158 results on '"Sang Jun Ha"'
Search Results
2. Development of an Object Tracking System using Sensor Fusion of a Camera and LiDAR
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Su-Jin Baek, A-Hyeon Kim, Young-Lim Choi, Sang-Jun Ha, and Jong-Wook Kim
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- 2022
3. Discovery of highly immunogenic spleen-resident FCGR3+CD103+ cDC1s differentiated by IL-33-primed ST2+ basophils
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Myeong-Ho Kang, JungHyub Hong, Jinjoo Lee, Min-Suk Cha, Sangho Lee, Hye-Young Kim, Sang-Jun Ha, Yong Taik Lim, and Yong-Soo Bae
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Infectious Diseases ,Immunology ,Immunology and Allergy - Abstract
Recombinant interleukin-33 (IL-33) inhibits tumor growth, but the detailed immunological mechanism is still unknown. IL-33-mediated tumor suppression did not occur in Batf3−/− mice, indicating that conventional type 1 dendritic cells (cDC1s) play a key role in IL-33-mediated antitumor immunity. A population of CD103+ cDC1s, which were barely detectable in the spleens of normal mice, increased significantly in the spleens of IL-33-treated mice. The newly emerged splenic CD103+ cDC1s were distinct from conventional splenic cDC1s based on their spleen residency, robust effector T-cell priming ability, and surface expression of FCGR3. DCs and DC precursors did not express Suppressor of Tumorigenicity 2 (ST2). However, recombinant IL-33 induced spleen-resident FCGR3+CD103+ cDC1s, which were found to be differentiated from DC precursors by bystander ST2+ immune cells. Through immune cell fractionation and depletion assays, we found that IL-33-primed ST2+ basophils play a crucial role in the development of FCGR3+CD103+ cDC1s by secreting IL-33-driven extrinsic factors. Recombinant GM-CSF also induced the population of CD103+ cDC1s, but the population neither expressed FCGR3 nor induced any discernable antitumor immunity. The population of FCGR3+CD103+ cDC1s was also generated in vitro culture of Flt3L-mediated bone marrow-derived DCs (FL-BMDCs) when IL-33 was added in a pre-DC stage of culture. FL-BMDCs generated in the presence of IL-33 (FL-33-DCs) offered more potent tumor immunotherapy than control Flt3L-BMDCs (FL-DCs). Human monocyte-derived DCs were also more immunogenic when exposed to IL-33-induced factors. Our findings suggest that recombinant IL-33 or an IL-33-mediated DC vaccine could be an attractive protocol for better tumor immunotherapy.
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- 2023
4. Beclin1-Deficient Adipocytes Promote Tumor Progression by YAP/TAZ-dependent Adipocyte Transformation
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Yaechan Song, Heeju Na, Seung Eon Lee, Taewook Nam, You Min Kim, Yul Ji, Young Jin, Jae-Hyung Park, Seok Chan Cho, Daehee Hwang, Sang-Jun Ha, Hyun Woo Park, Jae Bum Kim, Han Woong Lee, and Jihyun Moon
- Abstract
Adipocytes are crucial components of the tumor microenvironment (TME) that play a prominent role in supporting tumor growth. However, the characteristics of cancer-associated adipocytes (CAAs) that contribute to the pro-tumorigenic niche remain to be fully established. Here, we used adipocyte-specific Beclin1 KO (BaKO) mice to investigate the role of maladaptive adipocytes in promoting tumor progression. BECN1-deficient adipocytes exhibited downregulation of adipogenic markers and activation of YAP/TAZ signaling, similar to the traits observed in CAAs. Thus, we generated adipocyte-specific Becn1/Yap1/Taz KO mice, which exhibit markedly restored phenotypes in adipose tissue, resulting in tumor regression compared to that in BaKO. Further, we observed dysregulation of the BECN1-YAP/TAZ axis in the adipose tissue of mice fed a high-fat diet (HFD). Treatment with the YAP/TAZ inhibitor, verteporfin, suppressed tumor progression in BaKO and HFD-fed mice, highlighting its efficacy against mice with metabolic dysregulation. Our findings provide insights into CAA formation and its significance in determining malignant TME, thereby suggesting a potential dual therapeutic strategy simultaneously targeting adipocyte homeostasis and cancer growth.
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- 2023
5. Chronic LCMV infection regulates the effector T cell response by inducing the generation of less immunogenic dendritic cells
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Seungbo Yoo, Yun Hee Jeong, Hong-Hee Choi, Sehyun Chae, Daehee Hwang, Sung Jae Shin, and Sang-Jun Ha
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Clinical Biochemistry ,Molecular Medicine ,Molecular Biology ,Biochemistry - Abstract
Chronic viral infection impairs systemic immunity in the host; however, the mechanism underlying the dysfunction of immune cells in chronic viral infection is incompletely understood. In this study, we studied the lineage differentiation of hematopoietic stem cells (HSCs) during chronic viral infection to elucidate the changes in dendritic cell (DC) differentiation and subsequent impact on T cell functionality using a chronic lymphocytic choriomeningitis virus (LCMV) infection model. We first investigated the lineage differentiation of HSCs in the bone marrow (BM) to elucidate the modulation of immune cell differentiation and found that the populations highly restrained in their differentiation were common myeloid progenitors (CMPs) and common dendritic cell progenitors (CDPs). Of interest, the main immune cells infected with LCMV Clone 13 (CL13) in the BM were CD11b/c+ myeloid DCs. We next characterized CD11b+ DCs that differentiated during chronic LCMV infection. These DCs displayed a less immunogenic phenotype than DCs in naive or acutely infected mice, showing low expression of CD80 but high expression of PD-L1, B7-H4, IDO, TGF-β, and IL-10. Consequently, these CD11b+ DCs induced less effective CD8+ T cells and more Foxp3+ regulatory T (Treg) cells. Furthermore, CD11b+ DCs generated during CL13 infection could not induce effective CD8+ T cells specific to the antigens of newly invading pathogens. Our findings demonstrate that DCs generated from the BM during chronic viral infection cannot activate fully functional effector CD8+ T cells specific to newly incoming antigens as well as persistent antigens themselves, suggesting a potential cause of the functional alterations in the T cell immune response during chronic viral infection.
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- 2023
6. Supplementary Figure 3 from Activation of IL-6R/JAK1/STAT3 Signaling Induces De Novo Resistance to Irreversible EGFR Inhibitors in Non–Small Cell Lung Cancer with T790M Resistance Mutation
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Byoung Chul Cho, Ji Hyun Lee, James G. Christensen, Ross A. Soo, Sang-Jun Ha, Flavio Solca, Joo Hang Kim, Yun Kyoung Hong, Oh-Joon Kwon, and Sun Mi Kim
- Abstract
PDF file, 22K, Activation of JAK family by treatment of afatinib.
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- 2023
7. Supplementary Figure 1 from Activation of IL-6R/JAK1/STAT3 Signaling Induces De Novo Resistance to Irreversible EGFR Inhibitors in Non–Small Cell Lung Cancer with T790M Resistance Mutation
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Byoung Chul Cho, Ji Hyun Lee, James G. Christensen, Ross A. Soo, Sang-Jun Ha, Flavio Solca, Joo Hang Kim, Yun Kyoung Hong, Oh-Joon Kwon, and Sun Mi Kim
- Abstract
PDF file, 104K, Effects of afatinib on cell cycle and cell death.
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- 2023
8. Supplementary Figure 4 from Activation of IL-6R/JAK1/STAT3 Signaling Induces De Novo Resistance to Irreversible EGFR Inhibitors in Non–Small Cell Lung Cancer with T790M Resistance Mutation
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Byoung Chul Cho, Ji Hyun Lee, James G. Christensen, Ross A. Soo, Sang-Jun Ha, Flavio Solca, Joo Hang Kim, Yun Kyoung Hong, Oh-Joon Kwon, and Sun Mi Kim
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PDF file, 29K, Effect of JAK2 knockdown on afatinib-induced cell cytotoxicity.
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- 2023
9. Supplementary Figure 6 from Activation of IL-6R/JAK1/STAT3 Signaling Induces De Novo Resistance to Irreversible EGFR Inhibitors in Non–Small Cell Lung Cancer with T790M Resistance Mutation
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Byoung Chul Cho, Ji Hyun Lee, James G. Christensen, Ross A. Soo, Sang-Jun Ha, Flavio Solca, Joo Hang Kim, Yun Kyoung Hong, Oh-Joon Kwon, and Sun Mi Kim
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PDF file, 20K, Effect of Src inhibitor on afatinib-induced STAT3 activation.
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- 2023
10. Supplementary Figure 7 from Activation of IL-6R/JAK1/STAT3 Signaling Induces De Novo Resistance to Irreversible EGFR Inhibitors in Non–Small Cell Lung Cancer with T790M Resistance Mutation
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Byoung Chul Cho, Ji Hyun Lee, James G. Christensen, Ross A. Soo, Sang-Jun Ha, Flavio Solca, Joo Hang Kim, Yun Kyoung Hong, Oh-Joon Kwon, and Sun Mi Kim
- Abstract
PDF file, 53K, Anti-proliferative effect of dacomitinib in NSCLC cells harboring EGFR T790M.
