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Andrographolide potentiates PD-1 blockade immunotherapy by inhibiting COX2-mediated PGE2 release
Institution:1. State Key Laboratory of Pharmaceutical Biotechnology, Department of Biotechnology and Pharmaceutical Sciences, School of Life Science, Nanjing University, 163 Xianlin Avenue, Nanjing 210023, China;2. State Key Laboratory of Innovative Nature Medicine and TCM Injections, Jiangxi Qingfeng Pharmaceutical Co., Ltd., Ganzhou 341000, China;3. Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing 210023, China
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.
Keywords:Immnuotherapy  Andrographolide  Anti-PD-1  COX2  PGE2
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