Akkermansia muciniphila improves gastric cancer treatment by modulating the immune microenvironment

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References

• 1. Thrift AP, El-Serag HB. Burden of gastric cancer. Clin. Gastroenterol Hepatol. 18(3), 534–542 (2020).
  MedlineGoogle Scholar
• 2. Sung H, Ferlay J, Siegel RL et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71(3), 209–249 (2021).
  MedlineGoogle Scholar
• 3. Li K, Zhang A, Li X, Zhang H, Zhao L. Advances in clinical immunotherapy for gastric cancer. Biochim. Biophys. Acta Rev. Cancer 1876(2), 188615 (2021).
  Medline CASGoogle Scholar
• 4. Smyth E, Knodler M, Giraut A et al. VESTIGE: adjuvant immunotherapy in patients with resected esophageal, gastroesophageal junction and gastric cancer following preoperative chemotherapy with high risk for recurrence (N+ and/or R1): an open label randomized controlled phase-2-study. Front. Oncol. 9, 1320 (2019).
  MedlineGoogle Scholar
• 5. Bang YJ, Van Cutsem E, Fuchs CS et al. KEYNOTE-585: phase III study of perioperative chemotherapy with or without pembrolizumab for gastric cancer. Future Oncol. 15(9), 943–952 (2019).
  CASGoogle Scholar
• 6. Janjigian YY, Shitara K, Moehler M et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet 398(10294), 27–40 (2021).
  Medline CASGoogle Scholar
• 7. Sun JM, Shen L, Shah MA et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet 398(10302), 759–771 (2021).
  Medline CASGoogle Scholar
• 8. Wang F, Wei XL, Wang FH et al. Safety, efficacy and tumor mutational burden as a biomarker of overall survival benefit in chemo-refractory gastric cancer treated with toripalimab, a PD-1 antibody in phase Ib/II clinical trial NCT02915432. Ann. Oncol. 30(9), 1479–1486 (2019).
  Medline CASGoogle Scholar
• 9. Jin X, Liu Z, Yang D, Yin K, Chang X. Recent progress and future perspectives of immunotherapy in advanced gastric cancer. Front. Immunol. 13, 948647 (2022).
  Medline CASGoogle Scholar
• 10. Meng C, Bai C, Brown TD, Hood LE, Tian Q. Human gut microbiota and gastrointestinal cancer. Genomics Proteomics Bioinformatics 16(1), 33–49 (2018).
  Medline CASGoogle Scholar
• 11. Correa P, Piazuelo MB. Helicobacter pylori infection and gastric adenocarcinoma. US Gastroenterol. Hepatol. Rev. 7(1), 59–64 (2011).
  MedlineGoogle Scholar
• 12. Routy B, Le Chatelier E, Derosa L et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359(6371), 91–97 (2018). • In vivo experiments showed that the PD-1-based immunotherapy Akkermansia muciniphila (AKK) strain improved antitumor activity.
  Medline CASGoogle Scholar
• 13. Zitvogel L, Ma Y, Raoult D, Kroemer G, Gajewski TF. The microbiome in cancer immunotherapy: diagnostic tools and therapeutic strategies. Science 359(6382), 1366–1370 (2018).
  Medline CASGoogle Scholar
• 14. Sivan A, Corrales L, Hubert N et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350(6264), 1084–1089 (2015).
  Medline CASGoogle Scholar
• 15. Das S, Suarez G, Beswick EJ, Sierra JC, Graham DY, Reyes VE. Expression of B7-H1 on gastric epithelial cells: its potential role in regulating T cells during Helicobacter pylori infection. J. Immunol. 176(5), 3000–3009 (2006).
  Medline CASGoogle Scholar
• 16. Reunanen J, Kainulainen V, Huuskonen L et al. Akkermansia muciniphila adheres to enterocytes and strengthens the integrity of the epithelial cell layer. Appl. Environ. Microbiol. 81(11), 3655–3662 (2015).
  Medline CASGoogle Scholar
• 17. Dao MC, Everard A, Aron-Wisnewsky J et al. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut 65(3), 426–436 (2016).
  Medline CASGoogle Scholar
• 18. Shin NR, Lee JC, Lee HY et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 63(5), 727–735 (2014).
