PO.ET02.14 · 实验与分子治疗
KRAS通路抑制与脂质体伊立替康联合治疗增强肿瘤消退、减轻促结缔组织增生并增加胰腺导管腺癌中的T细胞浸润
Combined KRAS pathway inhibition and liposomal irinotecan treatment enhances tumor regression, attenuates desmoplasia, and augments T cell infiltration in pancreatic ductal adenocarcinoma
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摘要 Abstract
中文摘要
背景：胰腺导管腺癌（PDAC）主要由致癌性KRAS信号驱动，其特征是免疫抑制性、纤维化的肿瘤微环境，限制了治疗反应。RMC-6236（一种pan-KRAS抑制剂）和脂质体伊立替康（一种在研抗肿瘤药物）在KRAS突变癌症中各自显示出部分活性。然而，它们在PDAC中的联合治疗潜力尚未探索。在此，我们在多种体外和体内PDAC模型中评估了RMC-6236、脂质体伊立替康和单用伊立替康以及双药联合的抗肿瘤疗效、生存获益和免疫调节作用。
方法：使用KPC、PANC-1、AsPC-1和PANC-02细胞系进行体外细胞毒性实验。在原位KPC和PANC-1肿瘤模型中开展体内治疗研究。RMC-6236以10 mg/kg口服给药；脂质体伊立替康和伊立替康以5 mg/kg静脉给药。分析肿瘤生长抑制、生存、胶原沉积和免疫细胞浸润。通过CD8、CD4、I型胶原和纤连蛋白的免疫组化定量肿瘤微环境重塑。
结果：RMC-6236与脂质体伊立替康联合在所有评估的PDAC细胞系中引发强效抗肿瘤作用，体外实现超过90%的生长抑制。在体内，联合治疗在KPC和PANC-1异种移植模型中均导致超过90%的肿瘤消退，显著超越各单药疗法及其他双药对照的疗效。联合治疗显著延长总生存期，并持续抑制肿瘤进展。机制分析显示肿瘤微环境内胶原和纤连蛋白沉积大幅减少，与促结缔组织增生的减轻相一致。免疫谱分析表明瘤内CD8⁺和CD4⁺ T细胞浸润显著增强，同时survivin表达明显降低。重要的是，治疗动物中未检测到可观察的全身毒性。
结论：RMC-6236与脂质体伊立替康联合产生协同抗肿瘤作用，重塑纤维化的PDAC微环境，增强T细胞浸润，并在侵袭性胰腺肿瘤模型中显著改善生存。这些发现为基于RMC-6236的联合疗法治疗KRAS驱动的PDAC的临床评估提供了有力依据。
查看英文原文 English abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is driven predominantly by oncogenic KRAS signaling and characterized by an immunosuppressive, fibrotic tumor microenvironment that limits therapeutic responses. RMC-6236, a pan-KRAS inhibitor, and liposomal irinotecan, an investigational anti-tumor agent, each demonstrate partial activity in KRAS-mutant cancers. However, their combined therapeutic potential in PDAC remains unexplored. Here, we evaluated the anti-tumor efficacy, survival benefit, and immunomodulatory effects of RMC-6236, liposomal irinotecan and irinotecan alone and dual combinations multiple in vitro and in vivo PDAC models.
Methods: In vitro cytotoxicity assays were performed using KPC, PANC-1, AsPC-1, and PANC-02 cell lines. In vivo therapeutic studies were conducted in orthotopic KPC and PANC-1 tumor models. RMC-6236 was administered orally at 10 mg/kg; liposomal irinotecan and irinotecan was administered intravenously at 5 mg/kg. Tumor growth inhibition, survival, collagen deposition, and immune cell infiltration were analyzed. Tumor microenvironment remodeling was quantified via immunohistochemistry for CD8, CD4, collagen I, and fibronectin.
Results: The combination of RMC-6236 and liposomal irinotecan elicited potent anti-tumor effects across all evaluated PDAC cell lines, achieving greater than 90% growth inhibition in vitro. In vivo, co-treatment resulted in more than 90% tumor regression in both KPC and PANC-1 xenograft models, markedly surpassing the efficacy of individual monotherapies and other dual-agent controls. Combination therapy significantly extended overall survival and produced sustained suppression of tumor progression. Mechanistic analyses revealed a substantial reduction in collagen and fibronectin deposition within the tumor microenvironment, consistent with attenuation of desmoplasia. Immune profiling demonstrated a robust enhancement of intratumoral CD8⁺ and CD4⁺ T-cell infiltration, along with a pronounced decrease in survivin expression. Importantly, no observable systemic toxicity was detected in treated animals.
Conclusions: RMC-6236 combined with liposomal irinotecan yields synergistic anti-tumor effects, remodels the fibrotic PDAC microenvironment, enhances T-cell infiltration, and significantly improves survival in aggressive pancreatic tumor models. These findings provide strong rationale for clinical evaluation of RMC-6236-based combination therapies for KRAS driven PDAC.
利益披露 Disclosure
H. Rachamala, None..
F. Wei, None.