Blocking EP4 down-regulates tumor metabolism and synergizes with anti-PD-1 therapy to activate natural killer cells in a lung adenocarcinoma model

被引:9
作者
Tokumasu, Miho [1 ]
Nishida, Mikako [1 ]
Kawaguchi, Takamasa [2 ]
Kudo, Ikuru [1 ]
Kotani, Tohru [2 ]
Takeda, Kazuhiko [2 ]
Yoshida, Takao [2 ]
Udono, Heiichiro [1 ]
机构
[1] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Immunol, 2-5-1 Shikata Cho,Kita ku, Okayama 7008558, Japan
[2] Ono Pharmaceut Co Ltd, Res Ctr Oncol, 3-1-1 Sakurai,Shimamoto Cho, Osaka 6188585, Japan
关键词
NK cells; prostaglandin; tumor immunity; tumor metabolism; tumor vessels; MACROPHAGES; PROSTAGLANDIN-E2; MICROENVIRONMENT; EXPRESSION; BLOCKADE;
D O I
10.1093/intimm/dxac004
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Prostaglandin E2 (PGE2), a product of the cyclooxygenase (COX) pathway, is produced by tumors and surrounding stromal cells. It stimulates tumor progression, promotes angiogenesis and suppresses the anti-tumor response. Pharmacological inhibition of PGE2 synthesis has been shown to suppress tumor initiation and growth in vivo. In the current study, we demonstrated that the growth of the Ptgs2-deficient 3LL lung adenocarcinoma cell line was down-regulated in vivo through natural killer (NK) cell activation and a reduction in the population of polymorphonuclear leukocyte-myeloid-derived suppressor cells (PMN-MDSCs) and tumor-associated macrophages (TAMs). On the basis of these results, the therapeutic effect of ONO-AE3-208 (EP4i), an inhibitor of EP4 (a PGE2 receptor), combined with anti-PD-1 antibody was evaluated. EP4i, but not anti-PD-1 antibody, decreased tumor metabolism including glycolysis, fatty acid oxidation and oxidative phosphorylation. EP4i induced IFN gamma production from only NK cells (not from T cells) and a shift from M2-like to M1-like macrophages in TAMs. These effects were further enhanced by anti-PD-1 antibody treatment. Although CD8 T-cell infiltration was increased, IFN gamma production was not significantly altered, even with combination therapy. Tumor hypoxia was ameliorated by either EP4i or anti-PD-1 antibody treatment, which was further affected by the combination. Normalization of tumor vessels was significant only for the combination therapy. The results indicated a novel effect of EP4i for the metabolic reprogramming of tumors and revealed unique features of EP4i that can synergize with anti-PD-1 antibody to promote IFN gamma production by NK cells, polarize TAMs into the M1 phenotype, and reduce hypoxia through normalization of the tumor vasculature.
引用
收藏
页码:293 / 302
页数:10
相关论文
共 31 条
[1]   Cyclooxygenase-2 blockade can improve efficacy of VEGF-targeting drugs [J].
Ben-Batalla, Isabel ;
Cubas-Cordova, Miguel ;
Udonta, Florian ;
Wroblewski, Mark ;
Waizenegger, Jonas S. ;
Janning, Melanie ;
Sawall, Stefanie ;
Gensch, Victoria ;
Zhao, Lin ;
Martinez-Zubiaurre, Inigo ;
Riecken, Kristoffer ;
Fehse, Boris ;
Pantel, Klaus ;
Bokemeyer, Carsten ;
Loges, Sonja .
ONCOTARGET, 2015, 6 (08) :6341-6358
[2]   NK Cells Stimulate Recruitment of cDC1 into the Tumor Microenvironment Promoting Cancer Immune Control [J].
Boettcher, Jan P. ;
Bonavita, Eduardo ;
Chakravarty, Probir ;
Blees, Hanna ;
Cabeza-Cabrerizo, Mar ;
Sammicheli, Stefano ;
Rogers, Neil C. ;
Sahai, Erik ;
Zelenay, Santiago ;
Reis e Sousa, Caetano .