  Medline CASGoogle Scholar
• 19. Barcena C, Valdes-Mas R, Mayoral P et al. Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice. Nat. Med. 25(8), 1234–1242 (2019).
  Medline CASGoogle Scholar
• 20. Bian X, Wu W, Yang L et al. Administration of Akkermansia muciniphila ameliorates dextran sulfate sodium-induced ulcerative colitis in mice. Front. Microbiol. 10, 2259 (2019).
  MedlineGoogle Scholar
• 21. Zhai R, Xue X, Zhang L, Yang X, Zhao L, Zhang C. Strain-specific anti-inflammatory properties of two Akkermansia muciniphila strains on chronic colitis in mice. Front. Cell. Infect. Microbiol. 9, 239 (2019).
  Medline CASGoogle Scholar
• 22. Ansaldo E, Slayden LC, Ching KL et al. Akkermansia muciniphila induces intestinal adaptive immune responses during homeostasis. Science 364(6446), 1179–1184 (2019). •• Showed that Akkermansia muciniphila is an intestinal bacterium associated with host metabolism and systemic effects of PD-1 checkpoint immunotherapy.
  Medline CASGoogle Scholar
• 23. Zhang M, Liu K, Zhang Q et al. Alpha fetoprotein promotes polarization of macrophages towards M2-like phenotype and inhibits macrophages to phagocytize hepatoma cells. Front. Immunol. 14, 1081572 (2023).
  Medline CASGoogle Scholar
• 24. Wang L, Tang L, Feng Y et al. A purified membrane protein from Akkermansia muciniphila or the pasteurised bacterium blunts colitis associated tumourigenesis by modulation of CD8(+) T cells in mice. Gut 69(11), 1988–1997 (2020). • AKK or Amuc_1100 ameliorates colitis and reduces infiltrating macrophages and CD8 cytotoxic T lymphocytes in the colon.
  Medline CASGoogle Scholar
• 25. Luo ZW, Xia K, Liu YW et al. Extracellular vesicles from Akkermansia muciniphila elicit antitumor immunity against prostate cancer via modulation of CD8(+) T cells and macrophages. Int. J. Nanomedicine 16, 2949–2963 (2021).
  MedlineGoogle Scholar
• 26. Zhou Y, Xia L, Liu Q et al. Induction of pro-inflammatory response via activated macrophage-mediated NF-κB and STAT3 pathways in gastric cancer cells. Cell. Physiol. Biochem. 47(4), 1399–1410 (2018).
  Medline CASGoogle Scholar
• 27. Jiang Y, Zhang M, Guo T, Yang C, Zhang C, Hao J. MicroRNA-21-5p promotes proliferation of gastric cancer cells through targeting SMAD7. Onco Targets Ther. 11, 4901–4911 (2018).
  MedlineGoogle Scholar
• 28. Li Y, Zhang D, Yu K et al. CMPD1 inhibited human gastric cancer cell proliferation by inducing apoptosis and G2/M cell cycle arrest. Biol. Res. 51(1), 11 (2018).
  MedlineGoogle Scholar
• 29. Yamaguchi T, Fushida S, Yamamoto Y et al. Tumor-associated macrophages of the M2 phenotype contribute to progression in gastric cancer with peritoneal dissemination. Gastric Cancer 19(4), 1052–1065 (2016).
  Medline CASGoogle Scholar
• 30. Zhao Q, Cao L, Guan L et al. Immunotherapy for gastric cancer: dilemmas and prospect. Brief. Funct. Genomics 18(2), 107–112 (2019).
  Medline CASGoogle Scholar
• 31. Hogner A, Moehler M. Immunotherapy in gastric cancer. Curr. Oncol. 29(3), 1559–1574 (2022).
  MedlineGoogle Scholar
• 32. Xu R, Wu J, Zhang X et al. Modified Bu-zhong-yi-qi decoction synergies with 5 fluorouracile to inhibits gastric cancer progress via PD-1/PD-L1-dependent T cell immunization. Pharmacol. Res. 152, 104623 (2020).
  Medline CASGoogle Scholar
• 33. Zhang T, Li Q, Cheng L, Buch H, Zhang F. Akkermansia muciniphila is a promising probiotic. Microb. Biotechnol. 12(6), 1109–1125 (2019).
