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

Koh, Jaemoon,Kim, Hye Young,Lee, Youngha,Park, In Kyu,Kang, Chang Hyun,Kim, Young Tae,Kim, Ji-Eun,Choi, Murim,Lee, Won-Woo,Jeon, Yoon Kyung,Chung, Doo Hyun American Association for Cancer Research 2019 Clinical Cancer Research Vol.25 No.13

<P><B>Purpose:</B></P><P>The plasticity of innate lymphoid cells (ILCs) has been reported <I>in vitro</I> 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.</P><P><B>Experimental Design:</B></P><P>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.</P><P><B>Results:</B></P><P>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<SUP>+</SUP> immune cells, the percentages of ILCs were higher in SqCCs than ADCs. Furthermore, the numbers of CD3<SUP>−</SUP>RORγt<SUP>+</SUP> ILC3, IL17 expression level, and IL23- or IL17RA-expressing tumor cells were associated with short survival of patients with SqCC but not ADC.</P><P><B>Conclusions:</B></P><P>Conversion from ILC1 into ILC3 by IL23-producing SqCCs promotes IL17-mediated tumor progression, resulting in a poor prognosis.</P>

EML4-ALK enhances programmed cell death-ligand 1 expression in pulmonary adenocarcinoma via hypoxia-inducible factor (HIF)-1α and STAT3

Koh, Jaemoon,Jang, Ji-Young,Keam, Bhumsuk,Kim, Sehui,Kim, Moon-Young,Go, Heounjeong,Kim, Tae Min,Kim, Dong-Wan,Kim, Chul-Woo,Jeon, Yoon Kyung,Chung, Doo Hyun Informa UK (Taylor Francis) 2016 Oncoimmunology Vol.5 No.3

<P>Programmed cell death (PD)-1/PD-1 ligand-1 (PD-L1)-targeted therapy has emerged as a promising therapeutic strategy for lung cancer. However, whether EML4-ALK regulates PD-L1 expression in lung cancer remains unknown. A total of 532 pulmonary adenocarcinomas (pADCs), including 58 ALK-translocated tumors, were immunohistochemically evaluated for PD-L1 and PD-1. H23 (EGFR(Wild-type)EML4-ALK(-)PD-L1(Low)) and H2228 (EGFR(Wild-type)EML4-ALK(+)PD-L1(High)) cells were transfected with EML4-ALK or ALK short interfering RNAs and used to investigate the alterations in PD-L1 expression. PD-L1 expression was detected in 81% of ALK-translocated pADCs; this value was significantly higher than those of pADCs with EGFR mutation, KRAS mutation or lacking ALK, EGFR or KRAS mutation (p<0.005 for all). Moreover, ALK-translocated pADC with PD-L1 expression showed significantly higher numbers of tumor-infiltrating PD-1(+) cells. ALK knockdown or inhibition (crizotinib treatment) in H2228 cells downregulated PD-L1 expression. Transfection of H23 cells with EML4-ALK enhanced PD-L1 expression, which was compromised by crizotinib treatment. This ALK-dependent upregulation of PD-L1 expression was mediated by STAT3 and hypoxia-inducible factor (HIF)-1 alpha under normoxia and hypoxia. Furthermore, EML4-ALK enhanced HIF-1 alpha expression through increasing transcription and decreasing ubiquitination of HIF-1 alpha. In ALK-translocated pADC tissues, significant positive correlations between PD-L1 and nuclear HIF-1 alpha (p < 0.05) or pSTAT3 expression levels (p<0.005) were observed. Among patients with ALK-translocated pADC, strong PD-L1 expression was significantly associated with shorter progression-free (p = 0.001) and overall survival (p = 0.002) after crizotinib treatment. Collectively, our findings demonstrate that ALK-derived pADCs increase PD-L1 expression via HIF-1 alpha and/or STAT3, thus providing a rationale for PD-1/PD-L1 pathway-targeted therapy in ALK-translocated lung cancer.</P>

Overexpression of endoplasmic reticulum stress-related proteins, XBP1s and GRP78, predicts poor prognosis in pulmonary adenocarcinoma

Kwon, Dohee,Koh, Jaemoon,Kim, Sehui,Go, Heounjeong,Min, Hye Sook,Kim, Young A,Kim, Deog Kyeom,Jeon, Yoon Kyung,Chung, Doo Hyun Elsevier 2018 Lung cancer Vol.122 No.-