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- 2023
11. Figure S4 from Sustained Type I Interferon Reinforces NK Cell–Mediated Cancer Immunosurveillance during Chronic Virus Infection
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Sang-Jun Ha, Kyung-Mi Lee, Eui-Cheol Shin, Heung Kyu Lee, Young Ho Ban, Seong Jin Choi, Myeong Joon Kim, and Ji Hoon Oh
- Abstract
Figure S4. shows the subcutaneous tumor growth in mice at different time points after chronic LCMV infection.
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- 2023
12. Supplementary Figure 5 from Activation of IL-6R/JAK1/STAT3 Signaling Induces De Novo Resistance to Irreversible EGFR Inhibitors in Non–Small Cell Lung Cancer with T790M Resistance Mutation
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Byoung Chul Cho, Ji Hyun Lee, James G. Christensen, Ross A. Soo, Sang-Jun Ha, Flavio Solca, Joo Hang Kim, Yun Kyoung Hong, Oh-Joon Kwon, and Sun Mi Kim
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PDF file, 14K, Inactivation of c-MET by treatment of afatinib.
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- 2023
13. Figure S1 from Sustained Type I Interferon Reinforces NK Cell–Mediated Cancer Immunosurveillance during Chronic Virus Infection
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Sang-Jun Ha, Kyung-Mi Lee, Eui-Cheol Shin, Heung Kyu Lee, Young Ho Ban, Seong Jin Choi, Myeong Joon Kim, and Ji Hoon Oh
- Abstract
Figure S1. shows NK cell phenotypes at different time points after chronic LCMV infection.
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- 2023
14. Supplementary Figure 2 from Activation of IL-6R/JAK1/STAT3 Signaling Induces De Novo Resistance to Irreversible EGFR Inhibitors in Non–Small Cell Lung Cancer with T790M Resistance Mutation
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Byoung Chul Cho, Ji Hyun Lee, James G. Christensen, Ross A. Soo, Sang-Jun Ha, Flavio Solca, Joo Hang Kim, Yun Kyoung Hong, Oh-Joon Kwon, and Sun Mi Kim
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PDF file, 19K, Enhancement of afatinib-induced apoptosis by STAT3 knockdown.
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- 2023
15. Supplementary Methods and Figure Legend from Activation of IL-6R/JAK1/STAT3 Signaling Induces De Novo Resistance to Irreversible EGFR Inhibitors in Non–Small Cell Lung Cancer with T790M Resistance Mutation
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Byoung Chul Cho, Ji Hyun Lee, James G. Christensen, Ross A. Soo, Sang-Jun Ha, Flavio Solca, Joo Hang Kim, Yun Kyoung Hong, Oh-Joon Kwon, and Sun Mi Kim
- Abstract
PDF file, 92K.
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- 2023
16. Figure S5 from Sustained Type I Interferon Reinforces NK Cell–Mediated Cancer Immunosurveillance during Chronic Virus Infection
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Sang-Jun Ha, Kyung-Mi Lee, Eui-Cheol Shin, Heung Kyu Lee, Young Ho Ban, Seong Jin Choi, Myeong Joon Kim, and Ji Hoon Oh
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Figure S5. shows the efficacy of depleting antibodies and the viral titers after treatment of depleting antibodies.
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- 2023
17. Figure S2 from Sustained Type I Interferon Reinforces NK Cell–Mediated Cancer Immunosurveillance during Chronic Virus Infection
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Sang-Jun Ha, Kyung-Mi Lee, Eui-Cheol Shin, Heung Kyu Lee, Young Ho Ban, Seong Jin Choi, Myeong Joon Kim, and Ji Hoon Oh
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Figure S2. shows the IFN-γ production of NK cells stimulated by cytokines.
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- 2023
18. Figure S6 from Sustained Type I Interferon Reinforces NK Cell–Mediated Cancer Immunosurveillance during Chronic Virus Infection
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Sang-Jun Ha, Kyung-Mi Lee, Eui-Cheol Shin, Heung Kyu Lee, Young Ho Ban, Seong Jin Choi, Myeong Joon Kim, and Ji Hoon Oh
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Figure S6. shows that there is no direct antitumor effect by LCMV replication.
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- 2023
19. Figure S3 from Sustained Type I Interferon Reinforces NK Cell–Mediated Cancer Immunosurveillance during Chronic Virus Infection
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Sang-Jun Ha, Kyung-Mi Lee, Eui-Cheol Shin, Heung Kyu Lee, Young Ho Ban, Seong Jin Choi, Myeong Joon Kim, and Ji Hoon Oh
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Figure S3. shows the analysis of tumor infiltrating lymphocytes in subcutaneous EG7 tumor model.
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- 2023
20. Data from Activation of IL-6R/JAK1/STAT3 Signaling Induces De Novo Resistance to Irreversible EGFR Inhibitors in Non–Small Cell Lung Cancer with T790M Resistance Mutation
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Byoung Chul Cho, Ji Hyun Lee, James G. Christensen, Ross A. Soo, Sang-Jun Ha, Flavio Solca, Joo Hang Kim, Yun Kyoung Hong, Oh-Joon Kwon, and Sun Mi Kim
- Abstract
The secondary T790M mutation in epidermal growth factor receptor (EGFR) is the major mechanism of acquired resistance to EGFR tyrosine kinase inhibitors (TKI) in non–small cell lung cancer (NSCLC). Although irreversible EGFR TKIs, such as afatinib or dacomitinib, have been introduced to overcome the acquired resistance, they showed a limited efficacy in NSCLC with T790M. Herein, we identified the novel de novo resistance mechanism to irreversible EGFR TKIs in H1975 and PC9-GR cells, which are NSCLC cells with EGFR T790M. Afatinib activated interleukin-6 receptor (IL-6R)/JAK1/STAT3 signaling via autocrine IL-6 secretion in both cells. Inhibition of IL-6R/JAK1/STAT3 signaling pathway increased the sensitivity to afatinib. Cancer cells showed stronger STAT3 activation and enhanced resistance to afatinib in the presence of MRC5 lung fibroblasts. Blockade of IL-6R/JAK1 significantly increased the sensitivity to afatinib through inhibition of afatinib-induced STAT3 activation augmented by the interaction with fibroblasts, suggesting a critical role of paracrine IL-6R/JAK1/STAT3 loop between fibroblasts and cancer cells in the development of drug resistance. The enhancement of afatinib sensitivity by inhibition of IL-6R/JAK1/STAT3 signaling was confirmed in in vivo PC9-GR xenograft model. Similar to afatinib, de novo resistance to dacomitinib in H1975 and PC9-GR cells was also mediated by dacomitinib-induced JAK1/STAT3 activation. Taken together, these findings suggest that IL-6R/JAK1/STAT3 signaling can be a potential therapeutic target to enhance the efficacy of irreversible EGFR TKIs in patients with EGFR T790M. Mol Cancer Ther; 11(10); 2254–64. ©2012 AACR.
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- 2023
21. Data from Sustained Type I Interferon Reinforces NK Cell–Mediated Cancer Immunosurveillance during Chronic Virus Infection
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Sang-Jun Ha, Kyung-Mi Lee, Eui-Cheol Shin, Heung Kyu Lee, Young Ho Ban, Seong Jin Choi, Myeong Joon Kim, and Ji Hoon Oh
- Abstract
The importance of natural killer (NK) cells in the early immune response to viral or bacterial infection is well known. However, the phenotype, function, and physiologic role of NK cells during the late stage of persistent viral infection have not been extensively studied. Here, we characterized NK cells in mice persistently infected with lymphocytic choriomeningitis virus clone 13 and showed that in contrast to NK cells from acutely infected or uninfected mice, NK cells from chronically infected mice expressed a terminally differentiated phenotype, stronger cytotoxicity, and reduced inhibitory receptor expression. In an in vivo tumor model, chronically infected mice exhibited significantly delayed tumor progression in an NK cell–dependent manner. NK cells from chronically infected mice also expressed high STAT1, and blocking the type I interferon (IFN) receptor revealed that type I IFN signaling directly regulated NK cell cytotoxicity. Our findings indicate that sustained type I IFN signaling during chronic viral infection potentiates the cytolytic function of NK cells and contributes to NK cell–dependent host immune surveillance.
