Publications by authors named "Doo Hyun Chung"

188 Publications

OASL1-Mediated Inhibition of Type I IFN Reduces Influenza A Infection-Induced Airway Inflammation by Regulating ILC2s.

Allergy Asthma Immunol Res 2022 Jan;14(1):99-116

Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.

Purpose: Three observations drove this study. First, 2'-5'-oligoadenylate synthetase-like protein (OASL) is a negative regulator of type I interferon (IFN). Second, type I IFN plays a central role during virus infections and the pathogenesis of various diseases, including asthma. Third, influenza A virus (IAV) causes non-eosinophilic asthma. To evaluate the potential relationships between OASL, type I IFN, and pulmonary innate immune cells in IAV-induced acute airway inflammation by using mice.

Methods: Asthma was induced in wild-type (WT) and mice with IAV or ovalbumin (OVA). Airway hyperreactivity (AHR) and immune cell infiltration in the bronchoalveolar lavage (BAL) fluids were measured. The immune cells in the lungs were analyzed by flow cytometry. To investigate the ability of type I IFN to shape the response of lung type 2 innate lymphoid cells (ILC2s), IFN-α was treated intratracheally. Plasmacytoid dendritic cells (pDCs) sorted from bone marrow and ILC2s sorted from lungs of naive mice were co-cultured with/without interferon-alpha receptor subunit 1 (IFNAR-1)-blocking antibodies.

Results: In the IAV-induced asthma model, mice developed greater AHR and immune cell infiltration in the BAL fluids than WT mice. This was not observed in OVA-induced asthma, a standard model of allergen-induced asthma. The lungs of infected mice also had elevated DC numbers and expression and depressed IAV-induced ILC2 responses, namely, proliferation and type 2 cytokine and amphiregulin production. Intratracheal administration of type I IFN in naïve mice suppressed lung ILC2 production of type 2 cytokines and amphiregulin. Co-culture of ILC2s with pDCs showed that pDCs inhibit the function of ILC2s by secreting type I IFN.

Conclusions: OASL1 may impede the IAV-induced acute airway inflammation that drives AHR by inhibiting IAV-induced type I IFN production from lung DCs, thereby preserving the functions of lung ILC2s, including their amphiregulin production.
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http://dx.doi.org/10.4168/aair.2022.14.1.99DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8724833PMC
January 2022

Serum amyloid A promotes emphysema by triggering the reciprocal activation of neutrophils and ILC3s.

Clin Transl Med 2021 12;11(12):e637

Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.

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http://dx.doi.org/10.1002/ctm2.637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8684768PMC
December 2021

A unique population of neutrophils generated by air pollutant-induced lung damage exacerbates airway inflammation.

J Allergy Clin Immunol 2021 Oct 20. Epub 2021 Oct 20.

Laboratory of Mucosal Immunology in Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address:

Background: Diesel exhaust particles (DEPs) are the main component of traffic-related air pollution and have been implicated in the pathogenesis and exacerbation of asthma. However, the mechanism by which DEP exposure aggravates asthma symptoms remains unclear.

Objective: This study aimed to identify a key cellular player of air pollutant-induced asthma exacerbation and development.

Methods: We examined the distribution of innate immune cells in the murine models of asthma induced by house dust mite and DEP. Changes in immune cell profiles caused by DEP exposure were confirmed by flow cytometry and RNA-Seq analysis. The roles of sialic acid-binding, Ig-like lectin F (SiglecF)-positive neutrophils were further evaluated by adoptive transfer experiment and in vitro functional studies.

Results: DEP exposure induced a unique population of lung granulocytes that coexpressed Ly6G and SiglecF. These cells differed phenotypically, morphologically, functionally, and transcriptionally from other SiglecF-expressing cells in the lungs. Our findings with murine models suggest that intratracheal challenge with DEPs induces the local release of adenosine triphosphate, which is a damage-associated molecular pattern signal. Adenosine triphosphate promotes the expression of SiglecF on neutrophils, and these SiglecF neutrophils worsen type 2 and 3 airway inflammation by producing high levels of cysteinyl leukotrienes and neutrophil extracellular traps. We also found Siglec8- (which corresponds to murine SiglecF) expressing neutrophils, and we found it in patients with asthma-chronic obstructive pulmonary disease overlap.

Conclusion: The SiglecF neutrophil is a novel and critical player in airway inflammation and targeting this population could reverse or ameliorate asthma.
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http://dx.doi.org/10.1016/j.jaci.2021.09.031DOI Listing
October 2021

Interactions between NCRILC3s and the Microbiome in the Airways Shape Asthma Severity.

Immune Netw 2021 Aug 22;21(4):e25. Epub 2021 Jul 22.

Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.

Asthma is a heterogeneous disease whose development is shaped by a variety of environmental and genetic factors. While several recent studies suggest that microbial dysbiosis in the gut may promote asthma, little is known about the relationship between the recently discovered lung microbiome and asthma. Innate lymphoid cells (ILCs) have also been shown recently to participate in asthma. To investigate the relationship between the lung microbiome, ILCs, and asthma, we recruited 23 healthy controls (HC), 42 patients with non-severe asthma, and 32 patients with severe asthma. Flow cytometry analysis showed severe asthma associated with fewer natural cytotoxicity receptor (NCR)ILC3s in the lung. Similar changes in other ILC subsets, macrophages, and monocytes were not observed. The asthma patients did not differ from the HC in terms of the alpha and beta-diversity of the lung and gut microbiomes. However, lung function correlated positively with both NCRILC3 frequencies and microbial diversity in the lung. Sputum NCRILC3 frequencies correlated positively with lung microbiome diversity in the HC, but this relationship was inversed in severe asthma. Together, these data suggest that airway NCRILC3s may contribute to a healthy commensal diversity and normal lung function.
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http://dx.doi.org/10.4110/in.2021.21.e25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410993PMC
August 2021

Mesenchymal Stem Cells Suppress Severe Asthma by Directly Regulating Th2 Cells and Type 2 Innate Lymphoid Cells.

Mol Cells 2021 Aug;44(8):580-590

Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea.

