Tumor-colonizing Lachnoclostridium-mediated chemokine expression enhances the immune infiltration of bladder urothelial carcinoma.

Abstract

Limited research into the tumor immune microenvironment (TIME) for bladder urothelial carcinoma (BUC), particularly the neglect of the intratumoral microbiota, has hindered the development of immunotherapies targeting BUC. Here, we collect 401 patients with BUC with host transcriptome samples and matched tumor microbiome samples from The Cancer Genome Atlas database. Besides, two independent BUC cohorts receiving immunotherapy were obtained. First, we find that the TIME profile is closely related to the prognosis of patients with BUC. Additionally, the genus Lachnoclostridium in tumors could regulate the accumulation of chemokines to recruit immune cell populations into bladder tumors. Among them, chemokines include CCL3, CCL4, CXCL9, CXCL10, and CXCL11, and immune cells mainly involve macrophages and CD8⁺ T cells. Analyses based on two independent immunotherapy cohorts suggest that these immune-related chemokines strongly influence the immunotherapeutic efficacy of BUC. Furthermore, drug predictive analyses show that immune-related chemokines impact patients' sensitivity to diverse drugs. These results suggest a dual role of immune-related chemokines in combination therapy against BUC. Collectively, our study provides new insights into the regulation of TIME by intratumoral microbiota and provides guidance for improving immunotherapy against BUC.