Dihydroartemisinin increased the abundance of Akkermansia muciniphila by YAP1 depression that sensitizes hepatocellular carcinoma to anti-PD-1 immunotherapy
The effect of anti-programmed cell death 1 (anti-PD-1) immunotherapy is limited in patients with hepatocellular carcinoma (HCC). Yes-associated protein 1 (YAP1) expression increased in liver tumor cells in early HCC, and Akkermansia muciniphila abundance decreased in the colon. The response to anti-PD-1 treatment is associated with A. muciniphila abundance in many tumors. However, the interaction between A. muciniphila abundance and YAP1 expression remains unclear in HCC. Here, anti-PD-1 treatment decreased A. muciniphila abundance in the colon, but increased YAP1 expression in the tumor cells by mice with liver tumors in situ. Mechanistically, hepatocyte-specific Yap1 knockout (Yap1LKO) maintained bile acid homeostasis in the liver, resulting in an increased abundance of A. muciniphila in the colon. Yap1 knockout enhanced anti-PD-1 efficacy. Therefore, YAP1 inhibition is a potential target for increasing A. muciniphila abundance to promote anti-PD-1 efficacy in liver tumors. Dihydroartemisinin (DHA), acting as YAP1 inhibitor, increased A. muciniphila abundance to sensitize anti-PD-1 therapy. A. muciniphila by gavage increased the number and activation of CD8+ T cells in liver tumor niches during DHA treatment or combination with anti-PD-1. Our findings suggested that the combination anti-PD-1 with DHA is an effective strategy for liver tumor treatment.
AB El-Khoueiry, B Sangro, T Yau, TS Crocenzi, M Kudo, C Hsu, TY Kim, SP Choo, J Trojan, TH 3rd Welling, T Meyer, YK Kang, W Yeo, A Chopra, J Anderson, Cruz C Dela, L Lang, J Neely, H Tang, HB Dastani, I Melero. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 2017; 389(10088): 2492–2502 https://doi.org/10.1016/S0140-6736(17)31046-2
pmid: 28434648
3
CG Kim, C Kim, SE Yoon, KH Kim, SJ Choi, B Kang, HR Kim, SH Park, EC Shin, YY Kim, DJ Kim, HC Chung, HJ Chon, HJ Choi, HY Lim. Hyperprogressive disease during PD-1 blockade in patients with advanced hepatocellular carcinoma. J Hepatol 2021; 74(2): 350–359 https://doi.org/10.1016/j.jhep.2020.08.010
pmid: 32810553
4
AX Zhu, RS Finn, J Edeline, S Cattan, S Ogasawara, D Palmer, C Verslype, V Zagonel, L Fartoux, A Vogel, D Sarker, G Verset, SL Chan, J Knox, B Daniele, AL Webber, SW Ebbinghaus, J Ma, AB Siegel, AL Cheng, M; KEYNOTE-224 investigators Kudo. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol 2018; 19(7): 940–952 https://doi.org/10.1016/S1470-2045(18)30351-6
pmid: 29875066
5
Z Ren, A Li, J Jiang, L Zhou, Z Yu, H Lu, H Xie, X Chen, L Shao, R Zhang, S Xu, H Zhang, G Cui, X Chen, R Sun, H Wen, JP Lerut, Q Kan, L Li, S Zheng. Gut microbiome analysis as a tool towards targeted non-invasive biomarkers for early hepatocellular carcinoma. Gut 2019; 68(6): 1014–1023 https://doi.org/10.1136/gutjnl-2017-315084
pmid: 30045880
6
B Routy, Chatelier E Le, L Derosa, CPM Duong, MT Alou, R Daillère, A Fluckiger, M Messaoudene, C Rauber, MP Roberti, M Fidelle, C Flament, V Poirier-Colame, P Opolon, C Klein, K Iribarren, L Mondragón, N Jacquelot, B Qu, G Ferrere, C Clémenson, L Mezquita, JR Masip, C Naltet, S Brosseau, C Kaderbhai, C Richard, H Rizvi, F Levenez, N Galleron, B Quinquis, N Pons, B Ryffel, V Minard-Colin, P Gonin, JC Soria, E Deutsch, Y Loriot, F Ghiringhelli, G Zalcman, F Goldwasser, B Escudier, MD Hellmann, A Eggermont, D Raoult, L Albiges, G Kroemer, L Zitvogel. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018; 359(6371): 91–97 https://doi.org/10.1126/science.aan3706