Patients with severe asthma have unmet clinical needs for effective and safe therapies. One possibility may be mesenchymal stem cell (MSC) therapy, which can improve asthma in murine models. However, it remains unclear how MSCs exert their beneficial effects in asthma. Here, we examined the effect of human umbilical cord blood-derived MSCs (hUC-MSC) on two mouse models of severe asthma, namely, Alternaria alternata-induced and house dust mite (HDM)/diesel exhaust particle (DEP)-induced asthma. hUC-MSC treatment attenuated lung type 2 (Th2 and type 2 innate lymphoid cell) inflammation in both models. However, these effects were only observed with particular treatment routes and timings. co-culture showed that hUC-MSC directly downregulated the interleukin (IL)-5 and IL-13 production of differentiated mouse Th2 cells and peripheral blood mononuclear cells from asthma patients. Thus, these results showed that hUC-MSC treatment can ameliorate asthma by suppressing the asthmogenic cytokine production of effector cells. However, the successful clinical application of MSCs in the future is likely to require careful optimization of the route, dosage, and timing.
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http://dx.doi.org/10.14348/molcells.2021.0101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424137PMC
August 2021

Ssu72 phosphatase directly binds to ZAP-70, thereby providing fine-tuning of TCR signaling and preventing spontaneous inflammation.

Proc Natl Acad Sci U S A 2021 08;118(35)

Laboratory of Immune Regulation, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea;

ZAP-70 is required for the initiation of T cell receptor (TCR) signaling, and Ssu72 is a phosphatase that regulates RNA polymerase II activity in the nucleus. However, the mechanism by which ZAP-70 regulates the fine-tuning of TCR signaling remains elusive. Here, we found that Ssu72 contributed to the fine-tuning of TCR signaling by acting as tyrosine phosphatase for ZAP-70. Affinity purification-mass spectrometry and an in vitro assay demonstrated specific interaction between Ssu72 and ZAP-70 in T cells. Upon TCR stimulation, Ssu72-deficient T cells increased the phosphorylation of ZAP-70 and downstream molecules and exhibited hyperresponsiveness, which was restored by reducing ZAP-70 phosphorylation. In vitro assay demonstrated that recombinant Ssu72 reduced tyrosine phosphorylation of ZAP-70 via phosphatase activity. -Cre mice showed a defect in the thymic development of invariant natural killer T cells and reductions in CD4 and CD8 T cell numbers in the periphery but more CD44CD62L memory T cells and fewer CD44CD62L naïve T cells, compared with wild-type mice. Furthermore, -Cre mice developed spontaneous inflammation at 6 mo. In conclusion, Ssu72 phosphatase regulates the fine-tuning of TCR signaling by binding to ZAP-70 and regulating its tyrosine phosphorylation, thereby preventing spontaneous inflammation.
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http://dx.doi.org/10.1073/pnas.2102374118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8536320PMC
August 2021

Increased GM-CSF-producing NCR ILC3s and neutrophils in the intestinal mucosa exacerbate inflammatory bowel disease.

Clin Transl Immunology 2021 8;10(7):e1311. Epub 2021 Jul 8.

Laboratory of Mucosal Immunology Department of Biomedical Sciences Seoul National University College of Medicine Seoul Korea.

Objectives: Inflammatory bowel disease (IBD) is characterised by dysregulated mucosal immune responses associated with genetic, environmental and microbial factors. Recent therapies targeting key inflammatory mediators such as tumor necrosis factor (TNF)-α emphasise the importance of innate immunity in the development of IBD.

Methods: We examined the distribution of innate immune cells such as innate lymphoid cells (ILCs) and myeloid cells in the intestinal epithelium from children diagnosed as IBD and murine models of colitis induced by dextran sulphate sodium (DSS) or an anti-CD40 antibodies.

Results: We found an increased number of type 3 ILCs (ILC3s) that do not express the natural cytotoxicity receptor (NCR) and neutrophils, in both human IBD patients and colitis-induced mice. A co-culture experiment of neutrophils with NCR ILC3s revealed that NCR ILC3s stimulate neutrophils by producing granulocyte-macrophage colony-stimulating factor (GM-CSF). Furthermore, a blockade of GM-CSF could inhibit the development of IBD by inhibiting neutrophil activity.

Conclusion: The NCR ILC3: GM-CSF: neutrophil axis could contribute to the development of IBD.
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http://dx.doi.org/10.1002/cti2.1311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264747PMC
July 2021

Soluble Fas ligand drives autoantibody-induced arthritis by binding to DR5/TRAIL-R2.

Elife 2021 07 5;10. Epub 2021 Jul 5.

Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea.

To date, no study has demonstrated that soluble Fas ligand (sFasL)-mediated inflammation is regulated via interaction with Fas in vivo. We found that FasL interacts specifically with tumor necrosis factor receptor superfamily (TNFRSF)10B, also known as death receptor (DR)5. Autoantibody-induced arthritis (AIA) was attenuated in FasL ()- and soluble FasL ()-deficient mice, but not in Fas ( and )- or membrane FasL ()-deficient mice, suggesting sFasL promotes inflammation by binding to a Fas-independent receptor. Affinity purification mass spectrometry analysis using human (h) fibroblast-like synovial cells (FLSCs) identified DR5 as one of several proteins that could be the elusive Fas-independent FasL receptor. Subsequent cellular and biochemical analyses revealed that DR5 interacted specifically with recombinant FasL-Fc protein, although the strength of this interaction was approximately 60-fold lower than the affinity between TRAIL and DR5. A microarray assay using joint tissues from mice with arthritis implied that the chemokine CX3CL1 may play an important downstream role of the interaction. The interaction enhanced transcription and increased sCX3CL1 production in FLSCs, possibly in an NF-κB-dependent manner. Moreover, the sFasL-DR5 interaction-mediated CX3CL1-CX3CR1 axis initiated and amplified inflammation by enhancing inflammatory cell influx and aggravating inflammation via secondary chemokine production. Blockade of FasL or CX3CR1 attenuated AIA. Therefore, the sFasL-DR5 interaction promotes inflammation and is a potential therapeutic target.
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http://dx.doi.org/10.7554/eLife.48840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257255PMC
July 2021

Immune Networks in Health and Disease.

