PO.TB03.01 · 肿瘤生物学
胰腺癌恶性腹水的新型靶向疗法
Novel targeted therapies for malignant ascites in pancreatic cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
恶性腹水（MA）仍然是包括胰腺癌在内的晚期癌症患者中一种严重、无法治疗的并发症，是导致其预后不良的原因之一。我们使用单细胞RNA测序（scRNA-seq）对从胰腺癌患者MA样本中分离的12,084个细胞进行了表征。我们发现免疫细胞是占主导地位的（90%）细胞群体，其中M2样巨噬细胞（62.4%）和T细胞（23.1%）占多数，而肿瘤细胞仅占细胞总数的7.5%。M2样巨噬细胞以高CD163和低CD80表达为特征，表达升高的血管内皮生长因子（VEGF）和集落刺激因子-1受体（CSF1R），可能通过增加内皮通透性促进肿瘤增殖、存活和腹水形成。T细胞大多为CD8阴性，表明细胞毒功能受到抑制，这与卵巢癌腹水中的发现一致。我们假设，靶向VEGF、CSF1R和免疫检查点蛋白（如PD-1和CTLA-4）可以重编程MA免疫微环境，减少腹水和腹膜肿瘤生长。为验证这一假设，我们通过将源自KPC模型的鼠源胰腺癌细胞腹腔内植入C57BL/6小鼠，建立了胰腺癌MA模型。这些小鼠在细胞注射后7-10天出现腹水，并在4-5周内死于该疾病。随后我们评估了抗PD-1和抗CTLA-4抗体作为单一药物或联合使用在KPC MA模型中的活性。两种抗体均显著减少了MA的形成并延长了小鼠的存活期。抗PD-1抗体（300μg/剂，每周3剂）将中位生存期从同型对照抗体组的25天延长至55天，而抗CTLA-4组（100μg/剂，每周3剂）和联合组的中位生存期在治疗开始后96天时均未达到。我们正在评估抗VEGFA抗体（2G11-2A05）和CSF1R抑制剂（PLX3397）在同一模型中的疗效。这些研究的结果可以建立临床前证据，支持这些新型治疗方案在治疗胰腺癌患者MA中的效用，并推动临床试验以解决这一关键的未满足需求。
查看英文原文 English abstract
Malignant ascites (MA) remains a severe, untreatable complication in patients with late-stage cancers including pancreatic cancer, contributing to their poor prognosis. Using single-cell RNA sequencing (scRNA-seq), we characterized 12,084 cells isolated in MA samples from patients with pancreatic cancer. We found that immune cells were the dominant (90%) cell population with M2-like macrophages (62.4%) and T cells (23.1%) prevailing, while tumor cells constituted only 7.5% of the total cell population. The M2-like macrophages, marked by high CD163 and low CD80 expression, expressed elevated vascular endothelial growth factor (VEGF) and colony-stimulating factor-1 receptor (CSF1R), potentially promoting tumor proliferation, survival, and ascites formation via increased endothelial permeability. The T cells were mostly CD8-negative, indicating suppressed cytotoxic function, consistent with findings in ovarian cancer ascites. We hypothesize that targeting VEGF, CSF1R, and immune checkpoint proteins (e.g., PD-1 and CTLA-4) can reprogram the MA immune microenvironment, reducing ascites and peritoneal tumor growth. To test this hypothesis, we established an MA model for pancreatic cancer by intraperitoneally implanting murine pancreatic cancer cells derived from the KPC model into C57BL/6 mice. These mice develop ascites 7-10 days after cell injection and succumb to the disease within 4-5 weeks. We then evaluated the activity of anti-PD-1 and anti-CTLA-4 antibodies as a single agent or in combination in the KPC MA model. Both antibodies significantly reduced the formation of MA and extended the survival of the mice. The anti-PD-1 antibody (300 µg/dose for 3 weekly doses) extended the median survival from 25 days in the isotype control antibody group to 55 days, while the median survivals for both the anti-CTLA-4 group (100 µg/dose for 3 weekly doses) and the combination group were not reached 96 days after the initiation of treatment. We are in the process of assessing the efficacy of an anti-VEGFA antibody (2G11-2A05) and a CSF1R inhibitor (PLX3397) in the same model. Results from the studies could establish preclinical evidence supporting the utility of these novel therapeutic regimens for treating MA in pancreatic cancer patients and lead to clinical trials to address this critical unmet need.
利益披露 Disclosure
K. Halder, None..
R. Munoz, None..
W. Lin, None..
A. Yang, None..
Y. Woo, None..
E. Borazanci, None..
H. Han, None..
D. Von Hoff, None.