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- 2023
22. Establishment of a mechanism-based in vitro coculture assay for evaluating the efficacy of immune checkpoint inhibitors
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Myeong Joon Kim, Kyeong Hee Hong, Bo Ryeong Lee, and Sang-Jun Ha
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Cancer Research ,Interleukin-7 ,Immunology ,CD8-Positive T-Lymphocytes ,Immune Checkpoint Proteins ,Ligands ,B7-H1 Antigen ,Coculture Techniques ,Oncology ,Neoplasms ,Leukocytes, Mononuclear ,Humans ,Interleukin-2 ,Immunology and Allergy ,Receptors, Immunologic ,Immune Checkpoint Inhibitors - Abstract
Cancer immunotherapy, which blocks immune checkpoint molecules, is an effective therapeutic strategy for human cancer patients through restoration of tumor-infiltrating (TI) cell function. However, evaluating the efficacy of immune checkpoint inhibitors (ICIs) is difficult because no standard in vitro assay for ICI efficacy evaluation exists. Additionally, blocking a particular immune checkpoint receptor (ICR) is insufficient to restore T cell functionality, because other ICRs still transduce inhibitory signals. Therefore, limiting inhibitory signals transduced via other ICRs is needed to more accurately assess the efficacy of ICIs targeting a particular immune checkpoint. Here, we introduce a newly developed in vitro coculture assay using human peripheral blood mononuclear cells (hPBMCs) and engineered human cancer cell lines. We enriched CD8
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- 2022
23. Analysis of steam generator tube rupture accidents for the development of mitigation strategies
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Dong-Wook Jerng, Jungjin Bang, Sung Won Bae, Sang Jun Ha, Sunghyon Jang, and Gi Hyeon Choi
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Flow control (data) ,SGTR ,Shutdown ,Nuclear engineering ,TK9001-9401 ,Flow (psychology) ,Steam generator ,Boiler (power generation) ,Accident management ,Mitigation strategy ,Coolant ,Power (physics) ,PWR type reactor ,Nuclear Energy and Engineering ,Operational mode ,Nuclear engineering. Atomic power ,Environmental science ,Tube (fluid conveyance) ,Safety valve - Abstract
We analyzed mitigation strategies for steam generator tube rupture (SGTR) accidents using MARS code under both full-power and low-power and shutdown (LPSD) conditions. In general, there are two approaches to mitigating SGTR accidents: supplementing the reactor coolant inventory using safety injection systems and depressurizing the reactor coolant system (RCS) by cooling it down using the intact steam generator. These mitigation strategies were compared from the viewpoint of break flow from the ruptured steam generator tube, the core integrity, and the possibility of the main steam safety valves opening, which is associated with the potential release of radiation. The “cooldown strategy” is recommended for break flow control, whereas the “RCS make-up strategy” is better for RCS inventory control. Under full power, neither mitigation strategy made a significant difference except for on the break flow while, in LPSD modes, the RCS cooldown strategy resulted in lower break and discharge flows, and thus less radiation release. As a result, using the cooldown strategy for an SGTR under LPSD conditions is recommended. These results can be used as a fundamental guide for mitigation strategies for SGTR accidents according to the operational mode.
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- 2022
24. Protective Efficacy and Immunogenicity of Rv0351/Rv3628 Subunit Vaccine Formulated in Different Adjuvants Against Mycobacterium tuberculosis Infection
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Kee Woong Kwon, Tae Gun Kang, Ara Lee, Seung Mo Jin, Yong Taik Lim, Sung Jae Shin, and Sang-Jun Ha
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Infectious Diseases ,Immunology ,Immunology and Allergy - Published
- 2023
25. Engineered Attenuated Salmonella typhimurium Expressing Neoantigen Has Anticancer Effects
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Jung Joon Min, Hyun Jun Cho, Jungheun Hyun, Duhee Bang, Hyeonseob Lim, Sung Hwan You, Soyeong Jun, and Sang Jun Ha
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Salmonella ,integumentary system ,Chemistry ,medicine.medical_treatment ,Biomedical Engineering ,Cancer ,General Medicine ,Immunotherapy ,medicine.disease_cause ,medicine.disease ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Neoantigen Peptide ,Immune system ,Cytokine ,In vivo ,medicine ,Cancer research ,Cytotoxic T cell - Abstract
Neoantigen vaccines are an immunotherapy strategy for treating cancer. The vaccine degrades quickly, so the strategy must include protection and precise targeting for immune cell stimulation. In this study, we engineered attenuated Salmonella typhimurium, which is highly infiltrative to tumors, to act as a carrier for Neoantigen peptide vaccine. Our system used a constitutive promoter vector, so that a single injection of Salmonella expressing Neoantigen could be used without requiring additional induction injections. In vivo experiments on bacteria-treated mice showed that Neoantigen expressed by the engineered carrier infiltrated tumors and resulted in suppressed tumor growth, higher survival rates and longer survival times, a relative increase of CD4 and CD8 T cells, and cytokine release. These results indicate that engineered Salmonella can be used as a carrier for Neoantigen immunotherapy.
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- 2021
26. Regulatory T cells in the tumour microenvironment of head and neck cancer: Emerging target in the era of immunotherapy
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Chang Gon Kim, Seyeon Park, Hye Ryun Kim, and Sang‐Jun Ha
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- 2022
27. Clinical Perspectives to Overcome Acquired Resistance to Anti–Programmed Death-1 and Anti–Programmed Death Ligand-1 Therapy in Non-Small Cell Lung Cancer
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Jii Bum Lee, Yong Jun Lee, Hye Ryun Kim, and Sang Jun Ha
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programmed death ligand-1 ,Lung Neoplasms ,medicine.drug_class ,medicine.medical_treatment ,Monoclonal antibody ,immune checkpoint inhibitors ,03 medical and health sciences ,0302 clinical medicine ,Acquired resistance ,Carcinoma, Non-Small-Cell Lung ,medicine ,Humans ,Lung cancer ,Molecular Biology ,non-small cell lung cancer ,programmed death-1 ,030304 developmental biology ,0303 health sciences ,business.industry ,acquired resistance ,Antibodies, Monoclonal ,Cell Biology ,General Medicine ,Immunotherapy ,medicine.disease ,Ligand (biochemistry) ,Clinical trial ,Drug Resistance, Neoplasm ,Cancer research ,Minireview ,Non small cell ,business ,030217 neurology & neurosurgery ,Programmed death - Abstract
Immune checkpoint inhibitors have changed the paradigm of treatment options for non-small cell lung cancer (NSCLC). Monoclonal antibodies targeting programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) have gained wide attention for their application, which has been shown to result in prolonged survival. Nevertheless, only a limited subset of patients show partial or complete response to PD-1 therapy, and patients who show a response eventually develop resistance to immunotherapy. This article aims to provide an overview of the mechanisms of acquired resistance to anti–PD-1/PD-L1 therapy from the perspective of tumor cells and the surrounding microenvironment. In addition, we address the potential therapeutic targets and ongoing clinical trials, focusing mainly on NSCLC.
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- 2021
28. Viral coinfection promotes tuberculosis immunopathogenesis by type I IFN signaling-dependent impediment of Th1 cell pulmonary influx
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Tae Gun Kang, Kee Woong Kwon, Kyungsoo Kim, Insuk Lee, Myeong Joon Kim, Sang-Jun Ha, and Sung Jae Shin
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CD4-Positive T-Lymphocytes ,Multidisciplinary ,Coinfection ,Humans ,Tuberculosis ,General Physics and Astronomy ,Mycobacterium tuberculosis ,General Chemistry ,Th1 Cells ,Lung ,Tuberculosis, Pulmonary ,General Biochemistry, Genetics and Molecular Biology - Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is often exacerbated upon coinfection, but the underlying immunological mechanisms remain unclear. Here, to elucidate these mechanisms, we use an Mtb and lymphocytic choriomeningitis virus coinfection model. Viral coinfection significantly suppresses Mtb-specific IFN-γ production, with elevated bacterial loads and hyperinflammation in the lungs. Type I IFN signaling blockade rescues the Mtb-specific IFN-γ response and ameliorates lung immunopathology. Single-cell sequencing, tissue immunofluorescence staining, and adoptive transfer experiments indicate that viral infection-induced type I IFN signaling could inhibit CXCL9/10 production in myeloid cells, ultimately impairing pulmonary migration of Mtb-specific CD4+ T cells. Thus, our study suggests that augmented and sustained type I IFNs by virus coinfection prior to the pulmonary localization of Mtb-specific Th1 cells exacerbates TB immunopathogenesis by impeding the Mtb-specific Th1 cell influx. Our study highlights a negative function of viral coinfection-induced type I IFN responses in delaying Mtb-specific Th1 responses in the lung.