Mol Cells 2021 05;44(5):279-280

Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Korea.

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http://dx.doi.org/10.14348/molcells.2021.0117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175147PMC
May 2021

Development and Functions of Alveolar Macrophages.

Mol Cells 2021 May;44(5):292-300

Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Korea.

Macrophages residing in various tissue types are unique in terms of their anatomical locations, ontogenies, developmental pathways, gene expression patterns, and immunological functions. Alveolar macrophages (AMs) reside in the alveolar lumen of the lungs and serve as the first line of defense for the respiratory tract. The immunological functions of AMs are implicated in the pathogenesis of various pulmonary diseases such as allergic asthma, chronic obstructive pulmonary disorder (COPD), pulmonary alveolar proteinosis (PAP), viral infection, and bacterial infection. Thus, the molecular mechanisms driving the development and function of AMs have been extensively investigated. In this review article, we discuss the roles of granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor (TGF)-β in AM development, and provide an overview of the anti-inflammatory and proinflammatory functions of AMs in various contexts. Notably, we examine the relationships between the metabolic status of AMs and their development processes and functions. We hope that this review will provide new information and insight into AM development and function.
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http://dx.doi.org/10.14348/molcells.2021.0058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175155PMC
May 2021

A case of concomitant EGFR/ALK alteration against a mutated EGFR background in early-stage lung adenocarcinoma.

J Pathol Transl Med 2021 Mar 22;55(2):139-144. Epub 2021 Jan 22.

Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Rare cases of lung adenocarcinoma (LUAD) with concomitant epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) translocation have been reported. However, their clonal and evolutional relationship remains unclear. We report a case of early-stage EGFR-mutated LUAD with a focal concomitant EGFR/ALK alteration. A 63-year-old male underwent lobectomy to remove a 1.9-cm-sized lung nodule, which was diagnosed with EGFR-mutated LUAD. ALK immunohistochemistry (IHC) showed focal positivity within the part of the tumor characterized by lepidic pattern, also confirmed by fluorescence in-situ hybridization (FISH). Targeted next-generation sequencing was performed separately on the ALK IHC/FISH-positive and -negative areas. EGFR L833V/L858R mutations were detected in both areas, whereas EML4 (echinoderm microtubule-associated protein-like 4)-ALK translocations was confirmed only in the ALK IHC/FISH-positive area, suggesting the divergence of an EGFR/ALK co-altered subclone from the original EGFR-mutant clone. Our study suggests that concurrent alterations of EGFR and ALK can arise via divergent tumor evolution, even in the relatively early phases of tumorigenesis.
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http://dx.doi.org/10.4132/jptm.2020.12.16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987517PMC
March 2021

Comparative analysis of the tumor immune-microenvironment of primary and brain metastases of non-small-cell lung cancer reveals organ-specific and EGFR mutation-dependent unique immune landscape.

Cancer Immunol Immunother 2021 Jul 9;70(7):2035-2048. Epub 2021 Jan 9.

Department of Pathology, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.

Background: To evaluate the characteristics of the tumor immune-microenvironment in brain metastases of non-small-cell lung cancer (NSCLC), we investigated the immunophenotype of primary NSCLC and its brain metastasis.

Methods: Expression profiling of 770 immune-related genes in 28 tissues from primary and brain metastases of NSCLC was performed using the NanoString nCounter PanCancer Immune Profiling Panel. The immune cell profiles were validated by immunohistochemistry of 42 matched samples.

Results: Based on unsupervised clustering and principal component analysis of the immune-related gene expression profile, tumors were primarily clustered according to the involved organ and further grouped according to the EGFR mutation status. Fifty-four genes were significantly differentially expressed between primary and brain metastatic tumors. Clustering using these genes showed that tumors harboring mutated EGFR tended to be grouped together in the brain. Pathway analysis revealed that various immune-related functions involving immune regulation, T cell activity, and chemokines were enriched in primary tumors compared to brain metastases. Diverse immune-related pathways were upregulated in brain metastases of EGFR-mutated compared to EGFR-wild-type adenocarcinoma, but not in primary tumors. The interferon-γ-related gene signature was significantly decreased in brain metastases. The anti-inflammatory markers TOLLIP and HLA-G were upregulated in brain metastases. The proportions of most immune cell subsets were decreased in brain metastases, but those of macrophages and CD56dim-NK-cells were increased, as was the ratios of CD163M2- to iNOSM1-macrophages and NCR1NK-cells to CD3T cells.

Conclusions: Our findings illustrate the immune landscape of brain metastases from NSCLC and reveal potential therapeutic strategies targeting cellular and non-cellular components of the tumor immune-microenvironment.
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http://dx.doi.org/10.1007/s00262-020-02840-0DOI Listing
July 2021

Pan-cancer methylation analysis reveals an inverse correlation of tumor immunogenicity with methylation aberrancy.

Cancer Immunol Immunother 2021 Jun 24;70(6):1605-1617. Epub 2020 Nov 24.

Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.

Tumor immunogenicity is driven by various genomic and transcriptomic factors but the association with the overall status of methylation aberrancy is not well established. We analyzed The Cancer Genome Atlas pan-cancer database to investigate whether the overall methylation aberrancy links to the immune evasion of tumor. We created the definitions of hypermethylation burden, hypomethylation burden and methylation burden to establish the values that represent the degree of methylation aberrancy from human methylation 450 K array data. Both hypermethylation burden and hypomethylation burden significantly correlated with global methylation level as well as methylation subtypes defined in previous literatures. Then we evaluated whether methylation burden correlates with tumor immunogenicity and found that methylation burden showed a significant negative correlation with cytolytic activity score, which represent cytotoxic T cell activity, in pan-cancer (Spearman rho = - 0.37, p < 0.001) and 30 of 33 individual cancer types. Furthermore, this correlation was independent of mutation burden and chromosomal instability in multivariate regression analysis. We validated the findings in the external cohorts and outcomes of patients who were treated with immune checkpoint inhibitors, which showed that high methylation burden group had significantly poor progression-free survival (Hazard ratio 1.74, p = 0.038). Overall, the degree of methylation aberrancy negatively correlated with tumor immunogenicity. These findings emphasize the importance of methylation aberrancy for tumors to evade immune surveillance and warrant further development of methylation biomarker.
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http://dx.doi.org/10.1007/s00262-020-02796-1DOI Listing
June 2021

Ssu72 regulates alveolar macrophage development and allergic airway inflammation by fine-tuning of GM-CSF receptor signaling.

