The immune mediated role of extracellular HMGB1 in a heterotopic model of bladder cancer radioresistance

Radical cystectomy (RC) together with bilateral pelvic lymph node dissection remains the standard treatment for muscle invasive bladder cancer (MIBC). However, radiation-based treatments such as tri-modal therapy (TMT) involving maximally performed transurethral resection of bladder tumor (TURBT), r...

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Bibliographic Details
Published in:Scientific reports 2019-04, Vol.9 (1), p.6348-6348, Article 6348
Main Authors: Ayoub, Mina, Shinde-Jadhav, Surashri, Mansure, Jose Joao, Alvarez, Fernando, Connell, Tanner, Seuntjens, Jan, Piccirillo, Ciriaco A, Kassouf, Wassim
Format: Article
Language:English
Subjects:
Animals
Autophagy
Bladder cancer
Cancer
Cancer therapies
Cell Line, Tumor
Cell Proliferation
DNA damage
DNA repair
Forkhead Transcription Factors - metabolism
Glycyrrhizic Acid - pharmacology
HMGB1 protein
HMGB1 Protein - antagonists & inhibitors
HMGB1 Protein - metabolism
Invasiveness
Lymph nodes
Macrophages - pathology
Metastases
Mice, Inbred C57BL
Myeloid-Derived Suppressor Cells - metabolism
Phagocytosis
Radiation therapy
Radiation Tolerance
Radioresistance
T-Lymphocytes, Regulatory - metabolism
Tumor cells
Tumor Microenvironment
Tumors
Urinary Bladder Neoplasms - genetics
Urinary Bladder Neoplasms - immunology
Urinary Bladder Neoplasms - pathology
Urinary Bladder Neoplasms - radiotherapy
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Summary:Radical cystectomy (RC) together with bilateral pelvic lymph node dissection remains the standard treatment for muscle invasive bladder cancer (MIBC). However, radiation-based treatments such as tri-modal therapy (TMT) involving maximally performed transurethral resection of bladder tumor (TURBT), radiotherapy (XRT), and a chemosensitizer represent an attractive, less invasive alternative. Nevertheless, 25-30% of MIBC patients will experience local recurrence after TMT and half will develop metastasis. Radioresistance of tumor cells could potentially be one of the causes for local recurrence post treatment. High mobility group box-1 (HMGB1) was shown to play a role in bladder cancer radioresistance through its intracellular functions in promoting DNA damage repair and autophagy. Recently, HMGB1 was found to be passively released from irradiated tumor cells. However, less is known about the involvement of extracellular HMGB1 in impairing radiation response and its exact role in modulating the tumor immune microenvironment after XRT. We identified a novel mechanism of bladder cancer radioresistance mediated by the immunological functions of HMGB1. The combination of radiation plus extracellular HMGB1 inhibition markedly improved the radiation response of tumors and resulted in marked changes in the immune landscape. Moreover, combining radiation and HMGB1 inhibition significantly impaired tumor infiltrating MDSCs and TAMs -but not Tregs- and shifted the overall tumor immune balance towards anti-tumoral response. We conclude that extracellular HMGB1 is involved in bladder cancer radioresistance through promoting pro-tumor immune mechanisms.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-019-42864-w