Andrographolide potentiates PD-1 blockade immunotherapy by inhibiting COX2-mediated PGE2 release.

Abstract

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-γ 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.

• Authors: Wen Liu, Ting Fan, Manru Li, Guohui Zhang, Wenjie Guo, Xiaoling Yang, Chunhong Jiang, Xiang Li, Xiangyu Xu, Anshu Tang, Keqin Liu, Lixuan Liu, Lingdong Kong, Qiang Xu, Yang Sun
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 81 Pg. 106206 (Apr 2020) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 32018066 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents, Immunological
• Diterpenes
• Immune Checkpoint Inhibitors
• Programmed Cell Death 1 Receptor
• andrographolide
• Interferon-gamma
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• Dinoprostone

Topics

• Animals
• Antineoplastic Agents, Immunological (therapeutic use)
• Cell Line, Tumor
• Colonic Neoplasms (immunology, therapy)
• Cyclooxygenase 2 (metabolism)
• Dinoprostone (metabolism)
• Disease Models, Animal
• Diterpenes (therapeutic use)
• Female
• Humans
• Immune Checkpoint Inhibitors (therapeutic use)
• Immunotherapy (methods)
• Interferon-gamma (metabolism)
• Mice
• Mice, Inbred BALB C
• Programmed Cell Death 1 Receptor (antagonists & inhibitors, immunology)
• Tumor Burden
• Xenograft Model Antitumor Assays