<P><B>Abstract</B></P> <P><B>Objectives</B></P> <P>Endoplasmic reticulum (ER) stress is associated with tumor development and progression via pro-tumorigenic and anti-tumorigenic effects. However, the clinicopathological implications of the ER stress pathway in non-small cell lung cancer remain unclear. Therefore, we sought to address these issues in this study.</P> <P><B>Materials and methods</B></P> <P>Expression of two ER stress-related proteins, GRP78 and XBP1 spliced-form (XBP1s), was evaluated in pulmonary adenocarcinoma (pADC; n = 369) and squamous cell carcinoma (pSqCC; n = 246) using immunohistochemistry.</P> <P><B>Results</B></P> <P>Expression levels of GRP78 and XBP1s were significantly higher in pADCs and pSqCCs, respectively (both, <I>P</I> < 0.0001). In the pADC group, XBP1s expression was higher in patients with <I>ALK</I> translocation than in those with wild-type <I>ALK</I>, wild-type <I>EGFR</I>, or <I>EGFR</I> mutation (<I>P</I> < 0.005). No significant difference in GRP78 expression according to <I>ALK</I> or <I>EGFR</I> status was noted. pADC harboring high GRP78 expression exhibited an increased XBP1s expression (<I>P</I> = 0.0067). Higher XBP1s expression was associated with shorter disease-free survival (DFS) in patients with pADC (<I>P</I> = 0.026) and in those with <I>ALK</I> translocation (<I>P</I> = 0.001). Higher GRP78 expression was associated with shorter DFS in patients with pADC (<I>P</I> = 0.029) and those with <I>EGFR</I> mutation (<I>P</I> = 0.005). Multivariate survival analysis revealed that high XBP1s expression was an independent predictor of poor DFS in pADC (<I>P</I> = 0.004, hazard ratio [HR] = 3.115), and that high GRP78 expression was an independent predictor of poor DFS in <I>EGFR</I>-mutated pADC (<I>P</I> = 0.007, HR = 2.168). Taken together, high expression of XBP1s or GRP78 was an independent poor prognostic factor in pADC (<I>P</I> = 0.002, HR = 2.403).</P> <P><B>Conclusion</B></P> <P>GRP78 and XBP1s are expressed variably in pADC, but their overexpression is associated with poor patient prognosis. The ER stress pathway may be a prognostic biomarker and potential therapeutic target for pADC.</P> <P><B>Highlights</B></P> <P> <UL> <LI> ER stress-related molecules, GRP78 and XBP1s, are variably expressed in lung cancer. </LI> <LI> GRP78 and XBP1s levels are related to histologic and genetic status of lung cancer. </LI> <LI> XBP1s and GRP78 expression have prognostic implication in adenocarcinoma of the lung. </LI> <LI> ER stress pathway may be a potential therapeutic target in lung cancer. </LI> </UL> </P>

Comparative analysis of PD-L1 expression between primary and metastatic pulmonary adenocarcinomas

Kim, Sehui,Koh, Jaemoon,Kwon, Dohee,Keam, Bhumsuk,Go, Heounjeong,Kim, Young A,Jeon, Yoon Kyung,Chung, Doo Hyun Elsevier 2017 European journal of cancer Vol.75 No.-

<P><B>Abstract</B></P> <P>Programmed death-ligand 1 (PD-L1) expression in pulmonary adenocarcinomas (pADCs) was implicated in predicting anti-PD-1/PD-L1 therapy efficacy. However, the differential expression of PD-L1 between primary and metastatic pADC remains unclear. Thus, we addressed this issue. In total, 161 paired primary and metastatic tumour tissues from 146 patients with pADC were collected. Most of the cases had regional nodal metastasis (134/161, 83.2%). PD-L1 expression was categorised based on the proportion of immunostained tumour cells using cutoff values of 1%, 5%, 10% and 50%. In primary tumours, PD-L1 positivity was observed in 28.1% (41/146), 27.4% (40/146), 22.6% (33/146) and 13.0% (19/146) of cases using cutoff values of 1%, 5%, 10% and 50%, respectively. The overall concordance rate for PD-L1 expression between primary and metastatic tumours was 75.2% (121/161). The concordance rate in primary tumours expressing PD-L1 in <1% or ≥50% of tumour cells was 87.2% (102/117) or 70% (14/20), respectively. In contrast, the concordance rate in tumours expressing PD-L1 in ≥1% to <50% of cells was only 20.8% (5/24). After dichotomising the cases using cutoff values of 1% and 50%, the concordance rate increased to 80.1% (129/161) and 90.7% (146/161) in all paired cases and to 70.4% (19/27) and 85.2% (23/27) in cases with distant metastases, respectively. This study demonstrates that the concordance of PD-L1 expression between primary and metastatic pADC is high when using cutoff values of 1% and 50%. Thus, evaluation of PD-L1 in either primary or metastatic tumours would be helpful for guiding anti–PD-1/PD-L1 immunotherapy in patients with advanced pADC.</P> <P><B>Highlights</B></P> <P> <UL> <LI> The concordance of programmed death-ligand 1 (PD-L1) expression between primary and metastatic pulmonary adenocarcinoma (pADC) was high when using cutoff values of 1% and 50%. </LI> <LI> PD-L1 expression of primary and corresponding metastatic pADCs was similar, irrespective of the EGFR mutation status. </LI> <LI> The concordance of PD-L1 expression was relatively preserved in metachronously or distantly metastatic tumours. </LI> <LI> PD-L1 expression in primary pADC can be a surrogate for the PD-L1 status in metastatic tumours, and vice versa. </LI> </UL> </P>