pmid: 29097494
7
V Matson, J Fessler, R Bao, T Chongsuwat, Y Zha, ML Alegre, JJ Luke, TF Gajewski. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018; 359(6371): 104–108 https://doi.org/10.1126/science.aao3290
pmid: 29302014
8
NJ Salgia, PG Bergerot, MC Maia, N Dizman, J Hsu, JD Gillece, M Folkerts, L Reining, J Trent, SK Highlander, SK Pal. Stool microbiome profiling of patients with metastatic renal cell carcinoma receiving anti-PD-1 immune checkpoint inhibitors. Eur Urol 2020; 78(4): 498–502 https://doi.org/10.1016/j.eururo.2020.07.011
pmid: 32828600
9
Y Zheng, T Wang, X Tu, Y Huang, H Zhang, D Tan, W Jiang, S Cai, P Zhao, R Song, P Li, N Qin, W Fang. Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with hepatocellular carcinoma. J Immunother Cancer 2019; 7(1): 193 https://doi.org/10.1186/s40425-019-0650-9
pmid: 31337439
10
M Shibata, K Ham, MO Hoque. A time for YAP1: tumorigenesis, immunosuppression and targeted therapy. Int J Cancer 2018; 143(9): 2133–2144 https://doi.org/10.1002/ijc.31561
pmid: 29696628
11
A Perra, MA Kowalik, E Ghiso, GM Ledda-Columbano, L Di Tommaso, MM Angioni, C Raschioni, E Testore, M Roncalli, S Giordano, A Columbano. YAP activation is an early event and a potential therapeutic target in liver cancer development. J Hepatol 2014; 61(5): 1088–1096 https://doi.org/10.1016/j.jhep.2014.06.033
pmid: 25010260
12
J Cao, C Zhang, GQ Jiang, SJ Jin, Q Wang, AQ Wang, DS Bai. Identification of hepatocellular carcinoma-related genes associated with macrophage differentiation based on bioinformatics analyses. Bioengineered 2021; 12(1): 296–309 https://doi.org/10.1080/21655979.2020.1868119
pmid: 33380242
13
M Yu, Z Peng, M Qin, Y Liu, J Wang, C Zhang, J Lin, T Dong, L Wang, S Li, Y Yang, S Xu, W Guo, X Zhang, M Shi, H Peng, X Luo, H Zhang, L Zhang, Y Li, XP Yang, S Sun. Interferon-γ induces tumor resistance to anti-PD-1 immunotherapy by promoting YAP phase separation. Mol Cell 2021; 81(6): 1216–1230.e9 https://doi.org/10.1016/j.molcel.2021.01.010
pmid: 33606996
14
T Hagi, SY Geerlings, B Nijsse, C Belzer. The effect of bile acids on the growth and global gene expression profiles in Akkermansia muciniphila. Appl Microbiol Biotechnol 2020; 104(24): 10641–10653 https://doi.org/10.1007/s00253-020-10976-3
pmid: 33159542
15
L Van den Bossche, P Hindryckx, L Devisscher, S Devriese, S Van Welden, T Holvoet, R Vilchez-Vargas, M Vital, DH Pieper, J Vanden Bussche, L Vanhaecke, T Van de Wiele, M De Vos, D Laukens. Ursodeoxycholic acid and its taurine- or glycine-conjugated species reduce colitogenic dysbiosis and equally suppress experimental colitis in mice. Appl Environ Microbiol 2017; 83(7): e02766–16 https://doi.org/10.1128/AEM.02766-16
pmid: 28115375
16
X Zheng, F Huang, A Zhao, S Lei, Y Zhang, G Xie, T Chen, C Qu, C Rajani, B Dong, D Li, W Jia. Bile acid is a significant host factor shaping the gut microbiome of diet-induced obese mice. BMC Biol 2017; 15(1): 120 https://doi.org/10.1186/s12915-017-0462-7
pmid: 29241453
17
S Anakk, M Bhosale, VA Schmidt, RL Johnson, MJ Finegold, DD Moore. Bile acids activate YAP to promote liver carcinogenesis. Cell Rep 2013; 5(4): 1060–1069 https://doi.org/10.1016/j.celrep.2013.10.030