J Allergy Clin Immunol 2021 04 8;147(4):1242-1260. Epub 2020 Sep 8.

Laboratory of Immune Regulation in Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea; Department of Pathology, Seoul National University College of Medicine, Seoul, Korea. Electronic address:

Background: Fine-tuning of immune receptor signaling is critical for the development and functioning of immune cells. Moreover, GM-CSF receptor (GM-CSFR) signaling plays an essential role in the development of certain myeloid lineage cells, including alveolar macrophages (AMs). However, the significance of fine-tuning of GM-CSFR signaling in AMs and its relevance in allergic inflammation have not been reported.

Objective: Our aim was to explore whether phosphatase Ssu72, originally identified as a regulator of RNA polymerase II activity, regulates AM development and allergic airway inflammation by regulating GM-CSF signaling.

Methods: To address these issues, we generated LysM-CreSsu72 and Cd11c-CreSsu72 mice and used ovalbumin- or house dust mite-induced allergic asthma models.

Results: Following GM-CSF stimulation, Ssu72 directly bound to the GM-CSFR β-chain in AMs, preventing phosphorylation. Consistently, mature Ssu72-deficient AMs showed higher phosphorylation of the GM-CSFR β-chain and downstream molecules, which resulted in greater dysregulation of cell cycle, cell death, cell turnover, mitochondria-related metabolism, and LPS responsiveness in AMs than in mature wild-type AMs. The dysregulation was restored by using a Janus kinase 2 inhibitor, which reduced GM-CSFR β-chain phosphorylation. LysM-CreSsu72 mice exhibited deficits in development and maturation of AMs, which were also seen postnatally in Cd11c-CreSsu72 mice. Furthermore, LysM-CreSsu72 mice were less responsive to ovalbumin- or house dust mite-induced allergic asthma models than the control mice were; however, their responsiveness was restored by adoptive transfer of JAK2 inhibitor-pretreated mature Ssu72-deficient AMs.

Conclusion: Our results demonstrate that Ssu72 fine-tunes GM-CSFR signaling by both binding to and reducing phosphorylation of GM-CSFR β-chain, thereby regulating the development, maturation, and mitochondrial functions of AMs and allergic airway inflammation.
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http://dx.doi.org/10.1016/j.jaci.2020.07.038DOI Listing
April 2021

Temporal evolution of programmed death-ligand 1 expression in patients with non-small cell lung cancer.

Korean J Intern Med 2021 07 6;36(4):975-984. Epub 2021 Apr 6.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.

Background/aims: Programmed death-ligand 1 (PD-L1) expression, a validated predictive biomarker for anti-PD-1/PD-L1 inhibitors, is reported to change over time. This poses challenges during clinical application in non-small cell lung cancer.

Methods: This study included patients with non-small cell lung cancer who underwent surgery or biopsy and evaluation of PD-L1 expression in tumor cells via immunohistochemistry more than twice. We set the threshold of PD-L1 positivity to 10% and categorized patients into four groups according to changes in PD-L1 expression. Clinicopathologic information was collected from medical records. Statistical analyses, including Fisher's exact test and log-rank test, were performed.

Results: Of 109 patients, 38 (34.9%) and 45 (41.3%) had PD-L1 positivity in archival and recent samples, respectively. PD-L1 status was maintained in 78 (71.6%) patients, but changed in 31 (28.4%), with 19 (17.4%) from negative to positive. There were no significant differences in characteristics between patients who maintained PD-L1 negativity and whose PD-L1 status changed from negative to positive. Patients harboring PD-L1 positivity in either archival or recent samples achieved better responses (p = 0.129) and showed longer overall survival than those who maintained PD-L1 negativity when they received immune checkpoint inhibitors after platinum failure (median overall survival 14.4 months vs. 4.93 months; hazard ratio, 0.43; 95% confidence interval, 0.20 to 0.93).

Conclusion: PD-L1 status changed in about one-fourth of patients. PD-L1 positivity in either archival or recent samples was predictive of better responses to immune checkpoint inhibitors. Therefore, archival samples could be used for assessment of PD-L1 status. The need for new biopsies should be decided individually.
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http://dx.doi.org/10.3904/kjim.2020.178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273838PMC
July 2021

Reciprocal change in Glucose metabolism of Cancer and Immune Cells mediated by different Glucose Transporters predicts Immunotherapy response.

Theranostics 2020 25;10(21):9579-9590. Epub 2020 Jul 25.

Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, Seoul, Republic of Korea.

The metabolic properties of tumor microenvironment (TME) are dynamically dysregulated to achieve immune escape and promote cancer cell survival. However, properties of glucose metabolism in cancer and immune cells are poorly understood and their clinical application to development of a biomarker reflecting immune functionality is still lacking. We analyzed RNA-seq and fluorodeoxyglucose (FDG) positron emission tomography profiles of 63 lung squamous cell carcinoma (LUSC) specimens to correlate FDG uptake, expression of glucose transporters (GLUT) by RNA-seq and immune cell enrichment score (ImmuneScore). Single cell RNA-seq analysis in five lung cancer specimens was performed. We tested the GLUT3/GLUT1 ratio, the GLUT-ratio, as a surrogate representing immune metabolic functionality by investigating the association with immunotherapy response in two melanoma cohorts. ImmuneScore showed a negative correlation with GLUT1 ( = -0.70, < 0.01) and a positive correlation with GLUT3 ( = 0.39, < 0.01) in LUSC. Single-cell RNA-seq showed GLUT1 and GLUT3 were mostly expressed in cancer and immune cells, respectively. In immune-poor LUSC, FDG uptake was positively correlated with GLUT1 ( = 0.27, = 0.04) and negatively correlated with ImmuneScore ( = -0.28, = 0.04). In immune-rich LUSC, FDG uptake was positively correlated with both GLUT3 ( = 0.78, = 0.01) and ImmuneScore ( = 0.58, = 0.10). The GLUT-ratio was higher in anti-PD1 responders than nonresponders ( = 0.08 for baseline; = 0.02 for on-treatment) and associated with a progression-free survival in melanoma patients who treated with anti-CTLA4 ( = 0.04). Competitive uptake of glucose by cancer and immune cells in TME could be mediated by differential GLUT expression in these cells.
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http://dx.doi.org/10.7150/thno.48954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449929PMC
June 2021

Effects of B7-H3 expression on tumour-infiltrating immune cells and clinicopathological characteristics in non-small-cell lung cancer.

