Neutrophil Extracellular Traps (NETs) Are Critical Players in Bladder Cancer Radioresistance - Expert Commentary

Radiation therapy is a cornerstone of bladder-sparing treatment regimens for patients with muscle-invasive bladder cancer (MIBC). However, a significant number of MIBCs are radioresistant. Components of tumor immune microenvironment (TIME) can mediate tumor radioresistance. Polymorphonuclear neutrophils (PMNs) are known to infiltrate the TIME post-radiation and are associated with adverse outcomes for patients with MIBC. PMNs extrude web-like structures composed of DNA and histones, known as neutrophil extracellular traps (NETs), but it is unclear if these NETs play a role in response to radiation.

A recent study by Shinde-Jadhav et al. in Nature Communications examined the contribution of PMNs and NETs to tumor radioresistance. The authors used a syngeneic heterotopic model of invasive urothelial carcinoma (the MB49 model). NETs were identified using two specific markers, neutrophil elastase (NE) and citrullinated histone-H3 (H3Cit). Exposure of the murine models to radiation led to PMNs infiltration and NETs formation compared to non-irradiated controls. Inhibition and degradation of NETs by DNAse I or a neutrophil elastase inhibitor resulted in a delay in tumor growth and longer overall survival of the irradiated mice compared to irradiated controls.

The authors explored pro-inflammatory factors that drive NETs formation post-radiation. HMGB1, a protein released by tumor cells post-radiation, was found to induce the formation of NETs through the Toll-like receptor 4 (TLR4). In addition, the investigators showed that inhibition of HMGB1 improved response to radiation. The investigators examined the spatial distribution of NETs and CD8 T-cells within the radiated TIME of the murine cancers. Interestingly, NETs formed a physical barrier between immune and tumor cells, suggesting that NETs prevent intratumoral CD8 T-cell infiltration post-radiation. Finally, the investigators examined the status of PMNs, CD8 T-cells, and NETs in a cohort of 104 patients with MIBC who received radiation. NETs were significantly detected in the TIME of radiation non-responders compared to responders (52% vs. 6%, p < 0.001).

These data suggest a critical role of PMNs and NETs in the response of bladder cancer to radiation. Further research needs to investigate NETs-targeting strategies in clinical settings and examine other critical functions of PMNs and NETs in the TIME of patients with MIBC.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York

References:

  1. Templeton AJ, McNamara MG, Šeruga B, Vera-Badillo FE, Aneja P, Ocaña A, et al. Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J Natl Cancer Inst. 2014 Jun;106(6):dju124. PMID: 24875653
  2. Shinde-Jadhav S, Mansure JJ, Rayes RF, Marcq G, Ayoub M, Skowronski R, et al. Role of neutrophil extracellular traps in radiation resistance of invasive bladder cancer. Nat Commun. 2021;12:2776. PMID: 33986291
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