37 results on '"Seongju Jeong"'
Search Results
2. 1046 A long-acting and Beta-intensified IL-2 analog, HM16390, significantly alters tumors to an immune favorable environment to potentiate PD-1 blockade
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Sang Hyun Park, Jaehyuk Choi, Jinyoung Kim, Seongju Jeong, Yuyon Kim, Sungmin Bae, Daejin Kim, and In Young Choi
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2023
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3. KIR+CD8+ and NKG2A+CD8+ T cells are distinct innate-like populations in humans
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Seong Jin Choi, June-Young Koh, Min-Seok Rha, In-Ho Seo, Hoyoung Lee, Seongju Jeong, Su-Hyung Park, and Eui-Cheol Shin
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CP: Immunology ,Biology (General) ,QH301-705.5 - Abstract
Summary: Subsets of the human CD8+ T cell population express inhibitory NK cell receptors, such as killer immunoglobulin-like receptors (KIRs) and NKG2A. In the present study, we examine the phenotypic and functional characteristics of KIR+CD8+ T cells and NKG2A+CD8+ T cells. KIRs and NKG2A tend to be expressed by human CD8+ T cells in a mutually exclusive manner. In addition, TCR clonotypes of KIR+CD8+ T cells barely overlap with those of NKG2A+CD8+ T cells, and KIR+CD8+ T cells are more terminally differentiated and replicative senescent than NKG2A+CD8+ T cells. Among cytokine receptors, IL12Rβ1, IL12Rβ2, and IL18Rβ are highly expressed by NKG2A+CD8+ T cells, whereas IL2Rβ is expressed by KIR+CD8+ T cells. IL-12/IL-18-induced production of IFN-γ is prominent in NKG2A+CD8+ T cells, whereas IL-15-induced NK-like cytotoxicity is prominent in KIR+CD8+ T cells. These findings suggest that KIR+CD8+ and NKG2A+CD8+ T cells are distinct innate-like populations with different cytokine responsiveness.
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- 2023
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4. IL-15 enhances CCR5-mediated migration of memory CD8+ T cells by upregulating CCR5 expression in the absence of TCR stimulation
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In-Ho Seo, Hyuk Soo Eun, Ja Kyung Kim, Hoyoung Lee, Seongju Jeong, Seong Jin Choi, Jeewon Lee, Byung Seok Lee, Seok Hyun Kim, Woo Sun Rou, Dong Hyeon Lee, Won Kim, Su-Hyung Park, and Eui-Cheol Shin
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IL-15 ,bystander-activated CD8+ T cells ,CCR5 ,migration ,Biology (General) ,QH301-705.5 - Abstract
Summary: During microbial infection, bystander CD8+ T cells that are not specific to infecting pathogens can be activated by interleukin (IL)-15. However, the tissue-homing properties of bystander-activated CD8+ T cells have not been elucidated. Here, we examine the effects of IL-15 on the expression of chemokine receptors on CD8+ T cells and their migration. IL-15 upregulates CCR5 in memory CD8+ T cells in the absence of T cell receptor (TCR) stimulation and enhances CCR5-dependent migration. IL-15-induced CCR5 upregulation is abrogated by TCR stimulation, indicating that CCR5 is upregulated in bystander-activated CD8+ T cells. Moreover, CCR5 signals increase proliferation and cytotoxic protein expression in IL-15-treated memory CD8+ T cells, although the increase has a small extent. CCR5 upregulation in bystander-activated CD8+ T cells is associated with severe liver injury in patients with acute hepatitis A. Altogether, the results indicate that CCR5 upregulation by IL-15 mediates the migration of bystander-activated CD8+ T cells.