Eur J Cancer 2020 07 21;133:74-85. Epub 2020 May 21.

Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Pathology, Seoul National University Hospital, Seoul, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address:

Purpose: B7-H3 has emerged as a promising target for cancer immunotherapy. We assessed the role of B7-H3 expression in tumour-infiltrating immune cells in non-small-cell lung cancer (NSCLC).

Methods: Tumour-infiltrating immune cell characterisation was performed by flow cytometry in a prospective cohort, whereas the relationship between B7-H3 expression and clinicopathological features was explored in a retrospective cohort.

Results: B7-H3 expression was detected in tumour/epithelial cells and immune cells, including macrophages, monocytes, dendritic cells (DCs) and myeloid-derived suppressor cells. B7-H3 was expressed at higher levels in cells within the tumour than in cells within non-neoplastic tissues. B7-H3 expression score in tumour cells positively correlated with the amount of CD45 immune cells (rho = 0.305, P = 0.010), CD8 T-cells (rho = 0.330, P = 0.005), and the percentage of CD8/CD3 T-cells (rho = 0.403, P < 0.001). Patients with high tumoural B7-H3 expression showed increased numbers of immune cells (P = 0.002), CD8 T-cells (P = 0.011), natural killer cells (P = 0.073) and plasmacytoid DCs (P = 0.015). Tumoural B7-H3 expression was higher in males, smokers, squamous cell carcinomas, tumours with wild-type EGFR, poor differentiation, larger size and nodal metastasis (P < 0.05, all). Tumoural B7-H3 expression was associated with PD-L1 expression (P = 0.001), shorter 5-year overall survival (P = 0.012) and poor survival after anti-PD-1 blockade (P = 0.026).

Conclusions: Tumoural B7-H3 overexpression was associated with increased tumour-infiltrating cytotoxic lymphocytes and poor prognosis in NSCLC. Thus, B7-H3 is a promising prognostic biomarker and immunotherapeutic target in NSCLC.
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http://dx.doi.org/10.1016/j.ejca.2020.03.033DOI Listing
July 2020

The effect of air pollutants on airway innate immune cells in patients with asthma.

Allergy 2020 09 5;75(9):2372-2376. Epub 2020 May 5.

Laboratory of mucosal immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.

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http://dx.doi.org/10.1111/all.14323DOI Listing
September 2020

Reduction of circulating innate lymphoid cell progenitors results in impaired cytokine production by innate lymphoid cells in patients with lupus nephritis.

Arthritis Res Ther 2020 03 29;22(1):63. Epub 2020 Mar 29.

Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, South Korea.

Background: Innate lymphoid cells (ILCs) play an essential role in maintaining homeostasis; however, they can also cause chronic inflammation and autoimmune disease. This study aimed to identify the role of ILCs in the pathogenesis of lupus nephritis (LN).

Methods: The percentage of ILCs within the peripheral blood mononuclear cell (PBMC) population and urine of patients with LN (n = 16), healthy controls (HC; n = 8), and disease controls (ANCA-associated vasculitis (AAV; n = 6), IgA nephropathy (IgAN; n = 9), and other glomerular diseases (n = 5)) was determined by flow cytometry analysis. In addition, ILCs were sorted and cultured with plasma from LN patients or HC to elucidate whether the reduced population of CD117 ILCs observed in LN was due to changes in the ILC progenitor population.

Results: The percentage of total ILCs and CD117 ILCs in LN was significantly lower than that in HC. The percentage of cytokine-secreting ILCs was also lower in LN; however, when the disease stabilized, cytokine production was restored to levels similar to those in HC. The increase in the number of exhausted ILCs (cells unable to secrete cytokines) correlated positively with disease activity. When CD117 ILCs were cultured with LN plasma, the number of CD117 ILCs fell, but that of other ILC subsets increased.

Conclusions: The percentage of CD117 ILCs and the capacity of ILCs to secrete cytokines fell as LN severity increased, suggesting that an inflammatory environment of LN induces persistent differentiation and exhaustion of ILCs.
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http://dx.doi.org/10.1186/s13075-020-2114-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104540PMC
March 2020

Utility of PD-L1 immunocytochemistry using body-fluid cell blocks in patients with non-small-cell lung cancer.

Diagn Cytopathol 2020 Apr 13;48(4):291-299. Epub 2020 Jan 13.

Department of Pathology, Seoul National University Hospital, Seoul, Republic of Korea.

Background: The expression of programmed cell death ligand-1 (PD-L1) is a biomarker in patients with non-small-cell lung carcinoma (NSCLC). Patients with advanced-stage NSCLC receive a variety of molecular genetic tests, possibly resulting in insufficient tissue for immunoassay of PD-L1. Thus, to determine whether effusion fluid specimens are a reliable alternative to tissue specimens for PD-L1 testing, we compared the results of PD-L1 immunostaining using body-fluid cell blocks and tumor tissues.

Methods: PD-L1 immunostaining was performed in 62 paired samples of cytology cell blocks (ie, immunocytochemistry) and tumor tissues (ie, immunohistochemistry) from 36 patients using the E1L3N, SP142, and SP263 anti PD-L1 antibody clones. Of the 62 cytology specimens, 50 were from malignant effusion fluid. PD-L1 expression was scored as the percentage of tumor cells with clear membranous staining.

