Enhanced Acid Sphingomyelinase Activity Drives Immune Evasion And

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Enhanced Acid Sphingomyelinase Activity Drives Immune Evasion And Published OnlineFirst September 7, 2017; DOI: 10.1158/0008-5472.CAN-16-3313 Cancer Microenvironment and Immunology Research Enhanced Acid Sphingomyelinase Activity Drives Immune Evasion and Tumor Growth in Non–Small Cell Lung Carcinoma Katerina Kachler1, Maximilian Bailer1, Lisanne Heim1, Fabian Schumacher2,3, Martin Reichel4,5, Corinna D. Holzinger1, Sonja Trump1, Susanne Mittler1, Juliana Monti5, Denis I. Trufa6, Ralf J. Rieker7, Arndt Hartmann7, Horia Sirbu6, Burkhard Kleuser2, Johannes Kornhuber5, and Susetta Finotto1 Abstract The lipid hydrolase enzyme acid sphingomyelinase (ASM) is rendered them resistant to serum starvation–induced apoptosis. required for the conversion of the lipid cell membrane compo- In a murine model of lung adenocarcinoma, ASM deficiency nent sphingomyelin into ceramide. In cancer cells, ASM-mediated reduced tumor development in a manner associated with signif- ceramide production is important for apoptosis, cell prolifera- icant enhancement of Th1-mediated and cytotoxic T-cell–medi- tion, and immune modulation, highlighting ASM as a potential ated antitumor immunity. Our findings indicate that targeting multimodal therapeutic target. In this study, we demonstrate ASM in NSCLC can act by tumor cell–intrinsic and –extrinsic elevated ASM activity in the lung tumor environment and blood mechanisms to suppress tumor cell growth, most notably by serum of patients with non–small cell lung cancer (NSCLC). enabling an effective antitumor immune response by the host. RNAi-mediated attenuation of SMPD1 in human NSCLC cells Cancer Res; 77(21); 1–14. Ó2017 AACR. Introduction ation of ceramide through sphingomyelin hydrolyzation is car- ried out by sphingomyelinases (SMases), enzymes that can be Sphingolipids are bioactive components of the cellular mem- classified into four different types, according to their characteristic brane that are involved in important cellular processes, as for pH-optimum and cofactor dependence (4). One of the best example cell death, proliferation, cell migration, and immune studied SMases is the acid sphingomyelinase (aSMase, ASM) that reactions. The most prevalent lipid in the outer leaflet of the cell is encoded by the SMPD1 (sphingomyelin phosphodiesterase 1) membrane is sphingomyelin that can be converted into ceramide gene (5). by enzyme acid sphingomyelinase (ASM)–mediated hydrolysis The major importance of ASM-mediated ceramide metabolism (1). Ceramide molecules are able to interact with each other, for normal cell function is evidenced by the Niemann–Pick forming isolated lipid "microdomains," which can promote disease (NPD), a rare, recessively inherited genetic disorder that receptor dimerization as well as other protein interactions within is caused by ASM deficiency. Depending on the type of NPD, the the lipid bilayer of the cell membrane (2). The balance between symptoms can range from severe visceral abnormalities to a ceramide and sphingosine-1-phosphate is referred to as the rapidly progressive neurodegeneration, leading to death by the "ceramide/sphingosine-1-phosphate rheostat," which regulates age of 2 to 3 years (6). In order to understand the mechanisms a proper balance between cell death and growth (3). The gener- behind this disease, several groups have studied ASM knockout mice, thereby identifying important functions of ASM for various cellular events. One of the most prominent observations was that 1Department of Molecular Pneumology, University Hospital, Friedrich-Alexan- ASM-deficient cells are resistant to apoptosis, induced by diverse € € 2 der-Universitat Erlangen-Nurnberg, Erlangen, Germany. Institute of Nutritional stimuli, including chemotherapy and TNFa treatment (7, 8). Science, University of Potsdam, Nuthetal, Germany. 3Department of Molecular Other studies have revealed that ceramide, which is generated by Biology, University of Duisburg-Essen, Essen, Germany. 4Department of Nephrology and Hypertension, University Hospital, Friedrich-Alexander- ASM, is required for the induction of cell-cycle arrest (9). In Universitat€ Erlangen-Nurnberg,€ Erlangen, Germany. 5Department of Psychiatry addition to that, it has been shown that ASM has an influence and Psychotherapy, University Hospital, Friedrich-Alexander-Universitat€ on the cells of the immune system. Thus, ASM is necessary for a Erlangen-Nurnberg,€ Erlangen, Germany. 