pmid: 24268772
18
T Wang, R Luo, W Li, H Yan, S Xie, W Xiao, Y Wang, B Chen, P Bai, J Xing. Dihydroartemisinin suppresses bladder cancer cell invasion and migration by regulating KDM3A and p21. J Cancer 2020; 11(5): 1115–1124 https://doi.org/10.7150/jca.36174
pmid: 31956358
19
Q Li, Q Ma, J Cheng, X Zhou, W Pu, X Zhong, X Guo. Dihydroartemisinin as a sensitizing agent in cancer therapies. OncoTargets Ther 2021; 14: 2563–2573 https://doi.org/10.2147/OTT.S297785
pmid: 33880035
20
Z LiG Tuteja J SchugKH Kaestner. Foxa1 and Foxa2 are essential for sexual dimorphism in liver cancer. Cell 2012; 148(1–2): 72–83 doi:10.1016/j.cell.2011.11.026
pmid: 22265403
21
J Zhang, X Bu, H Wang, Y Zhu, Y Geng, NT Nihira, Y Tan, Y Ci, F Wu, X Dai, J Guo, YH Huang, C Fan, S Ren, Y Sun, GJ Freeman, P Sicinski, W Wei. Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance. Nature 2018; 553(7686): 91–95 https://doi.org/10.1038/nature25015
pmid: 29160310
22
Z Jiang, SO Lim, M Yan, JL Hsu, J Yao, Y Wei, SS Chang, H Yamaguchi, HH Lee, B Ke, JM Hsu, LC Chan, GN Hortobagyi, L Yang, C Lin, D Yu, MC Hung. TYRO3 induces anti-PD-1/PD-L1 therapy resistance by limiting innate immunity and tumoral ferroptosis. J Clin Invest 2021; 131(8): e139434 https://doi.org/10.1172/JCI139434
pmid: 33855973
23
L Hao, Y Guo, Q Peng, Z Zhang, J Ji, Y Liu, Y Xue, C Li, K Zheng, X Shi. Dihydroartemisinin reduced lipid droplet deposition by YAP1 to promote the anti-PD-1 effect in hepatocellular carcinoma. Phytomedicine 2022; 96: 153913 https://doi.org/10.1016/j.phymed.2021.153913
pmid: 35026515
24
Y Guo, Q Peng, L Hao, J Ji, Z Zhang, Y Xue, Y Liu, Y Gao, C Li, X Shi. Dihydroartemisinin promoted FXR expression independent of YAP1 in hepatocellular carcinoma. FASEB J 2022; 36(6): e22361 https://doi.org/10.1096/fj.202200171R
pmid: 35616366
25
J Li, S Lin, PM Vanhoutte, CW Woo, A Xu. Akkermansia muciniphila protects against atherosclerosis by preventing metabolic endotoxemia-induced inflammation in Apoe–/– mice. Circulation 2016; 133(24): 2434–2446 https://doi.org/10.1161/CIRCULATIONAHA.115.019645
pmid: 27143680
26
MC Collado, M Derrien, E Isolauri, WM de Vos, S Salminen. Intestinal integrity and Akkermansia muciniphila, a mucin-degrading member of the intestinal microbiota present in infants, adults, and the elderly. Appl Environ Microbiol 2007; 73(23): 7767–7770 https://doi.org/10.1128/AEM.01477-07
pmid: 17933936
27
R Pieper, J Bindelle, B Rossnagel, A Van Kessel, P Leterme. Effect of carbohydrate composition in barley and oat cultivars on microbial ecophysiology and proliferation of Salmonella enterica in an in vitro model of the porcine gastrointestinal tract. Appl Environ Microbiol 2009; 75(22): 7006–7016 https://doi.org/10.1128/AEM.01343-09
pmid: 19783749
28
L Wang, L Tang, Y Feng, S Zhao, M Han, C Zhang, G Yuan, J Zhu, S Cao, Q Wu, L Li, Z Zhang. A purified membrane protein from Akkermansia muciniphila or the pasteurised bacterium blunts colitis associated tumourigenesis by modulation of CD8+ T cells in mice. Gut 2020; 69(11): 1988–1997 https://doi.org/10.1136/gutjnl-2019-320105
pmid: 32169907
29
X Jiu, Y Liu, J Wen. Artesunate combined with verteporfin inhibits uveal melanoma by regulation of the MALAT1/yes-associated protein signaling pathway. Oncol Lett 2021; 22(2): 597 https://doi.org/10.3892/ol.2021.12858
