Andrographolide potentiates PD-1 blockade immunotherapy by inhibiting COX2-mediated PGE2 release
Andrographolide potentiates PD-1 blockade immunotherapy by inhibiting COX2-mediated PGE2 release
复制标题
穿心莲内酯通过抑制 COX2 介导的 PGE2 释放来增强 PD-1 阻断免疫疗法
DOI：
10.1016/j.intimp.2020.106206
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发表时间：
2020-04-01
影响因子：
5.6
通讯作者：
Sun, Yang
中科院分区：
文献类型：
--
作者：
Liu, Wen;Fan, Ting;Sun, Yang
癌症免疫治疗现已成为多种肿瘤的一线治疗。然而，免疫检查点阻断疗法的临床表现通常受到低应答率或包括细胞因子风暴的副作用的限制。穿心莲内酯是从穿心莲中提取的天然二萜类化合物，具有独特的抗炎作用，在亚洲已被用于治疗支气管炎、百日咳和细菌性痢疾。然而，其对抗肿瘤免疫的作用仍然难以捉摸。在这项研究中，我们发现穿心莲内酯与抗PD-1抗体的组合在CT 26结肠癌的鼠异种移植模型中显示出比单独治疗更高的治疗益处。因此，穿心莲内酯和抗PD-1抗体共治疗增强了CD 4（+）和CD 8（+）T细胞的功能，这通过相当大的组织浸润、IFN-γ分泌升高和细胞毒性T细胞相关分子（包括FasL、穿孔素和颗粒酶B）的表达增强来证明，这显著降低了肿瘤负荷。在机制上，穿心莲内酯治疗在体内和体外均抑制COX 2活性和PGE 2释放，这增强了抗PD-1疗法的抗肿瘤效率。最后，我们证实了人类结肠癌样本中的COX 2水平与肿瘤促进因子正相关。我们的研究为结直肠癌的免疫治疗提供了一种潜在的组合策略。
Cancer immunotherapy has now become a first line therapy for several kinds of tumors. However, the clinical performance of immnuocheckpoint blockade therapy is usually limited by low response rate or side effects including cytokine storm. Andrographolide, a natural diterpenoid from Andrographis paniculata, has been used in Asia for treatment of bronchitis, paristhmitis and bacillary dysentery for its unique anti-inflammatory effect. However, its effect on anti-tumor immunity remains elusive. In this study, we found that andrographolide in combination with anti-PD-1 antibody showed a higher therapeutic benefit than individual therapy in murine xenograft model of CT26 colon cancer. Consequently, andrographolide and anti-PD-1 antibody co-treatment boosted the function of CD4(+) and CD8(+) T cells evidenced by considerable tissue infiltration, elevated IFN-gamma secretion and enhanced expression of cytotoxic T-cell related molecules including FasL, perforin and Granzyme B, which significantly decreases the tumor load. Mechanistically, andrographolide treatment inhibited COX2 activity and PGE2 release both in vivo and in vitro, which augments anti-tumor efficiency of anti-PD-1 therapy. Finally, we confirmed that COX2 level in human colon cancer sample positively correlated with tumor-promoting factors. Our study here provides a potential combination strategy for immunotherapy against colorectal cancer.