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- 2021
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5. Novel anti-4-1BB×PD-L1 bispecific antibody augments anti-tumor immunity through tumor-directed T-cell activation and checkpoint blockade
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Lei Fang, Wenqing Jiang, Zhengyi Wang, Su-Hyung Park, Eui-Cheol Shin, Minwoo Jeon, Jaeho Jung, Hyunjoo Kim, Hyung-Don Kim, Shin Hwang, Seongju Jeong, Eunyoung Park, Eunsil Sung, Jaehyoung Jeon, Youngkwang Kim, Ui-jung Jung, Yong-Gyu Son, Youngeun Hong, Hanbyul Lee, Shinai Lee, Yangmi Lim, and Jonghwa Won
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background Stimulation of 4-1BB with agonistic antibodies is a promising strategy for improving the therapeutic efficacy of immune checkpoint inhibitors (ICIs) or for overcoming resistance to ICIs. However, dose-dependent hepatotoxicity was observed in clinical trials with monoclonal anti-4-1BB agonistic antibodies due to the activation of 4-1BB signaling in liver resident Kupffer cells.Methods To avoid this on-target liver toxicity, we developed a novel bispecific antibody (4-1BB×PD-L1 bispecific antibody, termed “ABL503”) uniquely designed to activate 4-1BB signaling only in the context of PD-L1, while also blocking PD-1/PD-L1 signaling.Results Functional evaluation using effector cells expressing both 4-1BB and PD-1 revealed superior biological activity of ABL503 compared with the combination of each monoclonal antibody. ABL503 also augmented T-cell activation in in vitro assays and further enhanced the anti-PD-L1-mediated reinvigoration of tumor-infiltrating CD8+ T cells from patients with cancer. Furthermore, in humanized PD-L1/4-1BB transgenic mice challenged with huPD-L1-expressing tumor cells, ABL503 induced superior anti-tumor activity and maintained an anti-tumor response against tumor rechallenge. ABL503 was well tolerated, with normal liver function in monkeys.Conclusion The novel anti-4-1BB×PD-L1 bispecific antibody may exert a strong anti-tumor therapeutic efficacy with a low risk of liver toxicity through the restriction of 4-1BB stimulation in tumors.
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- 2021
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6. HIF-1α activation in myeloid cells accelerates dextran sodium sulfate-induced colitis progression in mice
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Young-Eun Kim, Minji Lee, Hyejung Gu, Jeongwoo Kim, Seongju Jeong, Sujin Yeo, You Jeong Lee, Sin-Hyeog Im, Young-Chul Sung, Hak Jae Kim, Irving L. Weissman, and G-One Ahn
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Hypoxia-inducible factor ,Myeloid cells ,Dextran sodium sulfate ,Colitis ,Medicine ,Pathology ,RB1-214 - Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease, in which the intestinal epithelium loses its barrier function. Given the existence of the oxygen gradient in the intestinal epithelium and that inflammation further contributes to the tissue hypoxia, we investigated the role of hypoxia-inducible factor (HIF), a transcription factor activated under hypoxic conditions in myeloid cells, in the progression of IBD. To do this, we utilized myeloid-specific knockout (KO) mice targeting HIF pathways, created by a Cre-loxP system with human MRP8 (hMRP8), an intracellular calcium-binding protein, as the myeloid promoter. By feeding 5% dextran sodium sulfate (DSS) to hMRP8 von Hippel Lindau (Vhl) KO mice, in which HIF-1α and HIF-2α are constitutively activated in myeloid cells, we found that these mice were highly susceptible to DSS-induced colitis, demonstrating greater body weight loss, increased mortality, faster onset of rectal bleeding, shortened colon length, and increased CD11b- or Gr-1-positive myeloid cells in the colon compared with wild-type (WT) mice. These parameters were restored to, if not better than, the WT levels when we examined hMRP8 Hif-1a KO mice upon 5% DSS feeding. hMRP8 Hif-2a KO mice, on the other hand, exhibited a similar degree of DSS-induced colitis to that of WT mice. Lastly, when DSS was given together with azoxymethane to induce tumorigenesis in the colon, we found that hMRP8 Hif-1a KO mice exhibited comparable levels of colorectal tumors to those of WT mice, indicating that HIF-1α in myeloid cells is dispensable for tumorigenesis. Collectively, our results suggest that HIF-1α activation in myeloid cells critically regulates IBD progression.
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- 2018
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7. Seismic and Infrasound Data Recorded at Regional Seismoacoustic Research Arrays in South Korea from the Six DPRK Underground Nuclear Explosions
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Brian Stump, Christopher Hayward, Paul Golden, Junghyun Park, Ray Kubacki, Chris Cain, Stephen Arrowsmith, Mihan H. McKenna Taylor, SeongJu Jeong, Tina Ivey, Mason MacPhail, Cathy Chickering Pace, Jeong-Soo Jeon, Il-Young Che, Kwangsu Kim, Byung-Il Kim, Tae-Sung Kim, In-Cheol Shin, and Myung-Soon Jun
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Geophysics - Abstract
Five seismoacoustic research arrays and one infrasound research array located across the southern Korean peninsula have been installed, maintained, and are cooperatively operated by Southern Methodist University and Korea Institute of Geoscience and Mineral Resources. The seismoacousitc arrays are each composed of 1–5 broadband seismometers spaced from 0.5 to 1.5 km and 4–16 infrasound sensors spaced from 0.1 to 1.5 km. The arrays—BRDAR, CHNAR, KSGAR, KMPAR, TJIAR, and YPDAR—have recorded regional seismic and infrasound signals from the six underground nuclear explosions conducted by Democratic People’s Republic of Korea. These seismoacoustic data are being made available for researchers interested in studying and quantifying the explosion source functions of these events as well as wave propagation effects in the solid earth and atmosphere as constrained by seismic and infrasound observations at regional distances.