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

Donghyun Kim,Jaemoon Koh,Jae Sung Ko,Hye Young Kim,Ho Lee,Doo Hyun Chung 대한면역학회 2019 Immune Network Vol.19 No.5

Astragalin Inhibits Nuclear Factor-κB Signaling in Human Colonic Epithelial Cells and Attenuates Experimental Colitis in Mice

( Yoo Min Han ),( Jaemoon Koh ),( Jee Hyun Kim ),( Jooyoung Lee ),( Jong Pil Im ),( Joo Sung Kim ) 대한소화기학회 2021 Gut and Liver Vol.15 No.1

Background/Aims: Astragalin (kaempferol-3-O-β-D-glucoside) is a flavonoid isolated from the leaves of persimmon or Rosa agrestis. Astragalin exhibits various anti-inflammatory properties; however, little is known about its therapeutic potential for inflammatory bowel disease (IBD). This study aims to investigate the anti-inflammatory effect of astragalin via blockade of the nuclear factor κB (NF-κB) signaling pathway in human colonic epithelial cells and a murine colitis model. Methods: HCT-116 and HT-29 human colonic epithelial cells were pretreated with astragalin and stimulated with tumor necrosis factor-α (TNF-α). Cell viability was assessed by the MTS assay. Real-time reverse transcription polymerase chain reaction was used to analyze the messenger RNA expression of the inflammatory cytokines interleukin (IL)-6 and IL-8. The effect of astragalin on the NF-κB pathway was evaluated by Western blot analysis of inhibitor of NF-κB alpha (IκBα) phosphorylation/degradation and by electrophoretic mobility shift assay. Dextran sulfate sodium (DSS)-induced acute murine colitis model was used for in vivo experiments. Results: Astragalin strongly suppressed the expression of proinflammatory cytokines in human colonic epithelial cells in a dose-dependent manner. Western blot analysis showed that astragalin inhibited IκBα phosphorylation/degradation. Additionally, astragalin reduced the DNA binding activity of NF-κB. Astragalin alleviated colon shortening and improved the pathologic scores in DSS-induced acute murine colitis model. Furthermore, astragalin reduced the level of phosphorylated IκBα and decreased the production of the inflammatory cytokines IL-6, IL-8, and TNF-α in the DSS-treated colon mucosa. Conclusions: Astragalin exerted an anti-inflammatory effect through NF-κB pathway inhibition and attenuated murine colitis. Astragalin is thus a potential therapeutic agent for IBD. (Gut Liver 2021;15:100-108)

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

( Chang Hyun Nam ),( Jaemoon Koh ),( Chan-young Ock ),( Miso Kim ),( Bhumsuk Keam ),( Tae Min Kim ),( Yoon Kyung Jeon ),( Dong-wan Kim ),( Doo Hyun Chung ),( Dae Seog Heo ) 대한내과학회 2021 The Korean Journal of Internal Medicine Vol.36 No.4

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). Conclusions: 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.

The invariant natural killer T cell–mediated chemokine X-C motif chemokine ligand 1–X-C motif chemokine receptor 1 axis promotes allergic airway hyperresponsiveness by recruiting CD103⁺ dendritic cells

Woo, Yeon Duk,Koh, Jaemoon,Kang, Hye-Ryun,Kim, Hye Young,Chung, Doo Hyun Elsevier 2018 The journal of allergy and clinical immunology Vol.142 No.6

