Journal of biomedical science · 2026
High-CD14-expressing urothelial cancer cells foster a neutrophil-rich tumor microenvironment that increases the risk of radiation-promoted distant metastasis.
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Chiang Yun, Tsai Yu-Chieh, Wang Chung-Chieh, Hsueh Fu-Jen, Huang Chao-Yuan, Chen Chung-Hsin, Pu Yeong-Shiau, Chueh Shih-Chieh, Tsai Xavier Cheng-Hong, Cheng Jason Chia-Hsien
Аннотация
BACKGROUND: Radiation (RT)-promoted distant metastasis (DM) is an underrecognized complication that can compromise the therapeutic efficacy of local RT. This study aimed to identify tumor microenvironment (TME) traits that predispose to RT-promoted DM and provide mechanistic insights for potential therapeutic intervention.
METHODS: We performed NanoString analysis on tumor samples from urothelial cancer patients to compare the TME profiles of those with and without RT-promoted DM. To complement clinical findings, we conducted RNA sequencing (RNAseq) of murine bladder cancer cell lines, MB49 (with RT-promoted DM) and MBT2 (without), followed by in vivo ectopic tumor modeling, flow cytometry of immune cell infiltrates, and cytokine array profiling.
RESULTS: NanoString analysis revealed a significant enrichment of C-X-C motif receptor 2 (CXCR2)-expressing neutrophils in the TME of patients with RT-promoted DM. These tumors also exhibited nuclear factor kappa B (NFκB) activation and increased secretion of neutrophil-recruiting chemokines. RNAseq and cytokine profiling identified CD14 expression in tumor cells as a key upstream regulator of neutrophilic TME via NFκB signaling. The use of antagonists to block neutrophils and inhibit CD14 expression in cancer cells, which reduces the secretion of neutrophil-recruiting chemokines, effectively mitigated RT-promoted DM in both the MB49 and LLC mouse models.
CONCLUSIONS: CD14 expression in tumor cells plays a pivotal role in shaping a neutrophil-enriched TME, which increases the susceptibility to RT-promoted DM. CD14 represents a potential predictive biomarker and therapeutic target for mitigating this adverse outcome.
METHODS: We performed NanoString analysis on tumor samples from urothelial cancer patients to compare the TME profiles of those with and without RT-promoted DM. To complement clinical findings, we conducted RNA sequencing (RNAseq) of murine bladder cancer cell lines, MB49 (with RT-promoted DM) and MBT2 (without), followed by in vivo ectopic tumor modeling, flow cytometry of immune cell infiltrates, and cytokine array profiling.
RESULTS: NanoString analysis revealed a significant enrichment of C-X-C motif receptor 2 (CXCR2)-expressing neutrophils in the TME of patients with RT-promoted DM. These tumors also exhibited nuclear factor kappa B (NFκB) activation and increased secretion of neutrophil-recruiting chemokines. RNAseq and cytokine profiling identified CD14 expression in tumor cells as a key upstream regulator of neutrophilic TME via NFκB signaling. The use of antagonists to block neutrophils and inhibit CD14 expression in cancer cells, which reduces the secretion of neutrophil-recruiting chemokines, effectively mitigated RT-promoted DM in both the MB49 and LLC mouse models.
CONCLUSIONS: CD14 expression in tumor cells plays a pivotal role in shaping a neutrophil-enriched TME, which increases the susceptibility to RT-promoted DM. CD14 represents a potential predictive biomarker and therapeutic target for mitigating this adverse outcome.