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- 2022
29. Overexpression of poliovirus receptor is associated with poor prognosis in head and neck squamous cell carcinoma patients
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Sang Jun Ha, Daehee Hwang, Eun Chang Choi, Min Hee Hong, Se-Heon Kim, Hye Ryun Kim, Sun Min Lim, Sun Och Yoon, Da Hee Kim, Yoon Woo Koh, and Sehyun Chae
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Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Stem cell marker ,B7-H1 Antigen ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Internal medicine ,Biomarkers, Tumor ,Humans ,Medicine ,Aged ,Retrospective Studies ,Univariate analysis ,Hematology ,Squamous Cell Carcinoma of Head and Neck ,business.industry ,General Medicine ,Prognosis ,medicine.disease ,Head and neck squamous-cell carcinoma ,Primary tumor ,eye diseases ,Survival Rate ,030104 developmental biology ,Head and Neck Neoplasms ,Surgical Procedures, Operative ,030220 oncology & carcinogenesis ,Receptors, Virus ,Immunohistochemistry ,Female ,sense organs ,business ,Poliovirus Receptor ,Follow-Up Studies - Abstract
We aimed to investigate the prognostic value of multiple immune cell markers including programmed death-ligand 1 (PD-L1) and poliovirus receptor (PVR) in head and neck squamous cell carcinoma (HNSCC) using archival tumor tissues METHODS: Patients diagnosed with HNSCC who have undergone surgical resection in 2005-2012 were included. Correlations between PVR and PD-L1 expression and patient characteristics were analyzed by analysis of variance. The Kaplan-Meier method and log-rank test were used to estimate survival. P values 0.05 were considered statistically significant.In total, 375 primary tumor tissues were analyzed using immunohistochemistry. High PVR expression was associated with a poor prognosis in terms of overall survival (OS) and recurrence-free survival (RFS), and tumors with high PVR expression were associated with a short OS. PD-L1 tumor expression did not have a prognostic impact on survival. Univariate analysis revealed that OS and RFS were affected by age and p16 and PVR expression; multivariate analysis revealed that age and p16 and PVR expression were the most important determinants of RFS.PVR overexpression is a poor prognostic factor in patients with HNSCC and co-targeting PVR and PD-L1 may be a promising therapeutic option that needs further investigation.
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- 2021
30. Biosynthesis of Nonimmunosuppressive ProlylFK506 Analogues with Neurite Outgrowth and Synaptogenic Activity
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Eunji Cheong, Ji Hoon Oh, Yeo Joon Yoon, Heon Joo Lee, Areum Hwangbo, Dong Jin Park, Soo Jung Lee, Sang Jun Ha, Ji Yoon Beom, Myoung Chong Song, and Jin A Jung
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Neurite ,Neuronal Outgrowth ,Pharmaceutical Science ,Neurotransmission ,Ring (chemistry) ,Hippocampus ,01 natural sciences ,Tacrolimus ,Analytical Chemistry ,chemistry.chemical_compound ,Biosynthesis ,Drug Discovery ,Animals ,Moiety ,Proline ,Cells, Cultured ,Neurons ,Pharmacology ,Mice, Inbred ICR ,Molecular Structure ,biology ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Streptomyces ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Complementary and alternative medicine ,Biochemistry ,Pipecolic Acids ,Fermentation ,biology.protein ,Molecular Medicine ,Immunosuppressive Agents ,Neurotrophin - Abstract
Separating the immunosuppressive activity of FK506 (1) from its neurotrophic activity is required to develop FK506 analogues as drugs for the treatment of neuronal diseases. Two new FK506 analogues, 9-deoxo-36,37-dihydro-prolylFK506 (2) and 9-deoxo-31-O-demethyl-36,37-dihydro-prolylFK506 (3) containing a proline moiety instead of the pipecolate ring at C-1 and modifications at the C-9/C-31 and C-36-C-37 positions, respectively, were biosynthesized, and their biological activities were evaluated. The proline substitution in 9-deoxo-36,37-dihydroFK506 and 9-deoxo-31-O-demethyl-36,37-dihydroFK506 reduced immunosuppressive activity by more than 120-fold, as previously observed. Compared with FK506 (1), 2 and 3 exhibited ∼1.2 × 105- and 2.2 × 105-fold reductions in immunosuppressive activity, respectively, whereas they retained almost identical neurite outgrowth activity. Furthermore, these compounds significantly increased the strength of synaptic transmission, confirming that replacement of the pipecolate ring with a proline is critical to reduce the strong immunosuppressive activity of FK506 (1) while enhancing its neurotrophic activity.
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- 2021
31. Programmed Death Ligand 1-Expressing Classical Dendritic Cells Mitigate -Induced Gastritis
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Sang Jun Ha, Woo Ho Kim, Su Hyung Lee, Sang Ho Woo, Seunghyun Lee, Dae Yong Kim, Kibyeong Kim, Jong Hwan Park, Jaehoon Choi, Kyu Seong Park, Kyeongdae Kim, and Du Min Go
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0301 basic medicine ,Hepatology ,biology ,T cell ,Gastroenterology ,Dendritic cell ,Helicobacter pylori ,biology.organism_classification ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immune system ,medicine.anatomical_structure ,Immunology ,Helicobacter felis ,Gastric mucosa ,medicine ,030211 gastroenterology & hepatology ,Helicobacter ,Gastritis ,medicine.symptom - Abstract
Background & Aims Helicobacter pylori has been reported to modulate local immune responses to colonize persistently in gastric mucosa. Although the induced expression of programmed cell death ligand 1 (PD-L1) has been suggested as an immune modulatory mechanism for persistent infection of H pylori, the main immune cells expressing PD-L1 and their functions in Helicobacter-induced gastritis still remain to be elucidated. Methods The blockades of PD-L1 with antibody or PD-L1–deficient bone marrow transplantation were performed in Helicobacter-infected mice. The main immune cells expressing PD-L1 in Helicobacter-infected stomach were determined by flow cytometry and immunofluorescence staining. Helicobacter felis or H pylori–infected dendritic cell (DC)-deficient mouse models including Flt3–/–, Zbtb46–diphtheria toxin receptor, and BDCA2–diphtheria toxin receptor mice were analyzed for pathologic changes and colonization levels. Finally, the location of PD-L1–expressing DCs and the correlation with H pylori infection were analyzed in human gastric tissues using multiplexed immunohistochemistry. Results Genetic or antibody-mediated blockade of PD-L1 aggravated Helicobacter-induced gastritis with mucosal metaplasia. Gastric classical DCs expressed considerably higher levels of PD-L1 than other immune cells and co-localized with T cells in gastritis lesions from Helicobacter-infected mice and human beings. H felis– or H pylori–infected Flt3–/– or classical DC-depleted mice showed aggravated gastritis with severe T-cell and neutrophil accumulation with low bacterial loads compared with that in control mice. Finally, PD-L1–expressing DCs were co-localized with T cells and showed a positive correlation with H pylori infection in human subjects. Conclusions The PD-1/PD-L1 pathway may be responsible for the immune modulatory function of gastric DCs that protects the gastric mucosa from Helicobacter-induced inflammation, but allows persistent Helicobacter colonization.
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- 2021
32. Disproportional enrichment of FoxP3 + CD4 + regulatory T cells shapes a suppressive tumour microenvironment in head and neck squamous cell carcinoma
- Author
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Seyeon Park, Chang Gon Kim, Dahee Kim, Min Hee Hong, Eun Chang Choi, Se‐Heon Kim, Young Min Park, Jinna Kim, Sun Ock Yoon, Gamin Kim, Sunhye Shin, Kyungsoo Kim, Yoon Woo Koh, Sang‐Jun Ha, and Hye Ryun Kim
- Subjects
Molecular Medicine ,Medicine (miscellaneous) - Published
- 2022
33. Genome-wide identification of differentially methylated promoters and enhancers associated with response to anti-PD-1 therapy in non-small cell lung cancer
- Author
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Hye Ryun Kim, Min Hee Hong, Sang Jun Ha, Insuk Lee, Byoung Chul Cho, Young Joon Kim, and Jae Won Cho
- Subjects
Adult ,Male ,Lung Neoplasms ,Clinical Biochemistry ,QD415-436 ,Pembrolizumab ,Biology ,Biochemistry ,Article ,Immunomodulation ,Prognostic markers ,Carcinoma, Non-Small-Cell Lung ,Cancer genomics ,Biomarkers, Tumor ,medicine ,Humans ,Epigenetics ,Promoter Regions, Genetic ,Immune Checkpoint Inhibitors ,Molecular Biology ,Aged ,Neoplasm Staging ,Aged, 80 and over ,Cancer ,Promoter ,Methylation ,DNA Methylation ,Middle Aged ,Immune Checkpoint Proteins ,Prognosis ,medicine.disease ,Survival Analysis ,Gene Expression Regulation, Neoplastic ,Enhancer Elements, Genetic ,Treatment Outcome ,Differentially methylated regions ,CpG site ,DNA methylation ,Cancer research ,Medicine ,Molecular Medicine ,Female ,Neoplasm Grading ,Signal Transduction - Abstract
Although approved programmed cell death protein (PD)-1 inhibitors show durable responses, clinical benefits to these agents are only seen in one-third of patients in most cancer types. Therefore, strategies for improving the response to PD-1 inhibitor for treating various cancers including non-small cell lung cancer (NSCLC) are urgently needed. Compared with genome and transcriptome, tumor DNA methylome in anti-PD-1 response was relatively unexplored. We compared the pre-treatment methylation status of cis-regulatory elements between responders and non-responders to treatment with nivolumab or pembrolizumab using the Infinium Methylation EPIC Array, which can profile ~850,000 CpG sites, including ~350,000 CpG sites located in enhancer regions. Then, we analyzed differentially methylated regions overlapping promoters (pDMRs) or enhancers (eDMRs) between responders and non-responders to PD-1 inhibitors. We identified 1007 pDMRs and 607 eDMRs associated with the anti-PD-1 response. We also identified 1109 and 1173 target genes putatively regulated by these pDMRs and eDMRs, respectively. We found that eDMRs contribute to the epigenetic regulation of the anti-PD-1 response more than pDMRs. Hypomethylated pDMRs of Cytohesin 1 Interacting Protein (CYTIP) and TNF superfamily member 8 (TNFSF8) were more predictive than programmed cell death protein ligand 1 (PD-L1) expression for anti-PD-1 response and progression-free survival (PFS) and overall survival (OS) in a validation cohort, suggesting their potential as predictive biomarkers for anti-PD-1 immunotherapy. The catalog of promoters and enhancers differentially methylated between responders and non-responders to PD-1 inhibitors presented herein will guide the development of biomarkers and therapeutic strategies for improving anti-PD-1 immunotherapy in NSCLC., Cancer: DNA modifications affecting response to treatment A study into natural regulatory DNA modifications that influence patient responses could guide strategies to help the roughly two-thirds of patients who respond poorly to treatment with anticancer drugs called PD-1 inhibitors. Researchers at Yonsei University in South Korea, led by Hye Ryun Kim and Insuk Lee, investigated the significance in lung cancer patients of pre-treatment levels of DNA methylation, in which methyl (CH3) groups are added to DNA. They identified > 1000 regions of DNA in which varying methylation levels were associated with differing responses to PD-1 inhibitors. These differences affected regions of DNA called enhancers and promoters, which have been implicated in controlling the activity of more than 1000 identified genes. The research could help predict response outcomes to potential treatments and suggest possibilities for new interventions that might improve responses.
