Sensitizing Immunotherapy-Resistant Cancers with Fusobacterium nucleatum

In Colorectal Cancer: Fusobacterium Nucleatum and Its Role in Supporting Immunotherapy

Colorectal cancer (CRC) is one of the most common cancers worldwide, and a large proportion of patients are classified as microsatellite stable (MSS) .

Approximately 85% of colorectal cancers (CRC) are Microsatellite Stable (MSS) . The remaining 15% consist of cancers with High Microsatellite Instability (MSI-H) .

• Microsatellite Stable (MSS): MSS refers to cancers that show no changes or instability in microsatellites (short, repeated DNA sequences). MSS CRC generally responds less well to immunotherapies .

• High Microsatellite Instability (MSI-H): MSI-H describes cancers with a high degree of microsatellite instability due to errors in DNA repair mechanisms. MSI-H CRC tends to be more sensitive to immunotherapies and has higher response rates to this treatment.

MSS CRC is a subgroup that has difficulty responding to immunotherapies, particularly programmed death-1 (PD-1) inhibitors. Consequently, many patients with MSS CRC do not benefit from these treatments. Developing strategies to increase sensitivity to immunotherapies and identifying biomarkers that accurately classify patients with MSS CRC are major needs for this group.

Fusobacterium nucleatum (Fn) is a pathogen frequently associated with CRC. Although its effect on the tumor microenvironment and its role in immunotherapy response are not yet fully understood, new findings suggest that Fn may enhance the effectiveness of PD-1 inhibitors in patients with MSS CRC. On October 14, 2024, Cancer Cell published a study detailing how Fn supports anti-PD-1 treatment and the molecular basis of this mechanism.

Main Findings and Methods

The study used both human and animal models to understand the effects of Fusobacterium nucleatum (Fn) on MSS CRC. Analyses of stool and tumor tissue from patients with human MSS colorectal cancer (CRC) showed that a high abundance of Fn within tumors was associated with more favorable responses to anti-PD-1 immunotherapy. This finding was also supported in mouse models through fecal microbiota transplantation (FMT) and administration of Fn alone.

• Related Topic: How Does the Microbiome Affect the Success of Cancer Treatment?

Fn's Molecular Mechanism: Butyrate Production and HDAC Inhibition

The study identified butyrate as the key component enhancing Fn's effects on MSS CRC. Butyrate is a short-chain fatty acid produced by Fn that acts as a histone deacetylase (HDAC) inhibitor. The study shows that butyrate inhibits HDAC3/8, suppressing PD-1 expression in CD8+ T cells and allowing these cells to become active again in the tumor microenvironment. Within the promoter region of a transcription factor called TBX21, butyrate was shown to promote H3K27 acetylation (epigenetic regulation) , increasing TBX21 expression and thereby suppressing PD-1.

The dependence of Fn's PD-1-lowering effect on butyrate production was confirmed when mutation of the gene responsible for butyrate production abolished this effect.

Fn and Anti-PD-1 Treatment Responses in MSS CRC: Clinical Observations and Preclinical Models

Clinical data from patients with MSS CRC showed that those with a high abundance of Fn responded more favorably to anti-PD-1 treatment. Their progression-free survival (PFS) and overall survival (OS) rates were significantly better than those of patients with low Fn levels.

In mouse models, FMT using MSS CRC samples with a high abundance of Fn, administered together with anti-PD-1 treatment, produced significant reductions in tumor volume and weight. PD-1 expression in CD8+ T cells was suppressed, while cytotoxic activity markers such as TNF-α, granzyme B (GZMB), and interferon-gamma (IFN-γ) increased. These findings show that Fn can enhance antitumor immune responses not only within tumors but also systemically .

Figure explanation: Fn's activity in MSS CRC, the butyric acid pathway, and epigenetic regulation. The beneficial effect of Fn on MSS CRC was shown to depend on butyric acid production. Acting as an HDAC3/8 inhibitor, this substance suppresses PD-1 expression in CD8+ T cells. Through butyrate production, Fn increases H3K27 acetylation at the Tbx21 promoter, raising TBX21 expression and thereby suppressing PD-1 expression.

Conclusions and Potential Applications

The study shows that Fusobacterium nucleatum may enhance the effectiveness of PD-1 inhibitors in patients with MSS CRC, and that a high abundance of Fn may be a potential biomarker for predicting their response to immunotherapy. These findings suggest that increasing butyric acid levels in the colon could be used as a clinical strategy to enhance anti-PD-1 treatment.

Study Limitations

The study has several limitations. First, functional and mechanistic investigations were conducted in mouse models. To fully understand the effects of Fn on anti-PD-1 effectiveness in patients with MSS CRC, further clinical research is needed. Second, the CD34+-humanized mouse models used may not reproduce the full spectrum of human immune cells, which may limit the immune response. Third, Fn has different subtypes within CRC, and the effects of each subtype on the immune response need to be investigated.

Overall Assessment and Recommendations for Future Research

A detailed understanding of the effects of Fusobacterium nucleatum on MSS CRC may enable the development of new strategies to improve these patients' response to immunotherapy. Fn and the butyric acid pathway reactivate immune responses by suppressing PD-1 expression through epigenetic regulation. This mechanism holds significant potential in the immunotherapy-resistant MSS CRC subgroup.