NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma

Daley, Donnele; Mani, Vishnu R.; Mohan, Navyatha; Akkad, Neha; Pandian, Gautam S. D. Balasubramania; Savadkar, Shivraj; Lee, Ki Buom; Torres‐Hernandez, Alejandro; Aykut, Berk; Diskin, Brian; Wang, Wei; Farooq, Mohammad Saad; Mahmud, Arif I.; Werba, Gregor; Morales, Eduardo J.; Lall, Sarah; Wadowski, Benjamin; Rubin, Amanda G.; Berman, Matthew E.; Narayanan, Rajkishen; Hundeyin, Mautin; Miller, George

doi:10.1084/jem.20161707

Cited by 199 publications

(159 citation statements)

References 48 publications

(69 reference statements)

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“…Inflammasome components are expressed not only by immune cells (e.g., macrophages) but also by non-immune cell types, including acinar and cancer cells. Previous studies indicated that activation of NLRP3 and AIM2 inflammasome contributes to pancreatitis (Hoque et al, 2011;Kang et al, 2016a) and that activation of the NLRP3 inflammasome within macrophages entails immune suppression in pancreatic cancer development (Daley et al, 2017). Here, we demonstrate that mitochondrial iron-mediated oxidative DNA injury results in AIM2 inflammasome activation in PDAC cells, which in turn induces HMGB1 release and subsequent CD274 expression.…”

Section: Discussionsupporting

confidence: 59%

PINK1 and PARK2 Suppress Pancreatic Tumorigenesis through Control of Mitochondrial Iron-Mediated Immunometabolism

et al. 2018

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Pancreatic cancer is an aggressive malignancy with changes in the tumor microenvironment. Here, we demonstrate that PINK1 and PARK2 suppressed pancreatic tumorigenesis through control of mitochondrial iron-dependent immunometabolism. Using mouse models of spontaneous pancreatic cancer, we show that depletion of Pink1 and Park2 accelerates mutant Kras-driven pancreatic tumorigenesis. PINK1-PARK2 pathway-mediated degradation of SLC25A37 and SLC25A28 increases mitochondrial iron accumulation, which leads to the HIF1A-dependent Warburg effect and AIM2-dependent inflammasome activation in tumor cells. AIM2-mediated HMGB1 release further induces expression of CD274/PD-L1. Consequently, pharmacological administration of mitochondrial iron chelator, anti-HMGB1 antibody, or genetic depletion of Hif1a or Aim2 in pink1 and park2 mice confers protection against pancreatic tumorigenesis. Low PARK2 expression and high SLC25A37 and AIM2 expression are associated with poor prognosis in patients with pancreatic cancer. These findings suggest that disrupted mitochondrial iron homeostasis may contribute to cancer development and hence constitute a target for therapeutic intervention.

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Section: Discussionsupporting

confidence: 59%

PINK1 and PARK2 Suppress Pancreatic Tumorigenesis through Control of Mitochondrial Iron-Mediated Immunometabolism

et al. 2018

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“…Thus, our data make a compelling case that pomalidomide-induced downregulation of IRF4 may reprogram macrophage populations in the pancreas to an inflammatory phenotype. However, futures studies should investigate if pomalidomide can also regulate other factors that control TAMinduced adaptive immune suppression in PDA, such as NLRP3/ IL10 signaling (39), or factors of the necrosome such as RIP3 and Mincle (40).…”

Section: Discussionmentioning

confidence: 99%

Pomalidomide Alters Pancreatic Macrophage Populations to Generate an Immune-Responsive Environment at Precancerous and Cancerous Lesions