Results: A strong positive correlation was observed between the immunostains on cytology cell blocks and tumor tissue (Pearson's correlation coefficient, R = .804, P < .001). When the score was categorized as <1%, ≥1% and <10%, ≥10% and <50%, and ≥50%, the overall concordance rate was 74.2% (46/62, Cohen's k = 0.568). After dichotomizing the cases using cutoff values of 1%, 10%, and 50%, the concordance rates were 84% to 100% for both adenocarcinoma and squamous cell carcinoma. The concordance rate was higher in patients with NSCLC with an EGFR mutation and using the SP263 rather than the E1L3N clone.

Conclusion: The results of PD-L1 immunostaining of cell blocks, particularly from effusion fluid, reflect the PD-L1 expression status of NSCLC tissue.
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http://dx.doi.org/10.1002/dc.24379DOI Listing
April 2020

Macrophage-derived progranulin promotes allergen-induced airway inflammation.

Allergy 2020 05 31;75(5):1133-1145. Epub 2020 Jan 31.

Division of Allergy and Clinical Immunology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Background: Progranulin (PGRN), mainly produced by immune and epithelial cells, has been known to be involved in the development of various inflammatory diseases. However, the function of PGRN in allergic airway inflammation has not been clearly elucidated, and we investigated the role of PGRN in allergic airway inflammation.

Methods: Production of PGRN and various type 2 cytokines was evaluated in mouse airways exposed to house dust mite allergen, and main cellular sources of these molecules were investigated using macrophage, airway epithelial cell, and NKT cell lines. We elucidated the role of PGRN in allergic airway inflammation in mouse models of asthma using macrophage-derived PGRN-deficient mice and NKT cell knockout mice by evaluating cytokine levels in bronchoalveolar lavage fluids and histopathology. We also supplemented recombinant PGRN in the mouse models to confirm the role of PGRN in allergic airway inflammation.

Results: PGRN production preceded other cytokines, mainly from macrophages, in the airway exposed to allergen. PGRN induced IL-4 and IL-13 production in NKT cells and IL-33 and TSLP in airway epithelial cells. PGRN-induced Th2 cytokine production was abolished in NKT-deficient mice. Finally, allergic inflammation was significantly attenuated in allergen-exposed PGRN-deficient mice, but inflammation was restored when recombinant PGRN was supplemented during the allergen sensitization period.

Conclusion: The presence of macrophage-derived PGRN in airways in the early sensitization period may be critical for mounting a Th2 immune response and for following an allergic airway inflammation pathway via induction of type 2 cytokine production in NKT and airway epithelial cells.
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http://dx.doi.org/10.1111/all.14129DOI Listing
May 2020

Invariant NKT Cells Functionally Link Microbiota-Induced Butyrate Production and Joint Inflammation.

J Immunol 2019 12 15;203(12):3199-3208. Epub 2019 Nov 15.

Laboratory of Immune Regulation, Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Korea;

Emerging evidence indicates that the gut microbiota contributes to the regulation of joint inflammation by modulating the function of immune cells. However, the mechanism by which the microbiota regulates joint inflammation is unclear. To address this, we investigated the effect of the gut microbiota on Ab-induced arthritis (AIA). Feeding mice a high-fiber diet attenuated AIA in a microbiota-dependent manner. Among the short-chain fatty acids produced by the microbiota, butyrate suppressed cytokine production by invariant NKT (NKT) cells by inhibiting class I histone deacetylases. Furthermore, butyrate alleviated AIA in wild-type, but not NKT cell-deficient Jα18 knockout (KO), mice. Adoptive transfer of butyrate-pretreated NKT cells had no effect on AIA in Jα18 KO mice, whereas transfer of untreated NKT cells into Jα18 KO mice restored AIA. In conclusion, our data indicate that gut microbiota-induced butyrate production attenuates AIA by inhibiting cytokine production by NKT cells. Thus, the microbiota/butyrate/NKT cell axis may be a therapeutic target for joint inflammation.
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http://dx.doi.org/10.4049/jimmunol.1801314DOI Listing
December 2019

Ubiquitin E3 Ligase Pellino-1 Inhibits IL-10-mediated M2c Polarization of Macrophages, Thereby Suppressing Tumor Growth.

Immune Netw 2019 Oct 17;19(5):e32. Epub 2019 Oct 17.

Laboratory of Immune Regulation in Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea.

Pellino-1 is a ubiquitin (Ub) E3 ligase that plays a role in M1, but not M2a polarization of macrophages. However, it is unknown whether Pellino-1 regulates IL-10-mediated M2c polarization of macrophages. Here, we found that Pellino-1 attenuated tumor growth by inhibiting M2c polarization of macrophages. Upon IL-10 stimulation, Pellino-1-deificient bone marrow-derived macrophages (BMDMs) showed higher expression of M2c markers, but not M2a, and M2b markers than wild-type (WT) BMDMs, indicating that Pellino-1 inhibits M2c polarization of macrophages. Pellino-1-deficient BMDMs exhibited a defect in mitochondria respiration, but enhancement of glycolysis during M2c polarization. During M2c polarization of macrophages, Pellino-1 increased STAT1 phosphorylation via K63-linked ubiquitination of IL-1 receptor associated kinase 1 (IRAK1). Furthermore, -Cre mice showed enhancement of tumor growth via regulating M2c polarization of tumor-associated macrophages. These results demonstrate that Pellino-1 inhibits IL-10-induced M2c macrophage polarization via K63-linked ubiquitination of IRAK1 and activation of STAT1, thereby inhibiting tumor growth .
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http://dx.doi.org/10.4110/in.2019.19.e32DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829073PMC
October 2019

Programmed cell death ligand-1-mediated enhancement of hexokinase 2 expression is inversely related to T-cell effector gene expression in non-small-cell lung cancer.

J Exp Clin Cancer Res 2019 Nov 12;38(1):462. Epub 2019 Nov 12.

Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.

Background: We investigated the role of PD-L1 in the metabolic reprogramming of non-small cell lung cancer (NSCLC).

