Introduction: Bacterial flora in the body has clinical significance for the host. However, there have been no report on the clinical significance of bacterial flora in the host bloodstream. Here, we aimed to clarify the clinical significance of blood flora in urothelial carcinoma patients.
Methods: Clinical serum samples were collected from 50 patients with localized UC who had undergone TURBT and evaluated the immune status within tumor microenvironment (Kawashima et al. Clin Genitourin Can 2019), and from 31 metastatic UC (mUC) patients who had undergone treatment with pembrolizumab. Bacterial DNA of extracellular vesicles (EVs) were extracted from each serum sample. Metagenomic sequencing was performed after amplification of V1-V2 region of the bacterial 16S rRNA gene. We identified the bacterial flora that correlated significantly with local immune status within tumor microenvironment using Linear discriminant analysis effect size analysis and evaluated whether it could become a predictive or prognostic factor for therapeutic response of mUC patients treated by pembrolizumab.
Results: The expression of EV-derived Firmicutes in blood was significantly correlated with the local immune status of cancer, with higher expression in Group I, where CD4 T cells were highly expressed, and lower expression in Group II, where CD8 and immune cell surface molecules were highly expressed (p=0.038). The expression of EV-derived Firmicutes in blood was also significantly correlated with the number of tissue infiltrating CD8 and CD4 lymphocytes into tumor tissues (CD8: p=0.016, CD4: p=0.002), and the expression level of Inducible co-stimulatory molecule on CD4 and CD8 T cells (CD8: p=0.016, CD4: p=0.002). Finally, we found that there were no patients with a therapeutic effect greater than SD in the higher expression group of Firmicutes in the blood (p=0.026). Also mUC patients with higher expression group of Firmicutes had significantly inferior prognosis in both progression-free survival (HR: 2.62, 95% CI: 1.07-6.36, p=0.034) and cancer specific survival (HR: 3.77, 95% CI: 1.44-9.86, p=0.007) in multivariate analysis.
Conclusions: To the best of our knowledge, this is the first study on the importance of peripheral bacterial EVs in cancer patients treated by cancer immunotherapy.
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