et al. 2019

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During development of pancreatic cancer, alternatively activated macrophages contribute to fibrogenesis, pancreatic intraepithelial neoplasia (PanIN) lesion growth, and generation of an immunosuppressive environment. Here, we show that the immunomodulatory agent pomalidomide depletes pancreatic lesion areas of alternatively activated macrophage populations. Pomalidomide treatment resulted in downregulation of interferon regulatory factor 4, a transcription factor for M2 macrophage polarization. Pomalidomide-induced absence of alternatively activated macrophages led to a decrease in fibrosis at PanIN lesions and in syngeneic tumors; this was due to generation of an inflammatory, immune-responsive environment with increased expression of IL1a and presence of activated (IFNg-positive) CD4 þ and CD8 þ T-cell populations. Our results indicate that pomalidomide could be used to decrease fibrogenesis in pancreatic cancer and may be ideal as a combination treatment with chemotherapeutic drugs or other immunotherapies. Significance: These findings reveal new insights into how macrophage populations within the pancreatic cancer microenvironment can be modulated, providing the means to turn the microenvironment from immunosuppressive to immuneresponsive.

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“…Inflammation affects all stages of tumorigenesis and the key signaling pathway triggering inflammation is to activate inflammasome, which lead to inflammatory responses . NLRP3 inflammasome, a protein complex composed of NLRP3, ASC, and caspase‐1, contributes to its biological function in the pathogenesis of cancers, such as oral squamous cell carcinoma, lymphoma, and pancreatic carcinomas . However, its specific role in inflammation‐related lung carcinogenesis has not yet been explored.…”

Section: Discussionmentioning

confidence: 99%

NLRP3 inflammasome activation involved in LPS and coal tar pitch extract‐induced malignant transformation of human bronchial epithelial cells

Duan

Wang

Huang

et al. 2019

Environmental Toxicology

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Inflammatory microenvironment has been found as a new characteristic of cancer; however, the mechanisms of inflammation-related lung cancer remain unclear. To explore the role of NLRP3 inflammsome activation in inflammation-related lung carcinogenesis, a cell model was set up. Human bronchial epithelial cells (BEAS-2B) were stimulated with 1 μg/mL lipopolysaccharide (LPS) for 24 hours, and then treated with 2.4 μg/mL coal tar pitch extract (CTPE) for 24 hours, after removal of LPS and CTPE, the cells were numbered passage 1 and were passaged and treated in this way until passage 30, which was called LPS + CTPE group. DMSO and Saline were used as vehicle controls. Malignant transformation of cells in passage 30 was evaluated by morphological change, platelet clone formation assay, and tumor formation in nude mice. The mRNA levels of NLRP3 and IL-1β were detected by real time-PCR. The combination of NLRP3 and caspase-1 were determined using immunofluorescence and confocal. The protein expression of NLRP3, cleaved caspase-1(p10), and cleaved IL-1β was detected using Western blot. It was shown that CTPE, LPS + CTPEstimulated BEAS-2B cells of passage 30 changed a lot morphologically. The clone formation rates, the rates of positive cells of NLRP3 and caspase-1 combination, the mRNA levels of NLRP3 and IL-1β, the protein expression of NLRP3, cleaved caspase-1(p10) and cleaved IL-1β of cells exposed with CTPE and LPS + CTPE at passage 30 were significantly increased compared to vehicle controls. Furthermore, the ability of tumor formation in nude mice, the rates of clone formation and positive cells, mRNA and protein levels of NLRP3 inflammasome activation-related factors in LPS + CTPE-induced cells were all higher than those in cells stimulated with CTPE alone. In conclusion, the cell model of inflammation-related lung cancer is set up successfully, and NLRP3 inflammasome activation may be involved in the malignant transformation of BEAS-2B cells which induced by CTPE alone or LPS combined with CTPE.

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NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma

Cited by 199 publications

References 48 publications

PINK1 and PARK2 Suppress Pancreatic Tumorigenesis through Control of Mitochondrial Iron-Mediated Immunometabolism

PINK1 and PARK2 Suppress Pancreatic Tumorigenesis through Control of Mitochondrial Iron-Mediated Immunometabolism

Pomalidomide Alters Pancreatic Macrophage Populations to Generate an Immune-Responsive Environment at Precancerous and Cancerous Lesions

NLRP3 inflammasome activation involved in LPS and coal tar pitch extract‐induced malignant transformation of human bronchial epithelial cells

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