Methods: Changes in glycolysis-related molecules and glycolytic activity were evaluated in PD-L1 and PD-L1 NSCLC cells after transfection or knockdown of PD-L1, respectively. Jurkat T-cell activation was assessed after co-culture with NSCLC cells. The association between PD-L1 and immune response-related molecules or glycolysis were analyzed in patients with NSCLC and The Cancer Genome Atlas (TCGA).

Results: Transfecting PD-L1 in PD-L1 cells enhanced hexokinase-2 (HK2) expression, lactate production, and extracellular acidification rates, but minimally altered GLUT1 and PKM2 expression and oxygen consumption rates. By contrast, knocking-down PD-L1 in PD-L1 cells decreased HK2 expression and glycolysis by suppressing PI3K/Akt and Erk pathways. Interferon-γ (IFNγ) secretion and activation marker expression was decreased in stimulated Jurkat T-cells when co-cultured with HK2-overexpressing vector-transfected tumor cells rather than empty vector-transfected tumor cells. Immunohistochemistry revealed that PD-L1 expression was positively correlated with HK2 expression in NSCLC (p < 0.001). In TCGA, HK2 exhibited a positive linear association with CD274 (PD-L1) expression (p < 0.001) but an inverse correlation with the expression of CD4, CD8A, and T-cell effector function-related genes in the CD274 rather than CD274 group. Consistently, there were fewer CD8 T-cells in PD-L1/HK2 tumors compared to PD-L1/HK2 tumors in squamous cell carcinoma.

Conclusions: PD-L1 enhances glycolysis in NSCLC by upregulating HK2, which might dampen anti-tumor immunity. PD-L1 may contribute to NSCLC oncogenesis by inducing metabolic reprogramming and immune checkpoint.
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http://dx.doi.org/10.1186/s13046-019-1407-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852926PMC
November 2019

IL-17A-Producing Innate Lymphoid Cells Promote Skin Inflammation by Inducing IL-33-Driven Type 2 Immune Responses.

J Invest Dermatol 2020 04 16;140(4):827-837.e9. Epub 2019 Oct 16.

Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea; Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea. Electronic address:

Atopic dermatitis (AD) is a chronic, pruritic, inflammatory skin disease characterized by type 2 cytokines secreted by T helper type 2 cells and group 2 innate lymphoid cells. Despite a high degree of heterogeneity, AD is still explained by type 2 immunity, and the role of IL-17A, which is increased in acute, pediatric, or Asian patients with AD, remains poorly understood. Here, we aimed to investigate the role of IL-17A-producing group 3 innate lymphoid cells (ILC3s), which are unexplored immune cells, in the pathogenesis of AD. We found that the numbers of ILC3s in the skin of AD-induced mice were increased, and that neutralizing IL-17A delayed development of AD. Moreover, adoptive transfer of ILC3s accelerated the symptoms of AD. Mechanically, ILC3s induced IL-33 production by nonimmune skin cells, keratinocytes, and fibroblasts, which promoted type 2 immune responses. Because AD has a complex pathophysiology and a broad spectrum of clinical phenotypes, the presence of ILC3s in the skin and their interaction with nonimmune skin cells could explain the pathogenesis of cutaneous AD.
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http://dx.doi.org/10.1016/j.jid.2019.08.447DOI Listing
April 2020

MET Receptor Tyrosine Kinase Regulates the Expression of Co-Stimulatory and Co-Inhibitory Molecules in Tumor Cells and Contributes to PD-L1-Mediated Suppression of Immune Cell Function.

Int J Mol Sci 2019 Sep 1;20(17). Epub 2019 Sep 1.

Cancer Research Institute, Seoul National University, Seoul 03080, Korea.

The MET tyrosine receptor kinase is essential for embryonic development and tissue regeneration by promoting cell survival, proliferation, migration, and angiogenesis. It also contributes to tumor development and progression through diverse mechanisms. Using human cancer cell lines, including Hs746T (-mutated/amplified), H596 (-mutated), and H1993 (-amplified) cells, as well as BEAS-2B bronchial epithelial cells, we investigated whether MET is involved in the regulation of immune checkpoint pathways. In a microarray analysis, MET suppression using a MET inhibitor or siRNAs up-regulated co-stimulatory molecules, including 4-1BBL, OX40L, and CD70, and down-regulated co-inhibitory molecules, especially PD-L1, as validated by measuring total/surface protein levels in Hs746T and H1993 cells. MET activation by HGF consistently increased PD-L1 expression in H596 and BEAS-2B cells. Co-culture of human peripheral blood mononuclear cells with Hs746T cells suppressed interferon-γ production by the immune cells, which was restored by MET inhibition or PD-L1 blockade. A significant positive correlation between MET and PD-L1 expression in lung cancer was determined in an analysis based on The Cancer Genome Atlas (TCGA) and in an immunohistochemistry study. The former also showed an association of MET overexpression in a PD-L1 tumor with the decreased expressions of T-cell effector molecules. In summary, our results point to a role for MET overexpression/activation in the immune escape of tumors by PD-L1 up-regulation. MET-targeted-therapy combined with immunotherapy may therefore be an effective treatment strategy in patients with MET-dependent cancer.
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http://dx.doi.org/10.3390/ijms20174287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747314PMC
September 2019

Tracing Oncogene Rearrangements in the Mutational History of Lung Adenocarcinoma.

Cell 2019 06 30;177(7):1842-1857.e21. Epub 2019 May 30.

Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, Seoul 03080, Korea; Seoul National University Cancer Research Institute, Seoul 03080, Korea. Electronic address:

Mutational processes giving rise to lung adenocarcinomas (LADCs) in non-smokers remain elusive. We analyzed 138 LADC whole genomes, including 83 cases with minimal contribution of smoking-associated mutational signature. Genomic rearrangements were not correlated with smoking-associated mutations and frequently served as driver events of smoking-signature-low LADCs. Complex genomic rearrangements, including chromothripsis and chromoplexy, generated 74% of known fusion oncogenes, including EML4-ALK, CD74-ROS1, and KIF5B-RET. Unlike other collateral rearrangements, these fusion-oncogene-associated rearrangements were frequently copy-number-balanced, representing a genomic signature of early oncogenesis. Analysis of mutation timing revealed that fusions and point mutations of canonical oncogenes were often acquired in the early decades of life. During a long latency, cancer-related genes were disrupted or amplified by complex rearrangements. The genomic landscape was different between subgroups-EGFR-mutant LADCs had frequent whole-genome duplications with p53 mutations, whereas fusion-oncogene-driven LADCs had frequent SETD2 mutations. Our study highlights LADC oncogenesis driven by endogenous mutational processes.
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http://dx.doi.org/10.1016/j.cell.2019.05.013DOI Listing
June 2019

Regulation of membrane phospholipid asymmetry by Notch-mediated flippase expression controls the number of intraepithelial TCRαβ+CD8αα+ T cells.