- Published
- 2020
34. Identification of MYC as an antinecroptotic protein that stifles RIPK1–RIPK3 complex formation
- Author
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Sang Jun Ha, Eun-Woo Lee, Seung Jun Kim, Manhyung Jeong, Jeong Yoon Shin, Jin-Ho Seo, Andrew Oberst, Ho-Chul Shin, Jeong Yeon Jo, Chi Hyun Hwang, Hwa Ryeon Kim, June-Won Cheong, Kwang-Hee Bae, Haeseung Lee, Wankyu Kim, Donghoon Shin, Ji Yoon Lee, Peter Vandenabeele, Daehyeon Seong, Hye Jung Kim, Young Woo Nam, Ji Hoon Oh, Jae Seok Roe, Jaewhan Song, and Sang Chul Lee
- Subjects
Programmed cell death ,Necroptosis ,necroptosis ,NUCLEAR TRANSLOCATION ,MYC ,RIPK3 ,BYPASSES APOPTOSIS ,Proto-Oncogene Proteins c-myc ,Mice ,RIPK1 ,Cell Line, Tumor ,Medicine and Health Sciences ,MIXED LINEAGE KINASE ,C-MYC ,Animals ,Humans ,Cell Proliferation ,PROGRAMMED NECROSIS ,Mice, Inbred BALB C ,Leukemia ,Multidisciplinary ,Oncogene ,MOLECULAR-MECHANISMS ,Chemistry ,Biology and Life Sciences ,Cell Biology ,Biological Sciences ,In vitro ,Cell biology ,Protein Transport ,CELL-DEATH ,SIGNALING PROTEINS ,Cytoplasm ,Receptor-Interacting Protein Serine-Threonine Kinases ,TNF-α ,Female ,Tumor necrosis factor alpha ,Signal transduction ,DOMAIN-LIKE PROTEIN ,RESISTANCE ,TNF-alpha ,Protein Binding ,Signal Transduction - Abstract
Significance A major yet perplexing question in the field of necroptosis is the role and involvement of necroptosis in cancer cells. Many cancer cells have protective mechanisms against necroptosis, but the underlying mechanism remains elusive. We report findings of cross-talk and a regulatory pathway that exist between MYC, a potent oncogene, and RIPK3, a pivotal factor in necroptosis. We find that MYC pathway is downregulated upon necroptotic, while MYC inhibits TNF-α–induced necroptosis. The inhibitory effect of MYC on necroptosis is unexpected because no transcriptional activity by MYC is required. Mechanistically, a direct interaction between MYC and RIPK3 takes place in the cytosol, preventing RIPK1–RIPK3 complex formation. Finally, MYC depletion enhances antitumor activity of necroptosis-inducing agents in a xenograft model., The underlying mechanism of necroptosis in relation to cancer is still unclear. Here, MYC, a potent oncogene, is an antinecroptotic factor that directly suppresses the formation of the RIPK1–RIPK3 complex. Gene set enrichment analyses reveal that the MYC pathway is the most prominently down-regulated signaling pathway during necroptosis. Depletion or deletion of MYC promotes the RIPK1–RIPK3 interaction, thereby stabilizing the RIPK1 and RIPK3 proteins and facilitating necroptosis. Interestingly, MYC binds to RIPK3 in the cytoplasm and inhibits the interaction between RIPK1 and RIPK3 in vitro. Furthermore, MYC-nick, a truncated form that is mainly localized in the cytoplasm, prevented TNF-induced necroptosis. Finally, down-regulation of MYC enhances necroptosis in leukemia cells and suppresses tumor growth in a xenograft model upon treatment with birinapant and emricasan. MYC-mediated suppression of necroptosis is a mechanism of necroptosis resistance in cancer, and approaches targeting MYC to induce necroptosis represent an attractive therapeutic strategy for cancer.
- Published
- 2020
35. Disproportional enrichment of FoxP3
- Author
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Seyeon, Park, Chang Gon, Kim, Dahee, Kim, Min Hee, Hong, Eun Chang, Choi, Se-Heon, Kim, Young Min, Park, Jinna, Kim, Sun Ock, Yoon, Gamin, Kim, Sunhye, Shin, Kyungsoo, Kim, Yoon Woo, Koh, Sang-Jun, Ha, and Hye Ryun, Kim
- Subjects
Head and Neck Neoplasms ,Squamous Cell Carcinoma of Head and Neck ,Tumor Microenvironment ,Humans ,Forkhead Transcription Factors ,T-Lymphocytes, Regulatory - Published
- 2022
36. Immune Checkpoint Inhibitors in 10 Years: Contribution of Basic Research and Clinical Application in Cancer Immunotherapy
- Author
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Jii Bum Lee, Hye Ryun Kim, and Sang-Jun Ha
- Subjects
Infectious Diseases ,Immunology ,Immunology and Allergy - Abstract
Targeting immune evasion via immune checkpoint pathways has changed the treatment paradigm in cancer. Since CTLA-4 antibody was first approved in 2011 for treatment of metastatic melanoma, eight immune checkpoint inhibitors (ICIs) centered on PD-1 pathway blockade are approved and currently administered to treat 18 different types of cancers. The first part of the review focuses on the history of CTLA-4 and PD-1 discovery and the preclinical experiments that demonstrated the possibility of anti-CTLA-4 and anti-PD-1 as anti-cancer therapeutics. The approval process of clinical trials and clinical utility of ICIs are described, specifically focusing on non-small cell lung cancer (NSCLC), in which immunotherapies are most actively applied. Additionally, this review covers the combination therapy and novel ICIs currently under investigation in NSCLC. Although ICIs are now key pivotal cancer therapy option in clinical settings, they show inconsistent therapeutic efficacy and limited responsiveness. Thus, newly proposed action mechanism to overcome the limitations of ICIs in a near future are also discussed.
- Published
- 2022
37. Differential Role of PD-1 Expressed by Various Immune and Tumor Cells in the Tumor Immune Microenvironment: Expression, Function, Therapeutic Efficacy, and Resistance to Cancer Immunotherapy
- Author
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Myeong Joon Kim and Sang-Jun Ha
- Subjects
QH301-705.5 ,animal diseases ,medicine.medical_treatment ,Review ,functional restoration ,Cell and Developmental Biology ,Immune system ,Cancer immunotherapy ,tumor microenvironment ,Medicine ,Biology (General) ,Receptor ,Tumor microenvironment ,cancer immunotherapy ,business.industry ,Effector ,Cancer ,Cell Biology ,medicine.disease ,Immune checkpoint ,programmed cell death protein 1 (PD-1) ,Cancer research ,business ,tumor-infiltrating effector cells ,CD8 ,tumor-infiltrating suppressive cells ,Developmental Biology - Abstract
In the tumor immune microenvironment (TIME), tumor cells interact with various cells and operate various strategies to avoid antitumor immune responses. These immune escape strategies often make the TIME resistant to cancer immunotherapy. Neutralizing immune escape strategies is necessary to overcome resistance to cancer immunotherapy. Immune checkpoint receptors (ICRs) expressed in effector immune cells inhibit their effector function via direct interaction with immune checkpoint ligands (ICLs) expressed in tumor cells. Therefore, blocking ICRs or ICLs has been developed as a promising cancer immunotherapy by reinvigorating the function of effector immune cells. Among the ICRs, programmed cell death 1 (PD-1) has mainly been antagonized to enhance the survival of human patients with cancer by restoring the function of tumor-infiltrating (TI) CD8+ T cells. It has been demonstrated that PD-1 is expressed not only in TI CD8+ T cells, but also in other TI immune cells and even tumor cells. While PD-1 suppresses the function of TI CD8+ T cells, it is controversial whether PD-1 suppresses or amplifies the suppressive function of TI-suppressive immune cells (e.g., regulatory T cells, tumor-associated macrophages, and myeloid cells). There is also controversy regarding the role of tumor-expressing PD-1. Therefore, a precise understanding of the expression pattern and function of PD-1 in each cell subset is important for improving the efficacy of cancer immunotherapy. Here, we review the differential role of PD-1 expressed by various TI immune cells and tumor cells. We focused on how cell-type-specific ablation or blockade of PD-1 affects tumor growth in a murine tumor model. Furthermore, we will also describe how the blockade of PD-1 acts on TI immune cells in human patients with cancer.
