新藤黄酸通过减弱髓系来源抑制细胞的抑制功能增强胰腺癌的抗 PD-1 免疫治疗效果。
Neogambogic acid enhances anti-PD-1 immunotherapy efficacy by attenuating suppressive function of MDSCs in pancreatic cancer.
机构信息
Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300100, China; Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Tianjin 300100, China; Institute of Integrative Medicine for Acute Abdominal Diseases, Tianjin 300100, China.
Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Tianjin 300100, China; Institute of Integrative Medicine for Acute Abdominal Diseases, Tianjin 300100, China; Integrated Chinese and Western Medicine Hospital, Tianjin University, Tianjin, China.
出版信息
Int Immunopharmacol. 2024 Sep 30;139:112696. doi: 10.1016/j.intimp.2024.112696. Epub 2024 Jul 16.
BACKGROUND
Anti-PD-1-based immunotherapy has limited benefits in patients with pancreatic cancer. Accumulating data indicate that natural products exert antitumor activity by remodeling the tumor immune microenvironment. It has been reported that neogambogic acid (NGA), an active natural monomer extracted from Garcinia, has anti-inflammatory and antitumor effects. Nevertheless, there are few systematic studies on the antitumor efficacy and immunomodulatory effects of NGA in pancreatic cancer.
METHODS
An orthotopic mouse model of pancreatic cancer was established and were treated with different doses of NGA. Tumor growth and ascites were observed. Flow cytometry and immunohistochemistry (IHC) were used to investigate the tumor immune microenvironment. CD11b MDSCs were infused back into mice with pancreatic cancer to observe tumor progression after NGA treatment. Bone marrow cells were induced to differentiate into MDSCs, and the effects of NGA on MDSCs were analyzed and the underlying mechanism was explored. The effects of NGA combined with an anti-PD-1 antibody on pancreatic cancer were further tested.
RESULTS
NGA significantly inhibited the tumor growth and improve ascites character in pancreatic cancer model mice. Flow cytometry and IHC analysis revealed that NGA decreased the MDSCs proportion and infiltration in the tumor microenvironment. Moreover, adoptive MDSCs largely attenuated the inhibitory effect of NGA on the progression of pancreatic cancer. In addition, we showed that NGA significantly promoted apoptosis and inhibited the differentiation, migration and immunosuppressive function of MDSCs and decreased level of STAT3 and p-STAT3. Furthermore, we demonstrated that NGA synergistically enhanced the efficacy of anti-PD-1 antibodies against pancreatic cancer.
CONCLUSION
NGA inhibited the progression of pancreatic cancer by inhibiting MDSCs in the tumor microenvironment, and enhanced the efficacy of anti-PD-1 therapy in the treatment of pancreatic cancer.
背景
抗 PD-1 免疫疗法在胰腺癌患者中的获益有限。越来越多的数据表明，天然产物通过重塑肿瘤免疫微环境发挥抗肿瘤活性。据报道，从藤黄中提取的活性天然单体新藤黄酸（NGA）具有抗炎和抗肿瘤作用。然而，关于 NGA 在胰腺癌中的抗肿瘤功效和免疫调节作用的系统研究较少。
方法
建立了胰腺癌原位小鼠模型，并给予不同剂量的 NGA 治疗。观察肿瘤生长和腹水情况。流式细胞术和免疫组织化学（IHC）用于研究肿瘤免疫微环境。将 CD11b MDSC 回输给胰腺癌小鼠，观察 NGA 治疗后肿瘤进展情况。诱导骨髓细胞分化为 MDSC，分析 NGA 对 MDSC 的作用，并探讨其潜在机制。进一步测试了 NGA 与抗 PD-1 抗体联合对胰腺癌的作用。
结果
NGA 显著抑制胰腺癌模型小鼠的肿瘤生长并改善腹水特征。流式细胞术和 IHC 分析显示，NGA 降低了肿瘤微环境中 MDSC 的比例和浸润。此外，过继转移 MDSC 大大减弱了 NGA 对胰腺癌进展的抑制作用。此外，我们表明 NGA 显著促进 MDSC 的凋亡并抑制其分化、迁移和免疫抑制功能，降低 STAT3 和 p-STAT3 的水平。此外，我们证明 NGA 协同增强了抗 PD-1 抗体治疗胰腺癌的疗效。
结论
NGA 通过抑制肿瘤微环境中的 MDSC 抑制胰腺癌的进展，并增强抗 PD-1 治疗在胰腺癌治疗中的疗效。
Zotero 插件