  MedlineGoogle Scholar
• 34. Cani PD, Depommier C, Derrien M, Everard A, de Vos WM. Akkermansia muciniphila: paradigm for next-generation beneficial microorganisms. Nat. Rev. Gastroenterol. Hepatol. 19(10), 625–637 (2022).
  MedlineGoogle Scholar
• 35. Gopalakrishnan V, Spencer CN, Nezi L et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359(6371), 97–103 (2018).
  Medline CASGoogle Scholar
• 36. Li T, Lin X, Shen B et al. Akkermansia muciniphila suppressing nonalcoholic steatohepatitis associated tumorigenesis through CXCR6(+) natural killer T cells. Front. Immunol. 13, 1047570 (2022).
  Medline CASGoogle Scholar
• 37. Jin Y, Dong H, Xia L et al. The diversity of gut microbiome is associated with favorable responses to anti-programmed death 1 immunotherapy in chinese patients with NSCLC. J. Thorac. Oncol. 14(8), 1378–1389 (2019). • AKK abundance significantly correlates with immune checkpoint inhibitors in non-small-cell lung cancer patients with better immune responses.
  Medline CASGoogle Scholar
• 38. Shi L, Sheng J, Chen G et al. Combining IL-2-based immunotherapy with commensal probiotics produces enhanced antitumor immune response and tumor clearance. J. Immunother. Cancer 8(2), e000973 (2020).
  MedlineGoogle Scholar
• 39. Zhuo Q, Yu B, Zhou J et al. Lysates of Lactobacillus acidophilus combined with CTLA-4-blocking antibodies enhance antitumor immunity in a mouse colon cancer model. Sci. Rep. 9(1), 20128 (2019).
  Medline CASGoogle Scholar
• 40. Riehl TE, Alvarado D, Ee X et al. Lactobacillus rhamnosus GG protects the intestinal epithelium from radiation injury through release of lipoteichoic acid, macrophage activation and the migration of mesenchymal stem cells. Gut 68(6), 1003–1013 (2019).
  Medline CASGoogle Scholar
• 41. Ngambenjawong C, Gustafson HH, Pun SH. Progress in tumor-associated macrophage (TAM)-targeted therapeutics. Adv. Drug Deliv. Rev. 114, 206–221 (2017).
  Medline CASGoogle Scholar
• 42. Sica A, Larghi P, Mancino A et al. Macrophage polarization in tumour progression. Semin. Cancer Biol. 18(5), 349–355 (2008).
  Medline CASGoogle Scholar
• 43. Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat. Immunol. 11(10), 889–896 (2010).
  Medline CASGoogle Scholar
• 44. Yunna C, Mengru H, Lei W, Weidong C. Macrophage M1/M2 polarization. Eur. J. Pharmacol. 877, 173090 (2020).
  MedlineGoogle Scholar
• 45. Komohara Y, Fujiwara Y, Ohnishi K, Takeya M. Tumor-associated macrophages: potential therapeutic targets for anti-cancer therapy. Adv. Drug Deliv. Rev. 99(Pt B), 180–185 (2016).
  Medline CASGoogle Scholar
• 46. Fan L, Xu C, Ge Q et al. A. muciniphila suppresses colorectal tumorigenesis by inducing TLR2/NLRP3-mediated M1-like TAMs. Cancer Immunol. Res. 9(10), 1111–1124 (2021).
  Medline CASGoogle Scholar
• 47. Jiang Y, Xu Y, Zheng C et al. Acetyltransferase from Akkermansia muciniphila blunts colorectal tumourigenesis by reprogramming tumour microenvironment. Gut 72(7), 1308–1318 (2023).
  Medline CASGoogle Scholar
• 48. Plovier H, Everard A, Druart C et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat. Med. 23(1), 107–113 (2017).
  Medline CASGoogle Scholar
• 49. Depommier C, Everard A, Druart C et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nat. Med. 25(7), 1096–1103 (2019).
  Medline CASGoogle Scholar
• 50. Zhu Z, Cai J, Hou W et al. Microbiome and spatially resolved metabolomics analysis reveal the anticancer role of gut Akkermansia muciniphila by crosstalk with intratumoral microbiota and reprogramming tumoral metabolism in mice. Gut Microbes 15(1), 2166700 (2023).
  MedlineGoogle Scholar