- Published
- 2021
38. MRGM: a mouse reference gut microbiome reveals a large functional discrepancy for gut bacteria of the same genus between mice and humans
- Author
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Sunmo Yang, Sang Jun Ha, Chan Yeong Kim, Insuk Lee, Nayeon Kim, and Dongjin Park
- Subjects
Genetics ,Genus ,Metagenomics ,Gut bacteria ,Microbiome ,Biology ,Genome ,Deep sequencing ,Feces ,Gut microbiome - Abstract
The gut microbiome is associated with human diseases and interacts with dietary components and drugs. In vivo mouse models may be effective for studying diet and drug effects on the gut microbiome. We constructed a mouse reference gut microbiome (MRGM, https://www.mbiomenet.org/MRGM/) that includes newly-assembled genomes from 878 metagenomes. Leveraging samples with ultra-deep metagenomic sequencing (>130 million read pairs), we demonstrated quality improvement in assembled genomes for mouse gut microbes as sequencing depth increased. MRGM provides a catalog of 46,267 non-redundant genomes with ≥70% completeness and ≤5% contamination comprising 1,689 representative bacterial species and 15.2 million non-redundant proteins. Importantly, MRGM significantly improved the taxonomic classification rate of sequencing reads from mouse fecal samples compared to previous databases. Using MRGM, we determined that reliable low-abundance taxa profiles of the mouse gut microbiome require sequencing >10 million reads. Despite the high overall functional similarity of the mouse and human gut microbiomes, only ~10% of MRGM species are shared with the human gut microbiome. Although ~80% of MRGM genera are present in the human gut microbiome, ~70% of the shared genera have Key PointsMRGM provides 46,267 genomes comprising 1,689 bacterial species of mouse gut microbiome.Despite high overlap of genera, functional discrepancy between mouse and human gut microbiota is large.Lineage-specific markers underestimate the completeness of assembled genomes for uncharacterized taxa.
- Published
- 2021
39. Distinct exhaustion features of T lymphocytes shape the tumor-immune microenvironment with therapeutic implication in patients with non-small-cell lung cancer
- Author
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Chang Gon Kim, Gamin Kim, Kyung Hwan Kim, Seyeon Park, Sunhye Shin, Dahee Yeo, Hyo Sup Shim, Hong In Yoon, Seong Yong Park, Sang-Jun Ha, and Hye Ryun Kim
- Subjects
Adult ,Male ,lymphocytes ,Cancer Research ,Lung Neoplasms ,Immunology ,chemical and pharmacologic phenomena ,CD8-Positive T-Lymphocytes ,Lymphocyte Depletion ,programmed cell death 1 receptor ,Lymphocytes, Tumor-Infiltrating ,Carcinoma, Non-Small-Cell Lung ,Tumor Microenvironment ,Immunology and Allergy ,Humans ,Immune Checkpoint Inhibitors ,Aged ,Pharmacology ,Aged, 80 and over ,Basic Tumor Immunology ,Middle Aged ,tumor-infiltrating ,Prognosis ,Survival Rate ,Oncology ,Molecular Medicine ,Female ,Follow-Up Studies - Abstract
BackgroundReinvigoration of T-cell exhaustion with antibodies has shown promising efficacy in patients with non-small-cell lung cancer (NSCLC). However, the characteristics of T-cell exhaustion with regard to tumor-infiltrating lymphocytes (TILs) are poorly elucidated in NSCLC. Here, we investigated the exhaustion status of TILs in NSCLC patients at the intraindividual and interindividual levels.MethodsWe obtained paired peripheral blood, normal adjacent tissues, peritumoral tissues, and tumor tissues from 96 NSCLC patients. Features of T-cell exhaustion were analyzed by flow cytometry. T cells were categorized according to their programmed cell death-1 (PD-1) expression (PD-1high, PD-1int, and PD-1neg cells). Patients were classified based on the presence or absence of discrete PD-1high CD8+ TILs. Production of effector cytokines by CD8+ TILs was measured after T-cell stimulation with or without antibodies against immune checkpoint receptors.ResultsProgressive T-cell exhaustion with marked expression of exhaustion-related markers and diminished production of effector cytokines was observed in PD-1high CD8+ TILs compared with PD-1int and PD-1neg CD8+ TILs. Patients with distinct PD-1high CD8+ TILs (PD-1high expressers) exhibited characteristics associated with a favorable anti-PD-1 response compared with those without these lymphocytes (non-PD-1high expressers). Combined inhibition of dual immune checkpoint receptors further restored effector cytokine production by CD8+ TILs following T-cell stimulation. PD-1high CD8+ T lymphocyte populations in the peripheral blood and tumors were significantly correlated.ConclusionsT-cell exhaustion was differentially regulated among individual patients and was prominent in a subgroup of NSCLC patients who may benefit from PD-1 blockade or combined blockade of other immune checkpoint receptors.
- Published
- 2021
40. Viral coinfection promotes tuberculosis immunopathogenesis by type I IFN signaling-dependent impediment of Th1 pulmonary influx
- Author
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Myeong Joon Kim, Kyung Soo Kim, Sang Jun Ha, Tae Gun Kang, Sung Jae Shin, Kee Woong Kwon, and Insuk Lee
- Subjects
Tuberculosis ,business.industry ,Immunology ,medicine ,Coinfection ,respiratory system ,medicine.disease ,business - Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is often exacerbated upon coinfection, but the underlying immunological mechanisms remain unclear. Here, to elucidate these mechanisms, we used a Mtb and lymphocytic choriomeningitis virus coinfection model. Viral coinfection significantly suppressed Mtb-specific IFN-γ production, with elevated bacterial loads and hyperinflammation in the lungs. Type I IFN signaling blockade rescued the Mtb-specific IFN-γ response and ameliorated lung immunopathology. Single-cell sequencing, tissue immunofluorescence staining, and adoptive transfer experiments revealed that type I IFN signaling produced in response to viral infection inhibited CXCL9/10 production in myeloid cells, resulting in impaired pulmonary migration of Mtb-specific CD4+ T cells from lymph nodes. Thus, virus coinfection-induced type I IFN signaling prior to the pulmonary localization of Mtb-specific Th1 cells exacerbates TB immunopathogenesis by impeding the Mtb-specific Th1 cell influx. Our study highlights another novel negative role of viral coinfection and/or type I IFNs in delaying Mtb-specific Th1 responses in the lung.
- Published
- 2021
41. Deletion of PD-1 destabilizes the lineage identity and metabolic fitness of tumor-infiltrating regulatory T cells
- Author
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Myeong Joon Kim, Kyungsoo Kim, Hyo Jin Park, Gil-Ran Kim, Kyeong Hee Hong, Ji Hoon Oh, Jimin Son, Dong Jin Park, Dahae Kim, Je-Min Choi, Insuk Lee, and Sang-Jun Ha
- Subjects
Immunology ,Immunology and Allergy - Abstract
Regulatory T (T
- Published
- 2021
42. Enriching CCL3 in the Tumor Microenvironment Facilitates T cell Responses and Improves the Efficacy of Anti-PD-1 Therapy
- Author
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Sang Jun Ha, Jihyun Moon, Hyojin Park, June Hyung Lee, and Tae Gun Kang
- Subjects
Tumor microenvironment ,business.industry ,T cell ,medicine.medical_treatment ,Immunology ,CCL3 ,hemic and immune systems ,Immunotherapy ,respiratory system ,Immune checkpoint ,Infectious Diseases ,medicine.anatomical_structure ,Immune system ,Cancer immunotherapy ,medicine ,Cancer research ,Immunology and Allergy ,Original Article ,business ,Macrophage inflammatory protein ,Immune checkpoint blockade ,Chemokine CCL3 - Abstract
Chemokines are key factors that influence the migration and maintenance of relevant immune cells into an infected tissue or a tumor microenvironment. Therefore, it is believed that the controlled administration of chemokines in the tumor microenvironment may be an effective immunotherapy against cancer. Previous studies have shown that CCL3, also known as macrophage inflammatory protein 1-alpha, facilitates the recruitment of dendritic cells (DCs) for the presentation of tumor Ags and promotes T cell activation. Here, we investigated the role of CCL3 in regulating the tumor microenvironment using a syngeneic mouse tumor model. We observed that MC38 tumors overexpressing CCL3 (CCL3-OE) showed rapid regression compared with the wild type MC38 tumors. Additionally, these CCL3-OE tumors showed an increase in the proliferative and functional tumor-infiltrating T cells. Furthermore, PD-1 immune checkpoint blockade accelerated tumor regression in the CCL3-OE tumor microenvironment. Next, we generated a modified CCL3 protein for pre-clinical use by fusing recombinant CCL3 (rCCL3) with a non-cytolytic hybrid Fc (HyFc). Administering a controlled dose of rCCL3-HyFc via subcutaneous injections near tumors was effective in tumor regression and improved survival along with activated myeloid cells and augmented T cell responses. Furthermore, combination therapy of rCCL3-HyFc with PD-1 blockade exhibited prominent effect to tumor regression. Collectively, our findings demonstrate that appropriate concentrations of CCL3 in the tumor microenvironment would be an effective adjuvant to promote anti-tumor immune responses, and suggest that administering a long-lasting form of CCL3 in combination with PD-1 blockers can have clinical applications in cancer immunotherapy.