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- 2022
8. IFITM3 Is Upregulated Characteristically in IL-15–Mediated Bystander-Activated CD8+ T Cells during Influenza Infection
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Seongju Jeong, Minwoo Jeon, Hoyoung Lee, So-Young Kim, Su-Hyung Park, and Eui-Cheol Shin
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Immunology ,Immunology and Allergy - Abstract
In bystander activation, pre-existing memory CD8+ T cells unrelated to the infecting microbes are activated by cytokines without cognate Ags. The detailed mechanisms and unique gene signature of bystander activation remain to be elucidated. In this study, we investigated bystander activation of OT-1 memory cells in a mouse model of influenza infection. We found that OT-1 memory cells are activated with upregulation of granzyme B and IFN-γ, during PR8 (A/Puerto Rico/8/1934) infection, and IL-15 is a critical cytokine for bystander activation. In transcriptomic analysis, the IFN-induced gene signature was upregulated in bystander-activated OT-1 memory cells during PR8 infection but not in the presence of TCR stimulation. Among the IFN-induced genes, upregulation of IFN-induced transmembrane protein 3 (IFITM3) distinguished bystander-activated OT-1 memory cells from TCR-activated OT-1 memory cells. Therefore, we reveal that bystander-activated memory CD8+ T cells have a unique transcriptomic feature compared with TCR-activated memory CD8+ T cells. In particular, IFITM3 upregulation can be used as a marker of bystander-activated memory CD8+ T cells at early infection.
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- 2022
9. Site Amplifications from Earthquake Data and VS30 in the Fort Worth Basin, Texas
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SeongJu Jeong, Brian W. Stump, and Heather R. DeShon
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Geophysics - Abstract
Following the development of unconventional oil and gas production in the Fort Worth Basin, Texas, a rapid increase in basin-wide seismicity began in 2008 that grew to include earthquakes affecting a substantial portion of the Dallas–Fort Worth metropolitan area. To assess and mitigate the seismic hazard, which in this region is impacted by the thickness of the sedimentary basin and accompanying soft soil layer, we estimate site effects at 22 seismic stations deployed to record these earthquakes. Site responses are derived using two different datasets and approaches: (1) a modified generalized inversion technique (GIT) based on the S-wave Fourier amplitude spectra from earthquakes; and (2) application of the quarter-wavelength approximation (QWA) using estimates of average shear-wave velocities in the upper 30 m, known as VS30. We find that site amplification estimates based on the two techniques are roughly consistent with one another (median of the amplification ratio = 0.92) over frequencies where a quarter-wavelength corresponds to ∼30 m depth. The site amplification factors from the two approaches are found on average to be about 3 at the quarter-wavelength frequency (QWF). These site amplification estimates are not well correlated with geologic characteristics including rock type and geologic age. Finally, QWA values at six sites do not match GIT site amplification at the QWF (outside of ± median absolute deviations boundary), which we attribute to a combination of the underlying assumptions of the QWA, uncertainty in VS30 estimates, and unmodeled site response complexity.