pmid: 34188699
30
R Liu, HS Choi, YC Ko, BS Yun, DS Lee. 5-Desmethylsinensetin isolated from Artemisia princeps suppresses the stemness of breast cancer cells via Stat3/IL-6 and Stat3/YAP1 signaling. Life Sci 2021; 280: 119729 https://doi.org/10.1016/j.lfs.2021.119729
pmid: 34146553
31
V Gopalakrishnan, CN Spencer, L Nezi, A Reuben, MC Andrews, TV Karpinets, PA Prieto, D Vicente, K Hoffman, SC Wei, AP Cogdill, L Zhao, CW Hudgens, DS Hutchinson, T Manzo, M Petaccia de Macedo, T Cotechini, T Kumar, WS Chen, SM Reddy, R Szczepaniak Sloane, J Galloway-Pena, H Jiang, PL Chen, EJ Shpall, K Rezvani, AM Alousi, RF Chemaly, S Shelburne, LM Vence, PC Okhuysen, VB Jensen, AG Swennes, F McAllister, E Marcelo Riquelme Sanchez, Y Zhang, E Le Chatelier, L Zitvogel, N Pons, JL Austin-Breneman, LE Haydu, EM Burton, JM Gardner, E Sirmans, J Hu, AJ Lazar, T Tsujikawa, A Diab, H Tawbi, IC Glitza, WJ Hwu, SP Patel, SE Woodman, RN Amaria, MA Davies, JE Gershenwald, P Hwu, JE Lee, J Zhang, LM Coussens, ZA Cooper, PA Futreal, CR Daniel, NJ Ajami, JF Petrosino, MT Tetzlaff, P Sharma, JP Allison, RR Jenq, JA Wargo. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018; 359(6371): 97–103 https://doi.org/10.1126/science.aan4236
pmid: 29097493
KS Sfanos, MC Markowski, LB Peiffer, SE Ernst, JR White, KJ Pienta, ES Antonarakis, AE Ross. Compositional differences in gastrointestinal microbiota in prostate cancer patients treated with androgen axis-targeted therapies. Prostate Cancer Prostatic Dis 2018; 21(4): 539–548 https://doi.org/10.1038/s41391-018-0061-x
pmid: 29988102
34
PL Miller, TL Carson. Mechanisms and microbial influences on CTLA-4 and PD-1-based immunotherapy in the treatment of cancer: a narrative review. Gut Pathog 2020; 12(1): 43 https://doi.org/10.1186/s13099-020-00381-6
pmid: 32944086
35
EJ Snider, G Compres, DE Freedberg, H Khiabanian, YR Nobel, S Stump, AC Uhlemann, CJ Lightdale, JA Abrams. Alterations to the esophageal microbiome associated with progression from Barrett’s esophagus to esophageal adenocarcinoma. Cancer Epidemiol Biomarkers Prev 2019; 28(10): 1687–1693 https://doi.org/10.1158/1055-9965.EPI-19-0008
pmid: 31466948
36
NT Baxter, JP Zackular, GY Chen, PD Schloss. Structure of the gut microbiome following colonization with human feces determines colonic tumor burden. Microbiome 2014; 2(1): 20 https://doi.org/10.1186/2049-2618-2-20
pmid: 24967088
37
MA Osman, HM Neoh, NS Ab Mutalib, SF Chin, L Mazlan, RA Raja Ali, AD Zakaria, CS Ngiu, MY Ang, R Jamal. Parvimonas micra, Peptostreptococcus stomatis, Fusobacterium nucleatum and Akkermansia muciniphila as a four-bacteria biomarker panel of colorectal cancer. Sci Rep 2021; 11(1): 2925 https://doi.org/10.1038/s41598-021-82465-0
pmid: 33536501
38
F Wang, K Cai, Q Xiao, L He, L Xie, Z Liu. Akkermansia muciniphila administration exacerbated the development of colitis-associated colorectal cancer in mice. J Cancer 2022; 13(1): 124–133 https://doi.org/10.7150/jca.63578
pmid: 34976176
39
M Santoni, F Piva, A Conti, A Santoni, A Cimadamore, M Scarpelli, N Battelli, R Montironi. Re: gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Eur Urol 2018; 74(4): 521–522 https://doi.org/10.1016/j.eururo.2018.05.033
pmid: 29891391
40