- Published
- 2021
43. Sustained Type I Interferon Reinforces NK Cell–Mediated Cancer Immunosurveillance during Chronic Virus Infection
- Author
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Seongjin Choi, Young Ho Ban, Eui-Cheol Shin, Heung Kyu Lee, Ji Hoon Oh, Sang Jun Ha, Myeong Joon Kim, and Kyung Mi Lee
- Subjects
0301 basic medicine ,Cancer Research ,Cell Survival ,Receptor expression ,Immunology ,Clone (cell biology) ,Lymphocytic Choriomeningitis ,Biology ,Lymphocytic choriomeningitis ,Virus ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Interferon ,Cell Line, Tumor ,Neoplasms ,medicine ,Animals ,Lymphocytic choriomeningitis virus ,Immunologic Surveillance ,Mice, Knockout ,medicine.disease ,Killer Cells, Natural ,Mice, Inbred C57BL ,Immunosurveillance ,030104 developmental biology ,Cell culture ,030220 oncology & carcinogenesis ,Chronic Disease ,Interferon Type I ,Cytokines ,Female ,medicine.drug - Abstract
The importance of natural killer (NK) cells in the early immune response to viral or bacterial infection is well known. However, the phenotype, function, and physiologic role of NK cells during the late stage of persistent viral infection have not been extensively studied. Here, we characterized NK cells in mice persistently infected with lymphocytic choriomeningitis virus clone 13 and showed that in contrast to NK cells from acutely infected or uninfected mice, NK cells from chronically infected mice expressed a terminally differentiated phenotype, stronger cytotoxicity, and reduced inhibitory receptor expression. In an in vivo tumor model, chronically infected mice exhibited significantly delayed tumor progression in an NK cell–dependent manner. NK cells from chronically infected mice also expressed high STAT1, and blocking the type I interferon (IFN) receptor revealed that type I IFN signaling directly regulated NK cell cytotoxicity. Our findings indicate that sustained type I IFN signaling during chronic viral infection potentiates the cytolytic function of NK cells and contributes to NK cell–dependent host immune surveillance.
- Published
- 2019
44. Observation-based CHF model development: Dry spot – Dry patch models
- Author
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Sang-Jun Ha, Jin Young Choi, In-Chul Ju, Moon Won Song, and Hee Cheon No
- Subjects
Nuclear and High Energy Physics ,Materials science ,Mechanical Engineering ,Bubble ,Nucleation ,Mechanics ,Leidenfrost effect ,Nuclear Energy and Engineering ,Boiling ,Thermal ,General Materials Science ,Dry spot ,Safety, Risk, Reliability and Quality ,Literature survey ,Waste Management and Disposal ,Nucleate boiling - Abstract
Recently advanced visualization techniques such as total reflection and IR methods have been applied to observe thermally and hydraulically the CHF mechanism at the surface as well as macroscopic bubble dynamics simultaneously. Based on observation Ha and No (1998a,b, 2000), and Choi et al. (2016) developed a Dry spot model and a Dry patch model, which is an extension version of the dry spot model. Experimental observations clearly showed that the production of unquenchable dry patches mainly contributes to the initiation of CHF. Based on the above observatory conclusions and extensive literature survey, we discussed the physical basis of the Dry Spot/Dry Patch model. In the dry spot model, we assume that the dry spot can become unquenchable one when it is surrounded by 5 neighboring dry spots based on the geometrical consideration, which was confirmed by validation process. In the dry patch model, both criteria from the hydraulic and thermal considerations were proposed to estimate the critical size of unquenchable dry patch at CHF. The wall dry area fraction can be calculated by applying a probabilistic concept for the creation of the unquenchable dry patch. We showed that the Dry Spot/Dry Patch model can be extended into CHF predictions in both pool boiling and forced convective boiling. For transition boiling, we proposed models to represent two suppression mechanisms deactivating potential nucleation sites: nucleation site deactivation and non-availability mechanism. For the physical model of the nucleation site deactivation mechanism we introduced the spatial randomness concept. For the non-availability mechanism we proposed the multi-stage calculation method which considers the sequential bubble activation and their interaction. Then, we showed that the dry spot model modified with the current transition model well predicted the whole boiling curve including CHF, nucleate boiling, transition boiling, and film boiling.
- Published
- 2019
45. The Ratio of Peripheral Regulatory T Cells to Lox-1+ Polymorphonuclear Myeloid-derived Suppressor Cells Predicts the Early Response to Anti–PD-1 Therapy in Patients with Non–Small Cell Lung Cancer
- Author
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Dmitry I. Gabrilovich, Seung Yong Seong, Inkyung Jung, Je In Youn, Hye Ryun Kim, Su Myeong Park, Sang Uk Seo, Byoung Chul Cho, Sang Jun Ha, and Hong In Yoon
- Subjects
Pulmonary and Respiratory Medicine ,business.industry ,Anti pd 1 ,Myeloid-derived Suppressor Cell ,Cancer research ,Medicine ,In patient ,Non small cell ,Critical Care and Intensive Care Medicine ,business ,Lung cancer ,medicine.disease ,Peripheral - Published
- 2019
46. IL-15 Generates IFN-γ-producing Cells Reciprocally Expressing Lymphoid-Myeloid Markers during Dendritic Cell Differentiation
- Author
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Hongmin Kim, Soon Myung Kang, Eunsol Choi, Sung Jae Shin, Sang Jun Ha, Woo-Sik Kim, Kee Woong Kwon, Joo Heon Yoon, and So Jeong Kim
- Subjects
Myeloid ,medicine.medical_treatment ,Population ,B220 ,Bone Marrow Cells ,Dendritic cell differentiation ,Applied Microbiology and Biotechnology ,CD19 ,Interferon-gamma ,03 medical and health sciences ,medicine ,Animals ,education ,IFN-γ ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,Interleukin-15 ,0303 health sciences ,education.field_of_study ,biology ,Macrophages ,Innate lymphoid cell ,Cell Differentiation ,Mycobacterium tuberculosis ,Dendritic Cells ,Cell Biology ,Flow Cytometry ,CD11c Antigen ,Cell biology ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Cytokine ,IL-15 ,Interleukin 15 ,biology.protein ,Leukocyte Common Antigens ,Female ,Intracellular ,Research Paper ,Developmental Biology - Abstract
Recently, interest in IL-15-differentiated cells has increased; however, the phenotypic definition of IL-15-differentiated bone marrow-derived cells (IL-15-DBMCs) is still under debate, particularly the generation of IFN-γ-producing innate cells such as premature NK (pre-mNK) cells, natural killer dendritic cells (NKDCs), interferon-producing killer dendritic cells (IKDCs), and type 1 innate lymphoid cells (ILC1s), all of which are IL-15-dependent. Here, we revisited the immunophenotypic characteristics of IFN-γ-producing IL-15-DBMCs and their functional role in the control of intracellular Mycobacterium tuberculosis (Mtb) infection. When comparing the cytokine levels between bone marrow-derived dendritic cells (BMDCs) and IL-15-DBMCs upon stimulation with various TLR agonists, only the CD11cint population of IL-15-DBMCs produced significant levels of IFN-γ, decreased levels of MHC-II, and increased levels of B220. Neither BMDCs nor IL-15-DBMCs were found to express DX5 or NK1.1, which are representative markers for the NK cell lineage and IKDCs. When the CD11cintB220+ population of IL-15-DBMCs was enriched, the Thy1.2+Sca-1+ population showed a marked increase in IFN-γ production. In addition, while depletion of the B220+ and Thy1.2+ populations of IL-15-DBMCs, but not the CD19+ population, inhibited IFN-γ production, enrichment of these cell populations increased IFN-γ. Ultimately, co-culture of sorted IFN-γ-producing B220+Thy1.2+ IL-15-DBMCs with Mtb-infected macrophages resulted in control of the intracellular growth of Mtb via the IFN-γ-nitric oxide axis in a donor cell number-dependent manner. Taken together, the results indicate that IFN-γ-producing IL-15-DBMCs could be redefined as CD11cintB220+Thy1.2+Sca-1+ cells, which phenotypically resemble both IKDCs and ILC1s, and may have therapeutic potential for controlling infectious intracellular bacteria such as Mtb.
