High-CD14-expressing urothelial cancer cells foster a neutrophil-rich tumor microenvironment that increases the risk of radiation-promoted distant metastasis

TL;DR

High CD14 expression in urothelial cancer cells creates a neutrophil-rich environment that increases the risk of radiation-induced distant metastasis.

Contribution

CD14 is identified as a novel predictive biomarker and therapeutic target for radiation-promoted distant metastasis in urothelial cancer.

Findings

Tumors with RT-promoted DM show increased CXCR2-expressing neutrophils and NFκB activation.

CD14 expression in tumor cells drives a neutrophil-rich TME via NFκB signaling.

Blocking CD14 or neutrophils reduces RT-promoted DM in mouse models.

Abstract

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.

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.

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.

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.

The online version contains supplementary material available at 10.1186/s12929-025-01201-2.

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