ZW Luo, K Xia, YW Liu, JH Liu, SS Rao, XK Hu, CY Chen, R Xu, ZX Wang, H Xie. Extracellular vesicles from Akkermansia muciniphila elicit antitumor immunity against prostate cancer via modulation of CD8+ T cells and macrophages. Int J Nanomedicine 2021; 16: 2949–2963 https://doi.org/10.2147/IJN.S304515
pmid: 33907401
41
S Septer, G Edwards, S Gunewardena, A Wolfe, H Li, J Daniel, U Apte. Yes-associated protein is involved in proliferation and differentiation during postnatal liver development. Am J Physiol Gastrointest Liver Physiol 2012; 302(5): G493–G503 https://doi.org/10.1152/ajpgi.00056.2011
pmid: 22194415
42
H Wu, L Wei, F Fan, S Ji, S Zhang, J Geng, L Hong, X Fan, Q Chen, J Tian, M Jiang, X Sun, C Jin, ZY Yin, Q Liu, J Zhang, F Qin, KH Lin, JS Yu, X Deng, HR Wang, B Zhao, RL Johnson, L Chen, D Zhou. Integration of Hippo signalling and the unfolded protein response to restrain liver overgrowth and tumorigenesis. Nat Commun 2015; 6(1): 6239 https://doi.org/10.1038/ncomms7239
pmid: 25695629
43
G Xie, X Wang, F Huang, A Zhao, W Chen, J Yan, Y Zhang, S Lei, K Ge, X Zheng, J Liu, M Su, P Liu, W Jia. Dysregulated hepatic bile acids collaboratively promote liver carcinogenesis. Int J Cancer 2016; 139(8): 1764–1775 https://doi.org/10.1002/ijc.30219
pmid: 27273788
44
Y Fang, SI Han, C Mitchell, S Gupta, E Studer, S Grant, PB Hylemon, P Dent. Bile acids induce mitochondrial ROS, which promote activation of receptor tyrosine kinases and signaling pathways in rat hepatocytes. Hepatology 2004; 40(4): 961–971 https://doi.org/10.1002/hep.1840400427
pmid: 15382121
P Luo, P Yin, R Hua, Y Tan, Z Li, G Qiu, Z Yin, X Xie, X Wang, W Chen, L Zhou, X Wang, Y Li, H Chen, L Gao, X Lu, T Wu, H Wang, J Niu, G Xu. A large-scale, multicenter serum metabolite biomarker identification study for the early detection of hepatocellular carcinoma. Hepatology 2018; 67(2): 662–675 https://doi.org/10.1002/hep.29561
pmid: 28960374
47
T Chen, G Xie, X Wang, J Fan, Y Qiu, X Zheng, X Qi, Y Cao, M Su, X Wang, LX Xu, Y Yen, P Liu, W Jia. Serum and urine metabolite profiling reveals potential biomarkers of human hepatocellular carcinoma. Mol Cell Proteomics 2011; 10(7): M110.004945 https://doi.org/10.1074/mcp.M110.004945
pmid: 21518826
48
E Loftfield, JA Rothwell, R Sinha, P Keski-Rahkonen, N Robinot, D Albanes, SJ Weinstein, A Derkach, J Sampson, A Scalbert, ND Freedman. Prospective investigation of serum metabolites, coffee drinking, liver cancer incidence, and liver disease mortality. J Natl Cancer Inst 2020; 112(3): 286–294 https://doi.org/10.1093/jnci/djz122
pmid: 31168595
49
Geerlings SY, Kostopoulos I, de Vos WM, Belzer C. Akkermansia muciniphila in the human gastrointestinal tract: when, where, and how? Microorganisms 2018; 6(3): 75 doi:10.3390/microorganisms6030075
pmid: 30041463
50
MH Foley, S O’Flaherty, R Barrangou, CM Theriot. Bile salt hydrolases: gatekeepers of bile acid metabolism and host-microbiome crosstalk in the gastrointestinal tract. PLoS Pathog 2019; 15(3): e1007581 https://doi.org/10.1371/journal.ppat.1007581
pmid: 30845232
51
C Grajeda-Iglesias, S Durand, R Daillère, K Iribarren, F Lemaitre, L Derosa, F Aprahamian, N Bossut, N Nirmalathasan, F Madeo, L Zitvogel, G Kroemer. Oral administration of Akkermansia muciniphila elevates systemic antiaging and anticancer metabolites. Aging (Albany NY) 2021; 13(5): 6375–6405 https://doi.org/10.18632/aging.202739
pmid: 33653967