- Published
- 2019
47. Perspectives on immune checkpoint ligands: expression, regulation, and clinical implications
- Author
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Yoo Min Oh, Jihyun Moon, and Sang Jun Ha
- Subjects
medicine.medical_treatment ,animal diseases ,Immune checkpoint ligand ,Gene Expression ,Tumor cells ,Biology ,Ligands ,Biochemistry ,Immune system ,Neoplasms ,medicine ,Humans ,Receptors, Immunologic ,Receptor ,Molecular Biology ,Tumor microenvironment ,Cancer ,General Medicine ,Immunotherapy ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,Immune Checkpoint Proteins ,Immune checkpoint ,Invited Mini Review ,Gene Expression Regulation, Neoplastic ,Immune checkpoint receptor ,Cancer research ,bacteria - Abstract
In the tumor microenvironment, immune checkpoint ligands (ICLs) must be expressed in order to trigger the inhibitory signal via immune checkpoint receptors (ICRs). Although ICL expression frequently occurs in a manner intrinsic to tumor cells, extrinsic factors derived from the tumor microenvironment can fine-tune ICL expression by tumor cells or prompt non-tumor cells, including immune cells. Considering the extensive interaction between T cells and other immune cells within the tumor microenvironment, ICL expression on immune cells can be as significant as that of ICLs on tumor cells in promoting antitumor immune responses. Here, we introduce various regulators known to induce or suppress ICL expression in either tumor cells or immune cells, and concise mechanisms relevant to their induction. Finally, we focus on the clinical significance of understanding the mechanisms of ICLs for an optimized immunotherapy for individual cancer patients. [BMB Reports 2021; 54(8): 403-412].
- Published
- 2021
48. Overexpression of PVR and PD-L1 and Its Association With Prognosis in Surgically Resected Squamous Cell Lung Carcinoma
- Author
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Jii Bum Lee, Min Hee Hong, Seong Yong Park, Sehyun Chae, Daehee Hwang, Sang-Jun Ha, Hyo Sup Shim, and Hye Ryun Kim
- Subjects
genetic structures ,eye diseases - Abstract
Background: Targeting T-Cell Immunoreceptor with Ig and ITIM domain-poliovirus receptor (PVR) pathway is a potential therapeutic strategy in lung cancer. We analyzed the expression of PVR and programmed death ligand-1 (PD-L1) in surgically resected squamous cell lung carcinoma (SQCC) and determined its prognostic significance.Methods: We collected archival surgical specimens of 259 patients with SQCC at Yonsei Cancer Center (1998–2020). Analysis of variance was used to analyze the correlations between PVR and PD-L1 expression and patient characteristics. Kaplan–Meier curves were used to estimate recurrence-free survival (RFS) and overall survival (OS). Results: Most patients were male (93%); the majority were diagnosed with stage 1 (47%), followed by stage 2 (29%) and stage 3 (21%). Overexpression of PVR resulted in a significantly shorter median RFS and OS (P = 0.01). PD-L1 expression was not significant in terms of prognosis. Patients were subdivided into four groups based on low and high PVR and PD-L1 expression. Those expressing high levels of PVR and PD-L1 had the shortest RFS (P = 0.03).Conclusions: PVR overexpression is associated with a poor prognosis in surgically resected SQCC. Inhibition of PVR as well as PD-L1 may help overcome the lack of response to immune checkpoint monotherapy.
- Published
- 2021
49. CU06-1004-Induced Vascular Normalization Improves Immunotherapy by Modulating Tumor Microenvironment
- Author
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Ji Hoon Oh, Sang Jun Ha, Haiying Zhang, Young Myeong Kim, Hye Jeong Kim, Young Guen Kwon, Ye Seul Kim, Minyoung Noh, Dong Jin Park, Yeomyung Kim, and Songyi Park
- Subjects
0301 basic medicine ,Male ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Apoptosis ,combination therapy ,Carcinoma, Lewis Lung ,Mice ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Antineoplastic Combined Chemotherapy Protocols ,Tumor Microenvironment ,Immunology and Allergy ,Cytotoxic T cell ,Immune Checkpoint Inhibitors ,Original Research ,Mice, Inbred BALB C ,Neovascularization, Pathologic ,Drug Synergism ,CU06-1004 ,Cell Hypoxia ,Tumor Burden ,immune checkpoint blockade (ICB) ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Colonic Neoplasms ,Immunotherapy ,Nivolumab ,lcsh:Immunologic diseases. Allergy ,T cell ,Immunology ,Mice, Nude ,vascular leakage blocker ,Adenocarcinoma ,cytotoxic T lymphocytes ,Capillary Permeability ,03 medical and health sciences ,Immune system ,Lymphocytes, Tumor-Infiltrating ,Cell Line, Tumor ,medicine ,Animals ,tumor microenvironment (TME) ,Tumor microenvironment ,business.industry ,Saponins ,Immune checkpoint ,Mice, Inbred C57BL ,030104 developmental biology ,drug delivery ,Cancer research ,anti-PD-1 ,Tumor Escape ,Endothelium, Vascular ,Drug Screening Assays, Antitumor ,business ,lcsh:RC581-607 ,CD8 ,T-Lymphocytes, Cytotoxic - Abstract
Blocking the immune evasion mechanism of tumor cells has become an attractive means for treating cancers. However, the usage of a drug such as nivolumab (αPD-1), which blocks programmed cell death protein 1 (PD-1), turned out to be only effective against certain types of cancer. Especially, vascular abnormal structures of which deter delivery route by leakage and cause the poor perfusion were considered to be environment unfavorable to T cells and immune checkpoint blockade (ICB) delivery within the tumor microenvironment (TME). Herein, we report stabilization of tumor blood vessels by endothelial dysfunctional blocker CU06-1004, which modified the TME and showed synergistic effects with immunotherapy anti-PD-1 antibody. CU06-1004 combination therapy consistently prolonged the survival of tumor-bearing mice by decreasing tumor growth. T-cell infiltration increased in the tumors of the combination group, with cytotoxic CD8+ T cell activity within the tumor parenchyma upregulated compared with anti-PD-1 monotherapy. Tumor inhibition was associated with reduced hypoxia and reduced vessel density in the central region of the tumor. These effects correlated significantly with enhanced expression of IFN gamma and PD-L1 in tumors. Taken together, our findings suggest that CU06-1004 is a potential candidate drug capable of improving therapeutic efficacy of anti-PD-1 through beneficial changes in the TME.
- Published
- 2020
50. Combination of PD-L1 and PVR determines sensitivity to PD-1 blockade
- Author
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Jihyun Moon, Sehyun Chae, Myeong Joon Kim, Hyo Sup Shim, Bo Ryeong Lee, Hyuk Wan Ko, Byoung Chul Cho, Sang Jun Ha, Hye Ryun Kim, Daehee Hwang, and Hankyu Lee
- Subjects
Male ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,B7-H1 Antigen ,Mice ,Cancer immunotherapy ,Carcinoma, Non-Small-Cell Lung ,PD-L1 ,Tumor Microenvironment ,Animals ,Humans ,Medicine ,Receptor ,Immune Checkpoint Inhibitors ,Aged ,Lung ,biology ,business.industry ,Cancer ,General Medicine ,Middle Aged ,medicine.disease ,Xenograft Model Antitumor Assays ,eye diseases ,Immune checkpoint ,Blockade ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Cancer research ,biology.protein ,Receptors, Virus ,Female ,business ,Poliovirus Receptor ,Research Article - Abstract
Expression of immune checkpoint ligands (ICLs) is necessary to trigger the inhibitory signal via immune checkpoint receptors (ICRs) in exhausted T cells under tumor immune microenvironment. Nevertheless,to our knowledge, ICL expression profile in cancer patients has not been investigated. Using previously reported RNA-seq data sets, we found that expression of ICLs was patient specific but their coexpression can be patterned in non–small-cell lung cancers (NSCLCs). Since the expression of PD-L1 and poliovirus receptor (PVR) among various ICLs was independently regulated, we could stratify the patients who were treated with anti–PD-1 later into 4 groups according to the expression level of PD-L1 and PVR. Of interest, high PVR and low PVR expressions in PD-L1–expressing patients enriched nonresponders and responders to PD-1 blockade, respectively, helping in further selection of responders. Using a genetically engineered cancer model, we also found that PVR-deficient and PD-L1–sufficient tumor-bearing mice were highly sensitive to anti–PD-1 therapy, whereas PVR-sufficient and PD-L1–deficient tumor-bearing mice were resistant to anti–PD-1 therapy. Taken together, our study provides a concept that combinatorial expression patterns of PVR and PD-L1 are key determinants for PD-1 blockade and furthermore suggest a better therapeutic usage of immune checkpoint blockades (ICBs).
- Published
- 2020
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