Ma Yilan, Ding Jin, Chen Yanping
Department of Gastroenterology, Jinhua Central Hospital, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, Zhejiang, China.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Sep 10. doi: 10.1007/s00210-025-04532-x.
The fourth leading cause of cancer-related fatalities in the USA is pancreatic ductal adenocarcinoma (PDAC), a particularly deadly illness that is resistant to immunotherapy. One of the Main Obstacles in cancer research is developing better treatments for PDAC, which has the lowest 5-year survival rate of any malignancy. Anti-CTLA-4, anti-PD-L1, and anti-PD-1 immune checkpoint blockade medications also have poor results in these patients, which may indicate the presence of other immunosuppressive mechanisms in the pancreatic tumor microenvironment (TME). A new therapeutic avenue for cancer immunotherapy is CD40 activation. When CD40 is activated, it can retrain macrophages to eliminate tumor stroma and license dendritic cells to encourage anticancer T-cell activation. Several different formulations of agonist CD40 antibodies have been tested in clinical settings and determined to be both viable and tolerated. A number of agonistic CD40 monoclonal antibody (mAb) clinical trials are now underway, but little is known about the biological consequences and treatment-related regulation of the TME. Because CD40 agonist antibodies (αCD40) improve macrophage tumoricidal activity and promote antigen-presenting cell (APC) development, they may change the pancreatic TME to make it more susceptible to immune checkpoint blockage. It is believed that CD40 agonists work through T-cells and macrophages to provide antitumor effects on PDAC. Rapid tumor infiltration, tumoricidal effects, and tumor stroma depletion were all boosted by CD40-activated macrophages. Therefore, this study provides a CD40-dependent strategy for targeting tumor stroma in cancer treatment, indicating that cancer immune surveillance does not necessarily rely on therapy-induced T-cells. The purpose of this study was to examine how CD40 agonist antibody therapy might change the microenvironment and treat PDAC in humans.
在美国，与癌症相关的死亡中，胰腺导管腺癌（PDAC）是第四大主要原因，这是一种特别致命的疾病，对免疫疗法具有抗性。癌症研究中的主要障碍之一是为PDAC开发更好的治疗方法，PDAC的5年生存率是所有恶性肿瘤中最低的。抗CTLA-4、抗PD-L1和抗PD-1免疫检查点阻断药物在这些患者中的效果也很差，这可能表明胰腺肿瘤微环境（TME）中存在其他免疫抑制机制。癌症免疫疗法的一条新治疗途径是CD40激活。当CD40被激活时，它可以重新训练巨噬细胞以消除肿瘤基质，并使树突状细胞具备促进抗癌T细胞激活的能力。几种不同配方的激动剂CD40抗体已在临床环境中进行了测试，并被确定为可行且耐受性良好。目前正在进行多项激动性CD40单克隆抗体（mAb）临床试验，但对于TME的生物学后果和与治疗相关的调节知之甚少。由于CD40激动剂抗体（αCD40）可提高巨噬细胞的杀肿瘤活性并促进抗原呈递细胞（APC）的发育，它们可能会改变胰腺TME，使其更容易受到免疫检查点阻断的影响。据信，CD40激动剂通过T细胞和巨噬细胞发挥作用，对PDAC产生抗肿瘤作用。CD40激活的巨噬细胞增强了肿瘤的快速浸润、杀肿瘤作用和肿瘤基质的消耗。因此，本研究提供了一种在癌症治疗中靶向肿瘤基质的CD40依赖性策略，表明癌症免疫监视不一定依赖于治疗诱导的T细胞。本研究的目的是研究CD40激动剂抗体疗法如何改变微环境并治疗人类的PDAC。
