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Tumor microbiome links cellular programs and immunity in pancreatic cancer.

ABSTRACT: Microorganisms are detected in multiple cancer types, including in putatively sterile organs, but the contexts in which they influence oncogenesis or anti-tumor responses in humans remain unclear. We recently developed single-cell analysis of host-microbiome interactions (SAHMI), a computational pipeline to recover and denoise microbial signals from single-cell sequencing of host tissues. Here we use SAHMI to interrogate tumor-microbiome interactions in two human pancreatic cancer cohorts. We identify somatic-cell-associated bacteria in a subset of tumors and their near absence in nonmalignant tissues. These bacteria predominantly pair with tumor cells, and their presence is associated with cell-type-specific gene expression and pathway activities, including cell motility and immune signaling. Modeling results indicate that tumor-infiltrating lymphocytes closely resemble T cells from infected tissue. Finally, using multiple independent datasets, a signature of cell-associated bacteria predicts clinical prognosis. Tumor-microbiome crosstalk may modulate tumorigenesis in pancreatic cancer with implications for clinical management.

SUBMITTER: Ghaddar B

PROVIDER: S-EPMC9556978 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Tumor microbiome links cellular programs and immunity in pancreatic cancer.

Ghaddar Bassel B Biswas Antara A Harris Chris C Omary M Bishr MB Carpizo Darren R DR Blaser Martin J MJ De Subhajyoti S

Cancer cell 20221001 10

Microorganisms are detected in multiple cancer types, including in putatively sterile organs, but the contexts in which they influence oncogenesis or anti-tumor responses in humans remain unclear. We recently developed single-cell analysis of host-microbiome interactions (SAHMI), a computational pipeline to recover and denoise microbial signals from single-cell sequencing of host tissues. Here we use SAHMI to interrogate tumor-microbiome interactions in two human pancreatic cancer cohorts. We id ...[more]

PMID: 36220074

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Project description:BackgroundBreast cancer, the most common cancer type among women, was recently found to contain a specific tumor microbiome, but its impact on host biology remains unclear. CD8+ tumor-infiltrating lymphocytes (TILs) are pivotal effectors of anti-tumor immunity that influence cancer prognosis and response to therapy. This study aims to elucidate interactions between CD8+ TILs and the breast tumor microbiome and metabolites, as well as how the breast tumor microbiome may affect the tumor metabolome.MethodsWe investigated the interplay among CD8+ TILs, the tumor microbiome, and the metabolome in a cohort of 46 breast cancer patients with mixed subtypes (Cohort A). We characterized the tumor metabolome by mass spectrometry and CD8+ TILs by immunohistochemistry. Microbiome composition and T cell gene transcript levels were obtained from data from our previous study, which utilized 16S rRNA gene sequencing and a targeted mRNA expression panel. To examine interactions between intratumoral Staphylococcus and specific breast cancer subtypes, we analyzed RNA sequencing data from an independent cohort of 370 breast cancer patients (Cohort B). We explored the functions of the tumor microbiome using mouse models of triple-negative breast cancer (TNBC).ResultsIn tumors from Cohort A, the relative abundance of Staphylococcus positively correlated with the expression of T cell activation genes. The abundances of multiple metabolites exhibited significant correlations with CD8+ TILs, of which NADH, γ-glutamyltryptophan, and γ-glutamylglutamate displayed differential abundance in Staphylococcus-positive versus Staphylococcus-negative breast tumors. In a larger breast cancer cohort (Cohort B), we observed positive correlations between tumoral Staphylococcus and CD8+ TIL activity exclusively in TNBC. Preclinical experiments demonstrated that intratumoral administration of S. aureus, the predominant species of Staphylococcus in human breast tumors, resulted in a depletion of total NAD metabolites, and reduced the growth of TNBC tumors by activating CD8+ TILs.ConclusionsWe identified specific metabolites and microbial taxa associated with CD8+ TILs, delineated interactions between the breast tumor microbiome and metabolome, and demonstrated that intratumoral Staphylococcus influences anti-tumor immunity and TIL-associated metabolites. These findings highlight the role of low-biomass microbes in tumor tissues and provide potential biomarkers and therapeutic agents for breast cancer immunotherapy that merit further investigation.

Dataset Information

Tumor microbiome links cellular programs and immunity in pancreatic cancer.

Publications

Tumor microbiome links cellular programs and immunity in pancreatic cancer.

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