Breast tumor microbiome regulates anti-tumor immunity and T cell-associated metabolites.

BACKGROUND

Breast 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.

METHODS

We 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 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).

RESULTS

In tumors from Cohort A, the relative abundance of 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 -positive versus -negative breast tumors. In a larger breast cancer cohort (Cohort B), we observed positive correlations between tumoral and CD8 TIL activity exclusively in TNBC. Preclinical experiments demonstrated that intratumoral administration of , the predominant species of in human breast tumors, resulted in a depletion of total NAD metabolites, and reduced the growth of TNBC tumors by activating CD8 TILs.

CONCLUSIONS

We identified specific metabolites and microbial taxa associated with CD8 TILs, delineated interactions between the breast tumor microbiome and metabolome, and demonstrated that intratumoral 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.