光（MxIF）和CosMx™全转录组空间分子成像仪（CosMx™ WTX SMI）分析。生成颅咽管瘤患者来源类器官（CrPDOs），并与源自外周血单个核细胞的自体免疫细胞（IMM）共培养。CrPDO/IMM共培养用于预测对酪氨酸激酶抑制剂cabozantinib（Cabo）联合pembrolizumab（Pembro）或atezolizumab（Atezo）联合治疗的潜在治疗益处。使用CrPDOs测试了针对衰老而设计的CD44v9导向抗体-药物偶联物（CD44v9-ADCs；Abzena）。结果：CosMx™ WTX SMI分析显示CD44和TROP2阳性细胞、癌症相关成纤维细胞以及髓源性抑制细胞（MDSCs）的表达，与PD-L1的染色模式一致。匹配的CrPDOs和组织的MxIF显示CD44v9在衰老的CD44阳性、空间定位的细胞群体中表达。用Cabo联合Pembro或Atezo对CrPDO/IMM共培养进行联合治疗，导致MDSCs耗竭，与细胞毒性T淋巴细胞增殖增加和肿瘤细胞死亡相关，同时存在持续的CD44v9+ CSC群体。用CD44v9-ADCs处理PDOs导致肿瘤细胞死亡，通过高内涵共聚焦显微镜以核不规则指数和碘化丙啶摄取进行测量。结论：携带溶解衰老细胞（senolytic）和抗氧化防御抑制载荷的CD44v9导向ADCs，是靶向残余CSC并预防ACP复发的一种潜在治疗方法。

查看英文原文 English abstract

Background: Craniopharyngiomas are rare epithelial tumors that are categorized as adamantinomatous craniopharyngioma (ACP) or papillary craniopharyngioma (PCP) subtype with distinct histological, pathological and genetic differences. The treatment of craniopharyngioma remains a medical challenge and is associated with the complex clinical outcomes that are related to the unique and undefined tumor biology. Significant advancement has been made for the treatment of PCPs. While patients with PCPs often respond well to BRAF-MEK inhibitors, the absence of the BRAF V600E mutation in ACPs presents a challenge. Alternative mRNA splicing of Cluster of Differentiation (CD) 44 transmembrane glycoprotein (CD44) generates the variant isoform CD44v9. Expressed in several tumors including craniopharyngiomas, CD44v9 is a known cancer stem cell (CSC) marker that regulates tumor cell proliferation, metastasis and chemotherapy resistance. Early studies also propose the potential therapeutic benefit of targeting PD-L1 and/or PD-1 in ACPs. Objective: The potential therapeutic benefit of targeting PD-L1 and/or PD-1, and CD44v9 for the treatment of ACPs was identified. Method: Rarecyte Orion ™ Multiplex Immunofluorescence (MxIF) and CosMx ™ Whole Transcriptome Spatial Molecular Imager (CosMx ™ WTX SMI) was performed using tumor tissues collected from patients with ACPs and PCPs. Craniopharyngioma patient-derived organoids (CrPDOs) were generated and co-cultured with autologous immune cells (IMM) generated from peripheral blood mononuclear cells. CrPDO/IMM co cultures were used to predict the potential therapeutic benefit in response to tyrosine kinase inhibitor cabozantinib (Cabo) plus pembrolizumab (Pembro) or atezolizumab (Atezo) combinatorial therapy. CD44v9-directed antibody-drug conjugates (CD44v9-ADCs; Abzena) designed to target senescence were tested using CrPDOs. Results: CosMx ™ WTX SMI analysis showed expression of CD44 and TROP2 positive cells, cancer associated fibroblasts and myeloid derived suppressor cells (MDSCs) consistent with the staining pattern of PD-L1. MxIF of matched CrPDOs and tissues showed expression of CD44v9 within senescent CD44 positive spatially mapped cell populations. Combinatorial treatment of CrPDO/IMM co-cultures with Cabo plus Pembro or Atezo led to depletion of MDSCs correlating with increased cytotoxic T lymphocyte proliferation and tumor cell death with a persistent CD44v9+ CSC population. Treatment of PDOs with CD44v9-ADCs resulted in tumor cell death, as measured by high-content confocal microscopy by nuclear irregularity index and propidium iodide uptake. Conclusion: CD44v9-directed ADCs, carrying senolytic and antioxidant defense-inhibiting payloads are a potential therapeutic approach for targeting residual CSCs and preventing recurrence of ACPs.

利益披露 Disclosure

A. G. Branch, None.. X. Sun, None.. A. A. Lujan, None.. J. Lin, None.. Y. Wu, None.. J. Eschbacher, None.. B. Hermes, None.. A. S. Little, None.. Y. Umemura, None.. S. Santagata, None.. Y. Zavros, None.

← 返回 AACR 2026 检索