Immunosuppression in the tumor microenvironment mediated by metabolites derived from the gut microbiota

The molecular mechanisms underlying carcinogenesis are intricate and harbor individual characteristics. A multitude of factors, encompassing genetic and epigenetic traits, age, lifestyle, dietary habits, smoking, exposure to radiation, and chemical substances, contribute to the initiation of malignant cell transformation and subsequent tumor progression. Recently, research has focused on the influence of the symbiotic microbiota on host health, particularly in the context of cancer development. The microbiota, evolving alongside the host organism, has significantly shaped the phenotypes of our ancestors and continues to do so. The intricate interplay between the host's metabolism and that of the microbiota, along with their shared signaling molecules, underscores the substantial role of microbial metabolites in the pathogenesis of various human diseases, including metabolic disorders, obesity, and several types of cancer.

The intestinal microbiota, specifically, can modulate the process of malignant transformation through three primary mechanisms: (1) altering the balance between cell proliferation and death, (2) modulating immune system functions, and (3) influencing the formation of metabolites synthesized by the host or by the microbiota itself. This review delves into the key microbiota factors that influence the creation of an immunosuppressive tumor microenvironment (TME).

The Role of the Tumor Microenvironment

Tumors thrive in a unique microenvironment that fosters their progression and invasion. The TME comprises not only tumor cells but also a diverse array of immune, stromal, and other cell types, along with intercellular substances, microvessels, and metabolites circulating within. A crucial aspect of the TME's pro-oncogenic properties lies in the establishment of an immunosuppressive environment that enables tumors to evade immune surveillance. This environment is primarily maintained by immune cells that secrete inflammatory cytokines and factors that inhibit the functions of cytotoxic T lymphocytes.

Gut Microbiota and Its Metabolites in TME Formation

The gut microbiota, consisting of bacteria, viruses, protozoans, archaea, and fungi, significantly impacts the host's immune response, DNA damage, and chronic inflammation, which can lead to the onset and progression of various cancers, including those of the gastrointestinal tract and breast. Bacterial dysbiosis, or an imbalance in the gut microbial composition, has been linked to an increased risk of breast cancer, with bacterial beta-glucuronidase modulating estrogen resorption and enterohepatic circulation.

Furthermore, specific bacterial metabolites, such as short-chain fatty acids (SCFAs), lithocholic acid (LCA), and cadaverine, have been shown to participate in the formation of a unique TME that favors tumor growth. These metabolites, upon entering the host's circulation, interact with immune cells and contribute to the immunosuppressive nature of the TME.

Key Microbiota Metabolites and Their Mechanisms

Short-Chain Fatty Acids (SCFAs): SCFAs, primarily acetate, propionate, and butyrate, are produced by bacterial fermentation of dietary fiber in the gut. They play a crucial role in maintaining gut health and modulating immune responses. However, in the context of cancer, SCFAs have been found to restrict the efficiency of certain immunotherapies, such as for metastatic melanoma, by increasing the proportion of regulatory T cells (Tregs) and decreasing the accumulation of tumor-specific and memory T cells.

Secondary Bile Acids (SBAs): SBAs, like deoxycholic acid (DCA) and lithocholic acid (LCA), are formed through microbial transformation of primary bile acids in the intestine. They can exert immunosuppressive effects by activating signaling pathways, such as the farnesoid X receptor (FXR), and by modulating inflammation and immune cell function.

Other Microbial Metabolites: Peptidoglycan derivatives, inosine, indole-3-carboxaldehyde, trimethylamine N-oxide, and others have been shown to have a significant impact on the immune system and immunotherapy efficiency. For instance, inosine enhances T cell-mediated tumor eradication by suppressing a specific ubiquitin-like modifier enzyme, whereas trimethylamine N-oxide drives immune system activation, increasing the efficacy of immunotherapy for pancreatic cancer.

Conclusions

The intricate interplay between the gut microbiota and its metabolites, on one hand, and the tumor microenvironment, on the other, underscores the crucial role of microbial factors in cancer development and progression. Understanding the mechanisms by which microbial metabolites modulate immune cell function and reshape the TME is vital for improving cancer therapies, particularly immunotherapies. Further research into the metabolic activity of the gut microbiota and its impact on cancer-related processes promises to reveal novel therapeutic targets and strategies for combating cancer.

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https://www.xiahepublishing.com/2996-3427/OnA-2023-00014

The study was recently published in the Oncology Advances.

Oncology Advances is dedicated to improving the diagnosis and treatment of human malignancies, advancing the understanding of molecular mechanisms underlying oncogenesis, and promoting translation from bench to bedside of oncological sciences. The aim of Oncology Advances is to publish peer-reviewed, high-quality articles in all aspects of translational and clinical studies on human cancers, as well as cutting-edge preclinical and clinical research of novel cancer therapies.

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