PLoS Biol 2019 05 9;17(5):e3000262. Epub 2019 May 9.

Department of Immunology and Parasitology, Graduate School of Medicine, Tokushima University, Tokushima, Japan.

Intestinal intraepithelial lymphocytes (IELs) expressing CD8αα on αβ T cells (TCRαβ+CD8αα+ IELs) have suppressive capabilities in enterocolitis, but the mechanism that maintains homeostasis and cell number is not fully understood. Here, we demonstrated that the number of TCRαβ+CD8αα+ IELs was severely reduced in mice lacking recombination signal binding protein for immunoglobulin kappa J region (Rbpj) or Notch1 and Notch2 in T cells. Rbpj-deficient TCRαβ+CD8αα+ IELs expressed low levels of Atp8a2, which encodes a protein with flippase activity that regulates phospholipid asymmetry of plasma membrane such as flipping phosphatidylserine in the inner leaflet of plasma membrane. Rbpj-deficient TCRαβ+CD8αα+ IELs cannot maintain phosphatidylserine in the inner leaflet of the plasma membrane. Furthermore, depletion of intestinal macrophages restored TCRαβ+CD8αα+ IELs in Rbpj-deficient mice, suggesting that exposure of phosphatidylserine on the plasma membrane in Rbpj-deficient TCRαβ+CD8αα+ IELs acts as an "eat-me" signal. Together, these results revealed that Notch-Atp8a2 is a fundamental regulator for IELs and highlighted that membrane phospholipid asymmetry controlled by Notch-mediated flippase expression is a critical determinant in setting or balancing the number of TCRαβ+CD8αα+ IELs.
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http://dx.doi.org/10.1371/journal.pbio.3000262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529014PMC
May 2019

IL23-Producing Human Lung Cancer Cells Promote Tumor Growth via Conversion of Innate Lymphoid Cell 1 (ILC1) into ILC3.

Clin Cancer Res 2019 07 12;25(13):4026-4037. Epub 2019 Apr 12.

Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.

Purpose: The plasticity of innate lymphoid cells (ILCs) has been reported and in the microenvironment of the intestine. However, whether ILC plasticity contributes to regulation of the tumor microenvironment remains unknown. In this study, we explored plasticity of ILCs in human lung cancer.

Experimental Design: We analyzed immune subsets and cytokine expression in lung cancers freshly obtained from 80 patients and explored conversion of ILC1 into ILC3 in coculture with lung cancer cells. Prognostic effects of converted ILC3 and related pathway were evaluated by retrospective cohort composed of 875 patients with lung cancer.

Results: Low percentages of ILC1, and high percentages of ILC3 were found in pulmonary squamous cell carcinomas (SqCC) but not adenocarcinomas (ADC). In non-small-cell lung cancers, the percentage of ILC3 was associated with IL23 expression in tumor cells but not immune cells. In cocultures, tumor cells of SqCCs converted ILC1 into ILC3 by producing IL23, thus promoting IL17-mediated tumor cell proliferation. Consistently, among IL17 immune cells, the percentages of ILCs were higher in SqCCs than ADCs. Furthermore, the numbers of CD3RORγt ILC3, IL17 expression level, and IL23- or IL17RA-expressing tumor cells were associated with short survival of patients with SqCC but not ADC.

Conclusions: Conversion from ILC1 into ILC3 by IL23-producing SqCCs promotes IL17-mediated tumor progression, resulting in a poor prognosis.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3458DOI Listing
July 2019

Tumor Suppressor miRNA-204-5p Regulates Growth, Metastasis, and Immune Microenvironment Remodeling in Breast Cancer.

Cancer Res 2019 04 8;79(7):1520-1534. Epub 2019 Feb 8.

Center for Medical Innovation, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea.

Various miRNAs play critical roles in the development and progression of solid tumors. In this study, we describe the role of miR-204-5p in limiting growth and progression of breast cancer. In breast cancer tissues, miR-204-5p was significantly downregulated compared with normal breast tissues, and its expression levels were associated with increased survival outcome in patients with breast cancer. Overexpression of miR-204-5p inhibited viability, proliferation, and migration capacity in human and murine breast cancer cells. In addition, miR-204-5p overexpression resulted in a significant alteration in metabolic properties of cancer cells and suppression of tumor growth and metastasis in mouse breast cancer models. The association between miR-204-5p expression and clinical outcomes of patients with breast cancer showed a nonlinear pattern that was reproduced in experimental assays of cancer cell behavior and metastatic capacities. Transcriptome and proteomic analysis revealed that various cancer-related pathways including PI3K/Akt and tumor-immune interactions were significantly associated with miR-204-5p expression. PIK3CB, a major regulator of PI3K/Akt pathway, was a direct target for miR-204-5p, and the association between PIK3CB-related PI3K/Akt signaling and miR-204-5p was most evident in the basal subtype. The sensitivity of breast cancer cells to various anticancer drugs including PIK3CB inhibitors was significantly affected by miR-204-5p expression. In addition, miR-204-5p regulated expression of key cytokines in tumor cells and reprogrammed the immune microenvironment by shifting myeloid and lymphocyte populations. These data demonstrate both cell-autonomous and non-cell-autonomous impacts of tumor suppressor miR-204-5p in breast cancer progression and metastasis. SIGNIFICANCE: This study demonstrates that regulation of PI3K/Akt signaling by miR-204-5p suppresses tumor metastasis and immune cell reprogramming in breast cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-0891DOI Listing
April 2019
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