Williams Cancer Institute

UNLOCKING THE IMMUNE SYMPHONY: GUT MICROBIOME’S ROLE IN CANCER THERAPY

UNLOCKING THE IMMUNE SYMPHONY: GUT MICROBIOME’S ROLE IN CANCER THERAPY


Cancer, recognized as a global public health challenge, has spurred extensive research to combat its growing social and economic burden. The intricate mechanisms governing tumor development, progression, and metastasis have been unveiled through decades of research, exposing the complex interplay between the host’s immune status and the external environment. Anti-tumor immunotherapy, particularly the inhibition of immune checkpoint pathways, has emerged as a promising avenue in this landscape.

Trillions of symbiotic microorganisms constitute the gut microbiota, often regarded as a “super organ” due to its vital role in maintaining a delicate balance influencing tumorigenesis. Studies have highlighted associations between microbial alterations and the development of various cancers. The gut microbiota plays a crucial role in regulating host immune modulation, sustaining the tumor microenvironment (TME), and influencing anti-tumor immune factors.

Remarkably, the efficacy of immune checkpoint inhibitors (ICIs) in anti-tumor therapy appears linked to the host’s microbiome environment. Commensal bacteria, such as Bacteroidetes, show a positive correlation with anti-tumor immune factors, while pathogenic subsets like Proteobacteria exhibit opposite trends. Modulating the gut microbiota has shown promise in enhancing the effectiveness of cancer therapies, especially immunotherapy, by influencing the immune response through microbial combinations.

In this context, Fecal Microbiota Transplantation (FMT) emerges as a promising tool for manipulating the gut microbiota. Aimed at restoring a healthy balance disrupted by conventional antibiotic therapy, FMT holds significant advantages. Concerns persist regarding the safety, efficacy, and precision of FMT, making rigorous screening of both donors and recipients essential to address potential risks and ensure effectiveness.

The review aims to shed light on the intricate association between gut microbiota and anti-tumor immunotherapy. Emphasis is placed on the clinical applications of FMT in enhancing therapeutic efficacy, providing an overview of FMT administration’s role in promoting anti-tumor immune responses in specific histopathological tumor types. Additionally, the blog discusses current challenges and prospects associated with FMT, recognizing the need for cautious evaluation and ongoing research in this promising field.

In recent decades, intestinal dysbiosis has been epidemiologically linked to autoimmune diseases and tumor development. This dysbiosis plays a role in tumorigenesis through various pathways, including the transformation of host genomes, virulence factors damaging DNA stability, metabolic dysregulation, inappropriate initiation of the immune system, and impairment of the barrier. Simultaneously, it has become increasingly clear that the gut microbiota can impact both tumor development and the immune response to tumors.

Beyond tumor development, microbiota is reported to affect the response to anti-tumor immunotherapy. Researchers, using advanced screening and sequencing techniques, identified the gut microbiome in patients with tumors responding differentially to ICIs. Associations between specific bacterial species and response to ICIs have been demonstrated across different cancer types, suggesting the existence of distinct “responder” and “non-responder” gut microbiome profiles.

Significant importance has been attached to the stable and functional commensal microbiota community. Dietary control is one modification strategy, as observed in the ketogenic diet inducing T cell-dependent tumor growth retardation. Supplementation of specific bacteria, such as Enterococcus modulating the response to anti-PD-1 immunotherapy in mouse models, has shown positive effects. Next-generation probiotics (NGPs), including Faecalibacterium prausnitzii and B. fragilis, have gained increasing attention.

FMT can modulate intestinal microbial homeostasis and immune balance to treat diseases. This cutting-edge technological advance has demonstrated secure efficacy in treating C. difficile infection. Numerous clinical trials are underway to ascertain the effectiveness of FMT in various cancerous disorders. FMT directly shapes the gut microbiota, selectively altering microbial composition and abundance, thereby indirectly affecting ICIs. FMT assisting anti-tumor immunotherapy has garnered attention, with several clinical trials in progress.

Mechanisms of FMT enhancing the efficacy of tumor immunotherapy include the alteration of gut microbiota diversity and composition. Davar et al. observed a long-lasting increase in alpha diversity in post-FMT feces, with more significant changes in responder recipients compared to non-responders. Various metabolites synthesized and transformed by gut microbiota, impacted by FMT, can influence anti-tumor immune responses during immunotherapy. Metabolites like inosine, produced by Bifidobacterium pseudolongum, stimulate T-cell-specific adenosine A2A receptor (A2AR) to promote Th1 cell differentiation. Short-chain fatty acids (SCFAs) promote anti-tumor cytotoxicity of CD8+ T cells and provide energy for immune cells. F. prausnitzii may enhance antitumor immune response through increased SCFAs-mediated CD8+ T cell memory potential.

Microbiota profiling suggests an association between gut microbiota composition and tumour-infiltrating immune cells in the tumor microenvironment (TME), influencing immunotherapy efficacy. Specific bacterial species like A. muciniphila, Faecalibacterium, Bifidobacterium, Collinsella, and Enterococcus have been linked to improved anti-PD-1 immunotherapy efficacy through increased antigen presentation and improved effector T cell function. Conversely, higher abundance of Bacteroidales is associated with poor prognosis, limiting immune cell infiltration and antigen presentation.

FMT has shown promise in various digestive and extra-digestive system tumors, including colorectal cancer, pancreatic cancer, melanoma, non-small-cell lung cancer (NSCLC), and renal cell carcinoma (RCC). Clinical trials and preclinical studies support the synergistic effects of FMT with immunotherapy in reshaping gut microbiota composition and improving the response to ICIs.

Despite promising results, concerns about the long-term safety of FMT persist, including the risk of transmitting multi-drug-resistant bacteria and unknown causative agents. Additionally, the optimal microbial profiles for different tumor types remain unclear. Successful FMT is determined by careful donor and recipient screening, matching, and consideration of delivery routes. Ongoing research is essential to address these challenges and optimize FMT as a microbial therapy to enhance tumor immunotherapy.

In conclusion, tumor immunotherapy, particularly with immune checkpoint inhibitors, has gained significant attention. The gut microbiota plays a crucial role in modulating anti-tumor therapeutic efficacy, and FMT emerges as a promising adjuvant to boost immunotherapy outcomes. However, challenges in evaluating the risks and benefits of FMT, optimizing donor-recipient matching, and determining the ideal microbiota composition for different cancers persist. Future research should focus on deeper investigations into “friendly microbiota” and their functions to optimize the effectiveness of immunotherapy across various tumor types.

Reference: Yang, Y., An, Y., Dong, Y., Chu, Q., Wei, J., Wang, B., & Cao, H. (2024). Fecal microbiota transplantation: no longer cinderella in tumour immunotherapy. EBioMedicine, 100(104967), 104967. https://www.sciencedirect.com/science/article/pii/S2352396424000021

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