CELL, 2018, 172 (05) :1022-+
[3]  
Cai Yi, 2020, Advances in Biological Regulation, V75, P100653, DOI 10.1016/j.jbior.2019.100653
[4]   Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression [J].
Chang, Chih-Hao ;
Qiu, Jing ;
O'Sullivan, David ;
Buck, Michael D. ;
Noguchi, Takuro ;
Curtis, Jonathan D. ;
Chen, Qiongyu ;
Gindin, Mariel ;
Gubin, Matthew M. ;
van der Windt, Gerritje J. W. ;
Tonc, Elena ;
Schreiber, Robert D. ;
Pearce, Edward J. ;
Pearce, Erika L. .
CELL, 2015, 162 (06) :1229-1241
[5]   Effect of Low-dose and Standard-dose Aspirin on PGE2 Biosynthesis Among Individuals with Colorectal Adenomas: A Randomized Clinical Trial [J].
Drew, David A. ;
Schuck, Madeline M. ;
Magicheva-Gupta, Marina, V ;
Stewart, Kathleen O. ;
Gilpin, Katherine K. ;
Miller, Patrick ;
Parziale, Melanie P. ;
Pond, Emily N. ;
Takacsi-Nagy, Oliver ;
Zerjav, Dylan C. ;
Chin, Samantha M. ;
Krems, Jennifer Mackinnon ;
Meixell, Dana ;
Joshi, Amit D. ;
Ma, Wenjie ;
Colizzo, Francis P. ;
Carolan, Peter J. ;
Nishioka, Norman S. ;
Staller, Kyle ;
Richter, James M. ;
Khalili, Hamed ;
Gala, Manish K. ;
Garber, John J. ;
Chung, Daniel C. ;
Yarze, Joseph C. ;
Zukerberg, Lawrence ;
Petrucci, Giovanna ;
Rocca, Bianca ;
Patrono, Carlo ;
Milne, Ginger L. ;
Wang, Molin ;
Chan, Andrew T. .
CANCER PREVENTION RESEARCH, 2020, 13 (10) :877-888
[6]   Immune-mediated antitumor effect by type 2 diabetes drug, metformin [J].
Eikawa, Shingo ;
Nishida, Mikako ;
Mizukami, Shusaku ;
Yamazaki, Chihiro ;
Nakayama, Eiichi ;
Udono, Heiichiro .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2015, 112 (06) :1809-1814
[7]  
Harris RE, 2005, ONCOL REP, V13, P559
[8]   M2 Macrophages Induced by Prostaglandin E2 and IL-6 from Cervical Carcinoma Are Switched to Activated M1 Macrophages by CD4+ Th1 Cells [J].
Heusinkveld, Moniek ;
van Steenwijk, Peggy J. de Vos ;
Goedemans, Renske ;
Ramwadhdoebe, Tamara H. ;
Gorter, Arko ;
Welters, Marij J. P. ;
van Hall, Thorbald ;
van der Burg, Sjoerd H. .
JOURNAL OF IMMUNOLOGY, 2011, 187 (03) :1157-1165
[9]   Prostaglandin E2 (PGE2) suppresses natural killer cell function primarily through the PGE2 receptor EP4 [J].
Holt, Dawn ;
Ma, Xinrong ;
Kundu, Namita ;
Fulton, Amy .
CANCER IMMUNOLOGY IMMUNOTHERAPY, 2011, 60 (11) :1577-1586
[10]   Direct Melanoma Cell Contact Induces Stromal Cell Autocrine Prostaglandin E2-EP4 Receptor Signaling That Drives Tumor Growth, Angiogenesis, and Metastasis [J].
Inada, Masaki ;
Takita, Morichika ;
Yokoyama, Satoshi ;
Watanabe, Kenta ;
Tominari, Tsukasa ;
Matsumoto, Chiho ;
Hirata, Michiko ;
Maru, Yoshiro ;
Maruyama, Takayuki ;
Sugimoto, Yukihiko ;
Narumiya, Shuh ;
Uematsu, Satoshi ;
Akira, Shizuo ;
Murphy, Gillian ;
Nagase, Hideaki ;
Miyaura, Chisato .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2015, 290 (50) :29781-29793