6Department of Thoracic Surgery, correct phagocytosis and can modulate T-cell activation and € € University Hospital, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlan- differentiation as well as the secretion of effector molecules from 7 þ gen, Germany. Institute of Pathology, University Hospital, Friedrich-Alexander- cytotoxic CD8 T-cell granules (10). Furthermore, ASM has been Universitat€ Erlangen-Nurnberg,€ Erlangen, Germany. recently shown to influence regulatory T-cell differentiation (11). Note: Supplementary data for this article are available at Cancer Research These findings have drawn the attention to ASM as a possible Online (http://cancerres.aacrjournals.org/). target for other human diseases in addition to NPD, especially Corresponding Author: Susetta Finotto, University of Erlangen, Hartmannstraße cancer. In fact, it is known that resistance to apoptosis, as it is 14, 91054 Erlangen, Germany. Phone: 0049-09131-8542-454; Fax: 0049-09131- found in ASM-deficient cells, is a typical characteristic of tumor 8535-977; E-mail: [email protected] cells (12). Besides that, ASM has been proven to be involved in the doi: 10.1158/0008-5472.CAN-16-3313 regulation of other biological processes such as the cell cycle and Ó2017 American Association for Cancer Research. the inactivation of the cells of the immune system resulting in www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst September 7, 2017; DOI: 10.1158/0008-5472.CAN-16-3313 Kachler et al. tumor cell development and tumor progression. Together, this board of the University of Erlangen (Re-No: 56_12B; DRKS-ID: raised the question, if ASM expression or activity might be DRKS00005376). The patient studies were conducted in accor- dysregulated both in cancer cells and in other cells of the immune dance with the ethical guidelines of the Declaration of Helsinki. system surrounding the tumor and to what extent that could Before undergoing surgery, 61 patients diagnosed with NSCLC contribute to the pathogenesis of the disease. gave their approval to being enrolled in this study. The confi- The hypothesis that ASM could be important for cancer biology dentiality of the patients was maintained. is supported by the observation that ceramide levels are signifi- Lung cancer diagnosis was based on pathologic confirmation. cantly decreased in different kinds of tumors, including colon The NSCLC patients were divided into subgroups according to the cancer, ovarian cancer, and glioma (13–15). However, previous classification of histologic types of lung cancer formulated by the studies that were conducted to clearly define the role of ASM either World Health Organization in 2004. Staging was based on the as a tumor promoter or a tumor suppressor yielded in different Cancer TNM Staging Manual by the International Association for results. For instance, it was found that low levels of ceramide as the Study of Lung Cancer, issued in 2010. well as ASM correlate with increasing malignancy of brain tumors During surgery, lung tissue samples were taken from two and melanoma, respectively (13, 16). Consistently, downregula- different regions: The tumoral area (TU: solid tumor tissue) and tion of ASM in murine melanoma cells triggers their proliferation the tumor-free control area (CTR: >5 cm away from solid tumor). as well as their metastatic capacity, and also the formation of Clinical data such as tumor size, clinical stage, and tumor grading liver metastases is enhanced in ASM-deficient mice (16, 17). were provided by the Department of Thoracic Surgery. This cohort Moreover, it has been shown that ASM-generated ceramide is of patients was already described (22). necessary for drug-induced apoptosis of ovarian carcinoma cells (18). Whereas these findings support the view of ASM as a tumor Determination of ASM activity in blood serum suppressor, a recently published study indicates the opposite. ASM activity was measured in blood serum as previously There, it has been demonstrated that ASM-deficient mice are described (23). In short, samples were incubated with N-(4,4- protected from the development of melanoma cell–derived difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-dodeca- metastases in the lung. That was explained by the necessity of noyl)-sphingosylphosphocholine (BODIPY FL C12-sphingo- ASM for the interaction between platelets and tumor cells, which myelin; Life Technologies). After separation by thin-layer chro- is a crucial process during an early phase of metastasis (19). In matography, the levels of ceramide and sphingomyelin were conclusion, these previous studies show that ASM can have determined using a Typhoon Trio scanner (GE Healthcare). protumoral as well as antitumoral properties, depending on the site of ASM expression as well as the tumor type. However, Mass spectrometry additional analyses are strongly required in order to understand Ceramides and sphingomyelin were extracted from lung tissue the role of ASM in tumor diseases. samples, blood serum, or pelleted cells and quantified as recently The aim of the present study was to analyze the role of ASM
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