Tumor microbiome provides new insights to enhance cancer treatment

In a recent study published in the journal cellresearchers used metagenomics, genomics, and transcriptomics to examine the microbiome genomes of over 4,000 metastatic tumor tissues. They analyzed the tumor microbiome and tumor microenvironment (TME), providing biological information and influencing the development of bacteria-focused technologies to complement and improve cancer treatments.

Microbial communities play important roles in the human body, influencing the immune system and anticancer therapies. They are present in primary tumors and interact with commensal microbiota. Gut microbiota may modulate immune checkpoint inhibitors (ICBs) and conventional chemotherapy. Fecal microbial transplantation may improve clinical response to ICB drugs. Understanding how tumor-resident bacteria shape tumor biology, immune infiltrates, and therapeutic responsiveness is essential for understanding tumor responses to ICBs.

study: Pan-cancer analysis of the microbiome in metastatic cancer

About research

In the current study, the researchers used bioinformatics to investigate the microbiota of metastatic malignancies, evaluating 4,160 specimens from different types of cancer.

Researchers used mapping and assembly-based metagenomics, genomics, transcriptomics, and clinical data to develop a pan-cancer repository that could help advance therapeutic technologies. They used his two different computational approaches, PathSeq and Kraken2, to define intratumoral microbiome communities at the genus level, and a metagenomic assembly-based approach at the species level. The team then shaped the metastatic tumor microbiome by identifying factors that influence its composition and assessing cancer type-specific microbial communities. They assessed the degree of hypoxia in metastatic cancer using characteristic hypoxic gene profiles and performed gene set enrichment analysis (GSEA). They also investigated whether the microbial community influences host immunity and the TME.

Researchers have demonstrated the relationship between Gram-negative bacteria and Toll-like receptor (TLR) expression in metastasis, and that lipopolysaccharide (LPS) obtained from dead or active bacteria plays a major role in TLR4 signaling in metastasis. We investigated whether it would work. They also investigated the relationship between bacterial composition and tumor gene expression, as well as the relationship between specific bacteria and immune cells.

To further understand the impact of metastatic heterogeneity and the persistence of tumor-resident microorganisms over time, the research team examined 185 pairs of 370 replicate tumor specimens from 173 different individuals. did. They examined changes in bacterial enrichment before and after tumor treatment with immunotherapy, targeted therapy, or hormonal therapy. They also investigated the reduction in bacterial counts after immunotherapy in responsive patients and whether these bacteria were more prevalent in non-responsive patients before treatment. Finally, they examined pre-treatment bacterial communities associated with lack of response to immunosuppressants in an ICB monotherapy cohort of NSCLC patients.

result

Researchers detected deoxyribonucleic acid (DNA) of tumor-resident bacteria in a pan-cancer metastasis cohort and assembled tumor-derived bacterial DNA, providing species-level genomic characterization. Bacterial diversity was correlated with cellular and molecular tumor immune characteristics. In NSCLC cohorts, high levels of Fusobacterium DNA mean a poor response to immunotherapy. The researchers investigated organ-specific microbial tropism, the enrichment of anaerobic bacteria in hypoxic tumors, the association between microbial diversity and tumor-infiltrating neutrophils, and the association of Fusobacteria with resistance to ICB therapy in lung cancer. discovered.

Using mapping-based techniques and genus screening to eliminate technical contamination and rarely seen genera, the team found 68% facultative/anaerobes and 49% Gram-negative anaerobes from 3,526 specimens. We cataloged 165 bacterial genera that are sexually active. They used tumor-derived microbial sequences to construct 514 metagenomic assembled genomes (MAGs) of moderate to near-high quality. The most common tumor types are colorectal, breast, prostate, lung, melanomaThe most common metastatic sites for tumor samples are lymph nodes, liver, and lungs.

The amount of reads of bacterial origin, expressed as a percentage of human mapped genetic reads, varied by cancer type, with a higher proportion for kidney and uterine malignancies and a lower burden for tumors of brain and spinal cord origin. Renal and colorectal metastases were the most diverse, but head and neck metastatic tumors showed more predominant microbial genera.

Tumor-resident microbial communities were associated with tumor biology, with a strong correlation between LPS load and TLR4 signaling, but not with Gram-positive lipoteichoic acid (LTA) load. Multivariate Cox proportional hazards modeling showed that overall survival (OS) and progression-free survival (PFS) were significantly correlated with continuous Fusobacterium abundance when considering genome-wide mutational burden. Ta. The researchers used a pan-cancer dataset to classify all tumors as either Fuso-high or Fuso-high based on a top quartile relative abundance cutoff similar to previously established criteria. Classified as low. Fuso-high tumors had significantly reduced expression profiles of cytotoxic, interferon gamma (IFN-γ), and major histocompatibility complex (MHC) class II genes.

This study provides the first large-scale, whole-cancer map of the intratumoral microbiome in metastatic malignancies, examining diversity across anatomical regions, initial tumor type, and treatment response, including immunotherapy. This study showed that the metastatic microbiome partially contains anaerobic bacteria that can change during treatment. This study also found an association between intratumoral microbes and activation of innate immune sensing pathways, showing that direct identification of bacterial ligands alters the tumor microenvironment.