Good news! Cancer is history (soon)!
"... that a metabolite derived from a gut microbe called trimethylamine N-oxide (abbreviated TMAO) boosts immunity against tumors by triggering immune activation in pancreatic cancer. ...
Pancreatic cancer is a particularly deadly disease with a tumor microenvironment that aggressively suppresses immune response. ... In the study, the researchers administered TMAO and observed effects on tumor growth and immune response in the tumor microenvironment. They found evidence that TMAO stimulated action from immune cells such as macrophages and T cells as well as increased pancreatic cancer’s responsiveness to ICB therapy, ultimately boosting the body’s ability to identify and attack cancer cells. ..."
Pancreatic cancer is a particularly deadly disease with a tumor microenvironment that aggressively suppresses immune response. ... In the study, the researchers administered TMAO and observed effects on tumor growth and immune response in the tumor microenvironment. They found evidence that TMAO stimulated action from immune cells such as macrophages and T cells as well as increased pancreatic cancer’s responsiveness to ICB therapy, ultimately boosting the body’s ability to identify and attack cancer cells. ..."
"Metabolite boosts immune checkpoint blockade
Despite its success, immune checkpoint blockade (ICB) has largely failed in patients with pancreatic cancer; how the microbiome contributes to this failure is unclear. Here, Mirji et al. used mouse pancreatic tumor modeling to establish that a metabolite produced from the gut microbiome, trimethylamine N-oxide (TMAO), delayed tumor growth. Treating mice with TMAO slowed tumor growth in a type I IFN–mediated manner, correlating to more immunostimulatory macrophages and CD8+ T cells in tumors. TMAO administration boosted the efficacy of ICB in mouse models and gut bacteria that produce a key enzyme for TMAO production positively correlated to survival in patients with cancer. Thus, targeting TMAO production in the gut microbiome might be a way to improve the efficacy of ICB in patients with pancreatic cancer."
From the abstract:
"The composition of the gut microbiome can control innate and adaptive immunity and has emerged as a key regulator of tumor growth, especially in the context of immune checkpoint blockade (ICB) therapy. However, the underlying mechanisms for how the microbiome affects tumor growth remain unclear. Pancreatic ductal adenocarcinoma (PDAC) tends to be refractory to therapy, including ICB. Using a nontargeted, liquid chromatography–tandem mass spectrometry–based metabolomic screen, we identified the gut microbe–derived metabolite trimethylamine N-oxide (TMAO), which enhanced antitumor immunity to PDAC. Delivery of TMAO intraperitoneally or via a dietary choline supplement to orthotopic PDAC-bearing mice reduced tumor growth, associated with an immunostimulatory tumor-associated macrophage (TAM) phenotype, and activated effector T cell response in the tumor microenvironment. Mechanistically, TMAO potentiated the type I interferon (IFN) pathway and conferred antitumor effects in a type I IFN–dependent manner. Delivering TMAO-primed macrophages intravenously produced similar antitumor effects. Combining TMAO with ICB (anti-PD1 and/or anti-Tim3) in a mouse model of PDAC significantly reduced tumor burden and improved survival beyond TMAO or ICB alone. Last, the levels of bacteria containing CutC (an enzyme that generates trimethylamine, the TMAO precursor) correlated with long-term survival in patients with PDAC and improved response to anti-PD1 in patients with melanoma. Together, our study identifies the gut microbial metabolite TMAO as a driver of antitumor immunity and lays the groundwork for potential therapeutic strategies targeting TMAO."
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