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- 2022
10. Tumour-infiltrating bystander CD8+T cells activated by IL-15 contribute to tumour control in non-small cell lung cancer
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Su-Hyung Park, Eui-Soon Kim, Jin Gu Lee, Yong Joon Lee, Seongjin Choi, Kun Woo Kim, Hyo Sup Shim, Minwoo Jeon, Eui-Cheol Shin, Jae-Ik Lee, Seongju Jeong, Seung Yeon Ha, Galam Leem, and Shin Myung Kang
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Pulmonary and Respiratory Medicine ,business.industry ,Interleukin ,NKG2D ,Antigen ,Interleukin 15 ,Interferon ,Cancer research ,Bystander effect ,Cytotoxic T cell ,Medicine ,business ,CD8 ,medicine.drug - Abstract
BackgroundTumour-unrelated, virus-specific bystander CD8+T cells were recently shown to be abundant among tumour-infiltrating lymphocytes (TILs). However, their roles in tumour immunity have not been elucidated yet.MethodsWe studied the characteristics of bystander CD8+TILs from non-small cell lung cancer (NSCLC) tissues (N=66) and their activation by interleukin (IL)-15 to repurpose them for tumour immunotherapy.ResultsWe show that bystander CD8+TILs specific to various viruses are present in human NSCLC tissues. We stimulated CD8+TILs ex vivo using IL-15 without cognate antigens and found that IL-15 treatment upregulated NKG2D expression on CD8+TILs, resulting in NKG2D-dependent production of interferon (IFN)-γ (p=0.0006). Finally, we tested whether IL-15 treatment can control tumour growth in a murine NSCLC model with or without a history of murine cytomegalovirus (MCMV) infection. IL-15 treatment reduced the number of tumour nodules in the lung only in mice with MCMV infection (p=0.0037). We confirmed that MCMV-specific bystander CD8+TILs produced interferon (IFN)-γ after IL-15 treatment, and that IL-15 treatment in MCMV-infected mice upregulated tumour necrosis factor-α and IFN-γ responsive genes in tumour microenvironment.ConclusionThus, the study demonstrates that bystander CD8+TILs can be repurposed by IL-15 for tumour immunotherapy.
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- 2021
11. Implication of CD69 + CD103 + tissue‐resident‐like CD8 + T cells as a potential immunotherapeutic target for cholangiocarcinoma
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Changhoon Yoo, Hyung-Don Kim, Jaehoon Shin, Yong Joon Lee, Su-Hyung Park, Sang-Yeob Kim, Jae Hoon Lee, Seongyeol Park, Gi-Won Song, Danbee Kim, Seongju Jeong, Eui-Cheol Shin, Shin Hwang, and Young Seok Ju
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Hepatology ,medicine.diagnostic_test ,Tumor-infiltrating lymphocytes ,hemic and immune systems ,chemical and pharmacologic phenomena ,Gene signature ,Biology ,CD38 ,Flow cytometry ,Immune system ,medicine ,Cancer research ,Cytotoxic T cell ,Immunohistochemistry ,CD8 - Abstract
BACKGROUND The heterogeneous immune landscapes of intrahepatic cholangiocarcinoma (ICC) remain largely unknown. Here we aimed to investigate the implications of tissue-resident memory (TRM)-related features of tumour-infiltrating CD8+ T cells (CD8+ TILs) from ICC patients. METHODS From ICC patients, we obtained blood samples and ICC surgical specimens (n = 33). We performed multicolour flow cytometry, multiplexed immunohistochemistry and RNA sequencing. RESULTS When compared to peripheral CD8+ T cells, the CD8+ TILs included significantly higher proportions of the CD69+ CD103- and CD69+ CD103+ TRM-like subsets (P
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- 2021
12. TOX-expressing terminally exhausted tumor-infiltrating CD8+ T cells are reinvigorated by co-blockade of PD-1 and TIGIT in bladder cancer
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Hyung-Don Kim, Ho Won Kang, Hye Sook Han, Chang Gok Woo, Su-Hyung Park, Min-Suk Kwon, A. Reum Kim, Hyung-Lae Kim, Hee Kyung Kim, Seok Joong Yun, Ki Hyeong Lee, Wun-Jae Kim, Sung Pil Seo, Seongju Jeong, Won-Tae Kim, and Eui-Cheol Shin
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0301 basic medicine ,Cancer Research ,Tumor microenvironment ,Bladder cancer ,business.industry ,medicine.medical_treatment ,hemic and immune systems ,chemical and pharmacologic phenomena ,Immunotherapy ,medicine.disease ,Tumor antigen ,Immune checkpoint ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,TIGIT ,030220 oncology & carcinogenesis ,Cancer research ,Cytotoxic T cell ,Medicine ,business ,CD8 - Abstract
Exhausted T cells in the tumor microenvironment are major targets of immunotherapies. However, the exhaustion status of CD8+ tumor-infiltrating lymphocytes (TILs) in bladder cancer has not been comprehensively evaluated. Herein, we examined distinct exhaustion status of CD8+ TILs based on the level of programmed cell death-1 (PD-1) and thymocyte selection-associated high mobility group box protein (TOX) expression in urothelial bladder cancer. We also evaluated the reinvigoration of exhausted CD8+ TILs upon ex vivo treatment with inhibitory checkpoint blockers. TOX-expressing PD-1highCD8+ TILs had the highest expression of immune checkpoint receptors (ICRs), the most terminally exhausted features, and the highest tumor antigen reactivity among PD-1+CD8+ TILs. Bladder cancer patients with a high percentage of PD-1highTOX+CD8+ TILs had more progressed T-cell exhaustion features and higher programmed death-ligand 1 expression in tumor tissues. TIGIT was the most frequent co-expressed ICR on PD-1+CD8+ TILs, and TIGIT blockade enhanced the PD-1 blockade-mediated cytokine production by CD8+ TILs from bladder cancer patients. Our findings provide an improved understanding of the heterogeneous exhaustion status of CD8+ TILs and additional immunotherapy strategies to improve outcomes of bladder cancer patients.
