Snail-regulated exosomal microRNA-21 suppresses NLRP3 inflammasome activity to enhance cisplatin resistance


A significant challenge in treating advanced tumours is the development of treatment resistance during disease progression. The genetic development of cancer cells and non-genetic therapeutic adaptation are two causes of the acquired resistance of malignant tumors. Cancer cells’ non-genetic flexibility makes it easier for them to evade anticancer immunosurveillance and use lineage swapping to adapt to their environment. Strategies for removing non-genetic adaptation-mediated resistance are very few compared to the rapid developments in sequencing technologies and the precision targeting of resistant mutants. Inflammasomes are multimolecular complexes that operate as primary sensors of innate immunity in mammals and respond to signals of danger. They are made up of a NOD-like receptor scaffold, caspase activation, adaptor proteins like ASC, and caspase-1. Amongst the inflammasomes family, NLRP3 inflammasome is the most characterized. There is not much research on how inflammasome post-therapeutic activation affects treatment response. Strategies for removing non-genetic adaptation-mediated resistance are scarce compared to the precision targeting of drug-resistant cancer cells that have undergone mutation. The roles inflammasomes in cancer remain rather complicated and elusive, moreover, it is still not known how inflammasomes react dynamically to cancer treatments.

In a recent study published in the peer-reviewed Journal for ImmunoTherapy of Cancer, National Yang Ming Chiao Tung University (NYCU) researchers: Mr. Han-Ying Cheng, Dr. Chia-Hsin Hsieh, Dr. Po-Han Lin, Dr. Yu-Tung Chen, Dr. Dennis Shin-Shian Hsu, Dr. Shyh-Kuan Tai, Dr. Pen-Yuan Chu, and led by Professor Muh-Hwa Yang showed for the first time that tumor cells suppressed the action of inflammasomes of tumor-associated macrophages (TAMs) in response to chemotherapy by delivering exosomal microRNA (miR)-21 to cancers undergoing Snail-induced epithelial-mesenchymal transition (EMT).

Recent studies suggest the importance of inflammasome activation in the augmentation of the chemotherapy response by an increase of antitumor immunity, notwithstanding arguments made regarding inflammasome activation in cancer development and therapeutic actions. Their clinical results demonstrated that the basal level of blood IL-1 in Human head and neck squamous cell carcinoma patients (HNSCC) who exhibited a higher Snail expression was comparatively high compared to the Snail-low individuals. However, the Snail-high HNSCC did not exhibit the post-treatment spike in IL-1 levels, which was linked to a worse chemotherapy response. In addition to these results, their study elucidates the context-dependent function of innate immune cells’ inflammasomes in cancer, wherein inflammasome-induced proinflammatory signals support tumour growth. According to the authors, miR-21 was the most prevalent exosomal miRNA in HNSCC, which is consistent with our knowledge on the miR-21’s oncogenic significance and abundance in several cancers. The authors believe that because the NLRP3 inflammasome’s component levels are generally high in cancer patients, the inflammasome’s assembly is essential for controlling its activities. Inflammasome activation is the catalyst for the subsequent immunological response in septic shock patients, hence it’s crucial to induce the expression of certain NLRP3 inflammasome components.

Professor Muh-Hwa Yang and his colleagues looked at the function of the Snail-miR-21 axis in antitumor immunity. They found that MiR-21-rich TEXs triggered by snails prevented macrophage NLRP3 inflammasome activity. Indeed, they observed in clinical samples of HNSCC. Moreover, a higher expression of Snail has a greater invasion of TAMs. When TAMs were given cisplatin treatment, mir-21 knockout in the murine oral cancer cell line MTCQ increased caspase-1 activation. The scRNA-seq study revealed that knocking down mir-21 decreased the percentage of CD4+ TILs while activating CD8+ TILs. They believe that both the TME-modulating action of exosomal miR-21 and the oncogenic effect of intracancerous miR-21 are responsible for the malignant tendencies of tumors with high levels of miR-21. MiR-21 may significantly impact innate immune cells in tumor-infiltrated immune cells in response to stimuli, emphasizing the significance of exosomal miR-21 transmission.

In summary, targeting the NLRP3 inflammasome or its downstream pathways, either solely or in combination with chemotherapy or other immunotherapeutic approaches, hold a promising potential in  treatment for head and neck cancer. NYMU scientists demonstrated the important role of Snail in the metastatic evolution of immunological adaptation-related chemoresistance. In response to therapeutic stimuli, the tumor-infiltrating immune cells are dynamically shaped by the plasticity of cancer cells, demonstrating the need for real-time refined treatment strategy modification while tumor progresses.


Cheng HY, Hsieh CH, Lin PH, Chen YT, Hsu DS, Tai SK, Chu PY, Yang MH. Snail-regulated exosomal microRNA-21 suppresses NLRP3 inflammasome activity to enhance cisplatin resistance. Journal for immunotherapy of cancer. 2022;10(8):e004832.

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