Gut Microbiota and Immunotherapy Response

Immunotherapy has revolutionized cancer treatment by harnessing the body's own immune system to combat tumors. However, a significant portion of patients exhibit variable responses, highlighting the need for personalized treatment strategies. Recent research suggests that the composition of gut microbiota, the trillions of microorganisms residing in the gastrointestinal tract, plays a crucial role in modulating the efficacy of immunotherapy.

Gut Microbiota and the Immune System

The gut microbiota maintains a symbiotic relationship with the host, influencing various physiological processes, including immune function. Specific bacterial communities promote immune homeostasis by stimulating the maturation and function of immune cells, such as dendritic cells (DCs) and T lymphocytes. Conversely, dysbiosis, an imbalance in gut microbial composition, can trigger chronic inflammation and impair anti-tumor immunity.

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Dynamic interactions between the gut microbiota and the immune system.

Mechanisms of Modulation

Studies suggest that gut microbiota can influence immunotherapy response through several mechanisms:


  • Modulation of antigen presentation: Specific gut microbes can metabolize dietary components into metabolites that activate DCs, enhancing their ability to present tumor antigens to T cells, thereby priming the adaptive immune response.
  • Regulation of T cell subsets: Certain bacterial species can promote the expansion and activation of effector T cells (cytotoxic T lymphocytes, Th1 cells) while suppressing regulatory T cells (Tregs) that dampen anti-tumor immunity.
  • Shaping the tumor microenvironment (TME): Gut microbiota can influence the TME by modulating the infiltration and function of immune cells within the tumor. Some bacteria can induce the production of pro-inflammatory cytokines and chemokines, leading to increased recruitment of cytotoxic T cells into the tumor site


The gut microbiota modulate innate immunity, adaptive immunity, and tumor antigens to improve ICI responses. A Innate immunity. DCs: Bifidobacterium, eleven strains and their metabolites, and Bacteroides fragilis promote DC maturation or activation and subsequent activation of CD8+ T cells and Th1 cells. NK cells: Lactobacillus plantarum increases NK cell activation; a high-salt diet increases intestinal permeability and localization of intratumoral Bifidobacterium and enhances NK cell activation to induce antitumor immunity. Monocyte: Feeding a high-fiber diet, monocolonization with cdAMP-producing A. muciniphila or transferring fecal microbiota from ICI responders can trigger the monocyte-IFN-I-NK-cell-DC cascade; Bifidobacterium facilitates CD47-based immunotherapy in a STING signaling and IFN-I-dependent fashion; Bacteroides fragilis induces macrophage phenotype polarization to M1. B Adaptive immunity. CD8+ T cells: Bifidobacterium, Enterococcus, Faecalibacterium, Ruminococcus, and Clostridiales promote CD8+ T cell infiltrates in tumor tissues; Phyla Firmicutes and Actinobacteria improve the activation of CD56+CD8+ T cells in the peripheral blood of ICI responders; and eleven strains increase the proportion of effector IFNγ+CD8+ T cells in the systemic circulation. CD4+ T cells: B. pseudolongum and Bacteroides fragilis stimulate Th1 immune responses; A. muciniphila triggers CCR9+CXCR3+CD4+ T lymphocyte recruitment into tumor beds; and Faecalibacterium increases the CD4+ T cell proportion. C Tumor cross-antigen. The gut microbiota increase the immunogenicity of tumor cells by providing tumor cross-antigens to ameliorate the efficacy of ICIs, including the antigen epitope TMP1 and the antigen epitope SVY

Clinical Evidence

Emerging clinical data support the link between gut microbiota and immunotherapy response. Studies have shown that patients with a more diverse and beneficial gut microbiota composition tend to have better clinical outcomes with immunotherapy compared to those with a depleted or dysbiotic microbiota. Conversely, antibiotic use, which disrupts gut microbial communities, has been associated with reduced efficacy of immunotherapy in some patients.

Fecal Microbiota Transplantation (FMT) and the Future

Fecal microbiota transplantation (FMT), the transfer of healthy gut microbiota from a donor to a recipient, is being explored as a potential strategy to manipulate the gut microbiome and improve immunotherapy response. Early-phase clinical trials have shown promising results, with FMT leading to increased response rates and reduced immune-related adverse events in some patients.


Therapeutic strategies utilizing the gut microbiome combined with ICI. Therapeutic strategies for manipulating gut microbiota include FMT, probiotics, engineered microbiome, and other strategies to increase ICI responses

Conclusion

The gut microbiota represents a novel and exciting target for optimizing immunotherapy efficacy. By elucidating the intricate interplay between gut microbes, the immune system, and tumor biology, researchers can develop strategies to manipulate the gut microbiome to enhance patient response and personalize cancer treatment. Future research will focus on identifying specific bacterial signatures associated with improved immunotherapy outcomes, refining FMT protocols, and exploring the development of prebiotics and probiotics to promote a beneficial gut microbiota for cancer patients.

For a closer look, watch "Gut Responses: Microbes, Inflammation, and Cancer" below.


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Gut Microbiota and Immunotherapy Response
Gen store May 24, 2024
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