Effect of immune-related intratumoral microbiota and host gene expression on cancer prognosis.

The intratumoral microbiota has been identified as an indispensable part of the tumor microenvironment (TME). However, the relationship between the intratumoral microbiota and host gene expression, as well as its impact on prognosis and TME immunity, remains unclear. We utilized a machine learning-based framework to identify microbiota-host gene associations across 14 tumors from The Cancer Genome Atlas (TCGA) and validated them in 11 tumors from the Gene Expression Omnibus. By calculating immune scores and identifying immune-related microbiota, we developed both a pan-cancer Immune and Prognosis-Related Microbial Score (IPRMS) and cancer-specific IPRMSs and analyzed the relationship between the cancer-specific IPRMSs and immune infiltration at bulk level and single-cell level. Furthermore, we systematically analyzed the potential mechanisms in which the intratumoral microbiota might affect prognosis using survival mediation analyses (SMAs). We identified gene subsets associated with microbiota, which were predominantly enriched in immune-related and cell signaling regulation pathways. Subsequently, we constructed the overall survival-related IPRMS and found that high-IPRMS patients had poorer prognosis in pan-cancer and increased presence of macrophage and cancer-associated fibroblasts. In contrast, low-IPRMS patients showed enrichment in tumor-infiltrating lymphocytes. SMAs suggest that intratumoral microbiota may influence prognosis by affecting immune cells, pathways, and host genes. High-IPRMSs were consistently associated with poorer prognosis and lower abundance of tumor-infiltrating lymphocytes. At the single-cell level, cancer-associated fibroblasts were predominantly enriched in the high-IPRMS group, while tumor-infiltrating lymphocytes were also mainly enriched in the low-IPRMS group. Our research indicates that the intratumoral microbiota was associated with immune and prognosis, which may impact the cancer prognosis by modifying immune cells, pathways, and host gene expression.

Importance: The intratumoral microbiota is a vital part of the tumor microenvironment, yet its interplay with host gene expression and immune regulation remains unclear. Based on a machine learning framework for the interaction analysis of intratumoral microbiota and host genes, as well as the construction of the Immune and Prognosis-Related Microbial Score, our findings suggest that intratumoral microbiota may influence gene expression by affecting host pathways, especially immune-related pathways. Moreover, immune-related intratumoral microbiota are significantly associated with patient survival and TME immunity and may influence prognosis by affecting immune cells, pathways, or gene expression, offering new perspectives and potential biomarkers for predicting personalized patient prognosis in the future.