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Published on: July 20, 2019
Myeloid PTEN promotes chemotherapy-induced NLRP3-inflammasome activation and antitumour immunity
Yi Huang1,2, Huanyu Wang1, Yize Hao1
1Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Abstract:
PTEN is a dual-specificity phosphatase that is frequently mutated in human cancer, and its deficiency in cancer has been associated with therapy resistance and poor survival. Although the intrinsic tumour-suppressor function of PTEN has been well established, evidence of its role in the tumour immune microenvironment is lacking. Here, we show that chemotherapy-induced antitumour immune responses and tumour suppression rely on myeloid-cell PTEN, which is essential for chemotherapy-induced activation of the NLRP3 inflammasome and antitumour immunity. PTEN directly interacts with and dephosphorylates NLRP3 to enable NLRP3-ASC interaction, inflammasome assembly and activation. Importantly, supplementation of IL-1β restores chemotherapy sensitivity in mouse myeloid cells with a PTEN deficiency. Clinically, chemotherapy-induced IL-1β production and antitumour immunity in patients with cancer is correlated with PTEN expression in myeloid cells, but not tumour cells. Our results demonstrate that myeloid PTEN can determine chemotherapy responsiveness by promoting NLRP3-dependent antitumour immunity and suggest that myeloid PTEN might be a potential biomarker to predict chemotherapy responses.
Insights
Myeloid cell PTEN is crucial for chemotherapy effectiveness by activating the NLRP3 inflammasome and promoting anti-tumor immunity. This finding suggests PTEN in myeloid cells could predict patient response to cancer therapy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- PTEN (phosphatase and tensin homolog) is a tumor suppressor frequently mutated in cancer, linked to therapy resistance.
- Its role in the tumor immune microenvironment remains largely unexplored.
- Understanding PTEN's function in immunity is critical for developing new cancer therapies.
Purpose of the Study:
- To investigate the role of PTEN in chemotherapy-induced anti-tumor immune responses.
- To elucidate the mechanism by which PTEN influences the tumor immune microenvironment.
- To determine if myeloid PTEN can serve as a predictive biomarker for chemotherapy response.
Main Methods:
- Utilized mouse models and cell-based assays to study PTEN's function in myeloid cells.
- Investigated the interaction between PTEN and the NLRP3 inflammasome components (NLRP3, ASC).
- Analyzed clinical patient data to correlate PTEN expression with chemotherapy outcomes and IL-1β production.
Main Results:
- Chemotherapy-induced anti-tumor immunity and tumor suppression depend on PTEN in myeloid cells.
- PTEN directly dephosphorylates NLRP3, facilitating inflammasome assembly and activation.
- Restoring IL-1β levels rescued chemotherapy sensitivity in PTEN-deficient myeloid cells.
- Clinical data showed PTEN expression in myeloid cells, not tumor cells, correlates with IL-1β production and anti-tumor immunity.
Conclusions:
- Myeloid PTEN is essential for chemotherapy efficacy through NLRP3 inflammasome-dependent anti-tumor immunity.
- PTEN's interaction with NLRP3 is a key mechanism linking innate immunity and chemotherapy response.
- Myeloid PTEN expression may serve as a predictive biomarker for chemotherapy responsiveness in cancer patients.
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