Human lung cancer-derived immunosuppressive plasmacytoid dendritic cells release IL-1α in an AIM2 inflammasome-dependent manner.
Plasmacytoid dendritic cells (pDCs) highly populate lung tumor masses and are strictly correlated to bad prognosis, yet their role in lung cancer is controversial. To understand their role in lung cancer, we isolated pDCs from human samples of lung obtained from non-small cell lung cancer patients undergoing thoracic surgery. Tumor masses presented a higher percentage of pDCs than healthy tissues; pDCs were in the immunosuppressive phenotype, as determined by higher levels of CD33 and PD-L1. Despite higher HLA-A and HLA-D expression, cancerous pDCs did not exert cytotoxic activity against tumor cells but instead promoted their proliferation. In this scenario, cancerous pDCs were able to produce high levels of IL-1α. This effect was observed on the specific activation of the inflammasome absent in melanoma 2 (AIM2), which led to higher cytoplasmic calcium release responsible for calpain activation underlying IL-1α release. The blockade of type I interferon receptor and of AIM2 via the addition of LL-37 significantly reduced the release of IL-1α, which was still high after Nod-like receptor P3 inhibition via glibenclamide. More important, mitochondrial-derived reactive oxygen species sequester diminished AIM2-dependent IL-1α release. Our data demonstrate that lung tumor-associated pDCs are responsive to the activation of AIM2 that promotes calcium efflux and reactive oxygen species from mitochondria, leading to calpain activation and high levels of IL-1α, which facilitate tumor cell proliferation in the lung.
Department of Pharmacy, University of Salerno, Fisciano, Italy. Electronic address: rsorrentino@unisa.it.
Rosalinda
R
Sorrentino
Department of Pharmacy, University of Salerno, Fisciano, Italy.
Michela
M
Terlizzi
Department of Medicine and Surgery, University of Salerno, Fisciano, Italy.
Vincenzo G
VG
Di Crescenzo
Department of Pharmacy, University of Salerno, Fisciano, Italy.
Ada
A
Popolo
Department of Pharmacy, University of Salerno, Fisciano, Italy.
Michela
M
Pecoraro
Division of the Respiratory System, A.O.U. San Giovanni di Dio e Ruggi D'Aragona, Salerno, Italy.
Giuseppe
G
Perillo
Division of Pneumological and Bronchial Endoscopy, A.O.U. San Giovanni di Dio e Ruggi D'Aragona, Salerno, Italy.
Antonio
A
Galderisi
Department of Pharmacy, University of Salerno, Fisciano, Italy.
Aldo
A
Pinto
D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology* / Q000473:pathology / Q000601:surgery; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000276:immunology; D058847:Inflammasomes / Q000276:immunology; D053582:Interleukin-1alpha / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000276:immunology* / Q000473:pathology / Q000601:surgery; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism
C410167:AIM2 protein, human; D004268:DNA-Binding Proteins; C508033:IFNAR2 protein, human; C508584:IL1A protein, human; D007166:Immunosuppressive Agents; D058847:Inflammasomes; D053582:Interleukin-1alpha; D017382:Reactive Oxygen Species; D053633:Receptor, Interferon alpha-beta