Fusobacterium nucleatum Facilitates Anti-PD-1 Therapy in Microsatellite Stable Colorectal Cancer

Basic Medical Sciences Oncology Life Sciences Immunology Gastroenterology Medicine Microbiology
microsatellite stable colorectal cancer Fusobacterium nucleatum anti-PD-1 therapy butyric acid CD8+ T cells immunotherapy

Fusobacterium nucleatum Promotes Anti-PD-1 Therapy in Microsatellite-Stable Colorectal Cancer

Background Introduction

With the rise of immune checkpoint blockade (ICB) therapy, a new dawn has emerged in cancer treatment. However, despite the approval of PD-1 targeting drugs (e.g., Pembrolizumab) for certain types of colorectal cancer (CRC) patients, the vast majority (about 85%) of CRC patients do not benefit, as they are microsatellite-stable (MSS) and have a poor response to ICB therapy. The current main challenge is how to identify potentially responsive MSS-type CRC patients for ICB therapy and improve their treatment outcomes.

The gut microbiota is thought to have a significant impact on the host immune system and plays an important role in the responsiveness to ICB therapy. In colorectal cancer pathology studies, the enrichment of certain gut microbiota has been associated with tumor progression. Among them, Fusobacterium nucleatum (FN) is an anaerobic bacterium considered a pathogen of CRC, its enrichment in CRC is closely related to tumor-infiltrating lymphocytes (TILs). However, the immune-regulatory function of FN in MSS-type CRC and its impact on ICB therapy remain unclear.

Research Objectives and Sources

This study, completed by Xueliang Wang et al., involves scientists from institutions such as the Chinese University of Hong Kong, Jinan University, and Sun Yat-sen University, and the findings were published in the journal Cancer Cell. The research team aimed to elucidate the potential regulatory mechanisms of FN on PD-1 monoclonal antibody therapy in MSS-type CRC patients and to explore the molecular mechanisms of FN and its metabolites in reversing CD8+ T cell exhaustion.

Research Methods

The study evaluated the effects of FN and its metabolites on anti-PD-1 efficacy through multi-step experiments, including the following key components:

  1. Patient Sample Analysis: The study recruited 25 MSS-type CRC patients undergoing anti-PD-1 therapy and utilized fluorescence in situ hybridization (FISH) to detect the relative abundance of FN in their tumor tissues, assessing the relationship between FN abundance and patients’ progression-free survival (PFS) and overall survival (OS).

  2. Mouse Model Experiments: The research team deployed germ-free mouse models by transplanting fecal microbes from FN high-abundance MSS-type CRC patients into germ-free mice to validate FN’s role in promoting anti-PD-1 efficacy. Additionally, they used humanized mouse models to assess the impact of FN alone or combined with anti-PD-1 therapy on MSS-type CRC xenograft models.

  3. Metabolite Mechanism Research: At the immune cell level, the team used flow cytometry and immunohistochemistry (IHC) to analyze the effects of FN and its metabolites on CD8+ T cells, particularly the inhibition of PD-1 expression, and further verified in germ-free mouse models whether FN enhances anti-PD-1 therapy through its metabolite butyric acid.

  4. In Vitro Co-culture System: By co-culturing MSS-type CRC tumor organoids with autologous peripheral blood mononuclear cell (PBMC)-derived CD8+ T cells, the study validated whether FN and its butyric acid can enhance CD8+ T cell effector functions in vitro, ultimately improving anti-PD-1 therapeutic effects.

Main Research Results

The study’s key findings and experimental data include:

  1. Positive Correlation of FN Abundance with Anti-PD-1 Efficacy: In MSS-type CRC patients receiving anti-PD-1 therapy, high abundance of FN in tumor tissues was positively correlated with patients’ PFS and OS, indicating that high FN abundance might be a potential predictive marker for treatment response.

  2. FN Promotes Effector Function of CD8+ T Cells: FN, through its metabolite butyric acid, acts on tumor-infiltrating CD8+ T cells (CD8+ TILs), inhibiting PD-1 expression and activating CD8+ T cell effector function via the HDAC3/8-TBX21 axis, thereby alleviating T cell exhaustion and restoring antitumor immunity.

  3. Butyric Acid Metabolic Pathway: FN-secreted butyric acid acts as an inhibitor of HDAC3/8, upregulating transcriptional activation of TBX21 in CD8+ T cells, suppressing PD-1 expression, and further enhancing anti-PD-1 efficacy. It was confirmed that FN mutants lacking butyric acid production could not activate CD8+ T cells nor enhance anti-PD-1 efficacy.

  4. FN and Immune Microenvironment Interactions: FN modulates the tumor immune microenvironment (TME), promoting CD8+ T cell infiltration and transforming MSS-type CRC from “immune cold” to “immune hot” tumors, thus improving anti-PD-1 therapeutic effects.

  5. Human Experiments and Humanized Mouse Model Validation: In human tumor organoid experiments and humanized mouse models, the research team further confirmed that FN and its metabolite butyric acid, through PD-1 inhibition, reverse T cell exhaustion and enhance antitumor immune responses, validating FN’s potential immunotherapeutic enhancement effects in MSS-type CRC.

Research Conclusion and Value

This study unveils a novel mechanism by which FN activates immune responses through its metabolite butyric acid, providing a new immunotherapy strategy for MSS-type CRC. Specifically, FN, by downregulating PD-1 and activating CD8+ T cell effector functions, extends the population of patients benefiting from anti-PD-1 therapy. High FN abundance not only serves as a potential predictive biomarker for MSS-type CRC anti-PD-1 therapy but also demonstrates the potential application value of increasing butyric acid levels to enhance immune efficacy.

The study suggests that FN could become an effective adjuvant to anti-PD-1 therapy, offering new treatment ideas for MSS-type CRC patients. In clinical practice, increasing the butyric acid levels in the gut of colorectal cancer patients may significantly improve the efficacy of anti-PD-1 therapy. The research also underscores the role of microbial metabolites in regulating the host immune system, providing strong evidence for the development of microbial therapies.

Research Highlights

  • Relationship between FN and Immunotherapy: FN enrichment can enhance the response of MSS-type CRC patients to anti-PD-1 treatment, overcoming the bottleneck of poor ICB therapy response in MSS-type CRC.
  • Novel Metabolic Regulation Mechanism: FN-secreted butyric acid inhibits HDAC3/8, regulates TBX21 expression, thereby weakening PD-1 signaling and enhancing the antitumor effects of CD8+ T cells.
  • Clinical Translation Potential: High FN abundance can serve as a potential biomarker for anti-PD-1 efficacy, providing a scientific basis for personalized treatment planning.

Study Limitations and Outlook

The limitations of this study include: First, the experiments are primarily based on mouse models, and further clinical trials are needed to verify the enhancement of anti-PD-1 efficacy in MSS-type CRC patients by FN. Second, humanized mice may not fully replicate the diversity of the human immune system. Third, the heterogeneity of FN strains may lead to varying effects in different patients.

Future research may further explore the impact of other FN metabolites on the immune microenvironment and develop more refined microbial metabolism regulation methods to enhance the clinical application effects of anti-PD-1 therapy.