<P><B>Background</B></P> <P>The chemokine X-C motif chemokine ligand 1 (XCL1)–X-C motif chemokine receptor 1 (XCR1) axis has been reported to play a role in immune homeostasis and inflammation. However, it is not known whether this axis has a critical function in patients with allergic asthma.</P> <P><B>Objective</B></P> <P>In the present study we explored whether the invariant natural killer T (<I>i</I>NKT) cell–mediated XCL1-XCR1 axis regulated allergic asthma.</P> <P><B>Methods</B></P> <P>Ovalbumin (OVA)– or house dust mite–induced asthma was developed in XCL1 or XCR1 knockout (KO) mice.</P> <P><B>Results</B></P> <P>XCL1 or XCR1 KO mice showed attenuation in airway hyperresponsiveness (AHR), numbers of CD103<SUP>+</SUP> dendritic cells (DCs), and T<SUB>H</SUB>2 responses in the lungs compared with wild-type (WT) mice during OVA- or house dust mite–induced asthma. These effects were reversed by intratracheal administration of recombinant XCL1 or adoptive transfer of CD103<SUP>+</SUP> DCs but not CD11b<SUP>+</SUP> DCs into XCL1 KO mice. Moreover, <I>i</I>NKT cells highly expressed XCL1 both <I>in vitro</I> and <I>in vivo</I>. On intranasal α-galactosyl ceramide challenge, CD103<SUP>+</SUP> DC numbers in the lungs were increased in WT but not XCL1 KO mice. Furthermore, adoptive transfer of WT <I>i</I>NKT cells increased AHR, CD103<SUP>+</SUP> DC recruitment, and T<SUB>H</SUB>2 responses in the lungs of CD1d KO mice during OVA-induced asthma, whereas adoptive transfer of XCL1-deficient <I>i</I>NKT cells did not. In human patients, percentages and XCL1 production capacity of <I>i</I>NKT cells from PBMCs were greater in patients with asthma than in healthy control subjects.</P> <P><B>Conclusion</B></P> <P>These data demonstrate that the <I>i</I>NKT cell–mediated XCL1-XCR1 axis promotes AHR by recruiting CD103<SUP>+</SUP> DCs into the lung in patients with allergic asthma.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Characteristics and Clinical Outcomes of Congenital Myenteric Hypoganglionosis (CMH) in Children

Sung-Ryung Choi,Dayoung Ko,Jaemoon Koh,Hyun-Young Kim 대한외과학회 2023 대한외과학회 학술대회 초록집 Vol.2023 No.5

Pellino-1 promotes lung carcinogenesis via the stabilization of Slug and Snail through K63-mediated polyubiquitination

Jeon, Yoon Kyung,Kim, Chung Kwon,Hwang, Kyung Rim,Park, Hye-Young,Koh, Jaemoon,Chung, Doo Hyun,Lee, Chang-Woo,Ha, Geun-Hyoung Nature Publishing Group 2017 Cell death and differentiation Vol.24 No.3

<P>Pellino-1 is an E3 ubiquitin ligase acting as a critical mediator for a variety of immune receptor signaling pathways, including Toll-like receptors, interleukin-1 receptor and T-cell receptors. We recently showed that the Pellino-1-transgenic (Tg) mice developed multiple tumors with different subtypes in hematolymphoid and solid organs. However, the molecular mechanism underlying the oncogenic role of Pellino-1 in solid tumors remains unknown. Pellino-1-Tg mice developed adenocarcinoma in the lungs, and Pellino-1 expression was higher in human lung adenocarcinoma cell lines compared with non-neoplastic bronchial epithelial cell lines. Pellino-1 overexpression increased the cell proliferation, survival, colony formation, invasion and migration of lung adenocarcinoma cells, whereas Pellino-1 knock-down showed the opposite effect. Pellino-1 overexpression activated PI3K/Akt and ERK signaling pathways and elicited an epithelial–mesenchymal transition (EMT) phenotype of lung adenocarcinoma cells. Pellino-1-mediated EMT was demonstrated through morphology, the upregulation of Vimentin, Slug and Snail expression and the downregulation of E-cadherin and <I>β</I>-catenin expression. Notably, Pellino-1 had a direct effect on the overexpression of Snail and Slug through Lys63-mediated polyubiquitination and the subsequent stabilization of these proteins. Pellino-1 expression level was significantly correlated with Snail and Slug expression in human lung adenocarcinoma tissues, and lung tumors from Pellino-1-Tg mice showed Snail and Slug overexpression. The Pellino-1-mediated increase in the migration of lung adenocarcinoma cells was mediated by Snail and Slug expression. Taken together, these results show that Pellino-1 contributes to lung tumorigenesis by inducing overexpression of Snail and Slug and promoting EMT. Pellino-1 might be a potential therapeutic target for lung cancer.</P>