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- 2021
13. Abstract LB222: An mRNA-based cancer vaccine multi-targeting KRAS mutations inhibits tumor growth by increasing immune response in KRAS mutant LL/2 mouse model
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Seung-Hyun Shin, Youngjin Han, Chang Gyu Lim, Yong Ho Heo, Seongju Jeong, Yu-Yon Kim, and In Young Choi
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Cancer Research ,Oncology - Abstract
Kirsten rat sarcoma viral oncogene (KRAS) mutations are present in 26% of non-small cell lung cancer (NSCLC) patients (The Cancer Genome Atlas data). Studies have reported the presence of spatial or intra-tumoral heterogeneity of KRAS mutations. Though resistance to mutant KRAS inhibitors targeting a specific form of major KRAS mutations (e.g, G12C or G12D) is multifaceted, intra-tumoral heterogeneity of KRAS mutation is one of the crucial factors for the intrinsic resistance to the inhibitor. Multi-targeting of different KRAS mutations can prevent resistance due to the heterogeneity of KRAS mutations within a tumor. To achieve this, we incorporated an mRNA-based cancer vaccine containing transcripts for multiple KRAS mutant antigens. Our KRAS cancer vaccine (CV) candidate showed significantly attenuated tumor growth by 37% in the syngeneic KRAS G12C-expressing LL/2 tumor-bearing mice. CV treatment group showed significantly decreased tumor size by 45.4% after biopsy. Moreover, the mice treated with KRAS CV showed spleen enlarged by 42.6% indicating increased immune responses. To confirm, the expansion of T cells in the cancer vaccine-treated group, we collected tumor tissues and analyzed proportions of CD4+ and CD8+ T lymphocytes in the tumor. We found a 14.5-fold increase in infiltration of CD8+ T cells and a 0.5-fold increase in CD8+ CD44+ memory/effector T cells in the tumors from mice treated with KRAS CV. Whereas CD4+ Foxp3+ Treg cells were decreased by 3.9-fold in the tumor. HLA-A*02 is the most common MHC class I allele. To investigate the changes in MHC expression, we conducted FACS analysis using HLA-A*02 antibodies after ex vivo treatment of KRAS CV on the human peripheral blood mononuclear cells (hPBMCs). KRAS CV treatment facilitated higher proportions of HLA-A*02+ monocytes (CD14+) and B cells (CD19+). Though LL/2 tumor model has been considered an immunosuppressive model, our results suggest that the KRAS CV can significantly enhance immune responses, thereby suppressing tumor growth. Citation Format: Seung-Hyun Shin, Youngjin Han, Chang Gyu Lim, Yong Ho Heo, Seongju Jeong, Yu-Yon Kim, In Young Choi. An mRNA-based cancer vaccine multi-targeting KRAS mutations inhibits tumor growth by increasing immune response in KRAS mutant LL/2 mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB222.
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- 2023
14. Abstract 1814: A long-acting and CD122-enhanced IL-2 analog, HM16390, shows a potent and durable anti-tumor effect in both syngeneic B16F10 or CT26 mouse models
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Jinyoung Kim, Jaehyuk Choi, Yu Yon Kim, Seongju Jeong, Sang Hyun Park, Sungmin Bae, Daejin Kim, and In Young Choi
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Cancer Research ,Oncology - Abstract
Although recombinant IL-2 (aldesleukin) was approved for the treatment of metastatic renal cell carcinoma and melanoma, its suboptimal ligand binding affinity required high-dose administrations, resulting in dose-limiting toxicity such as vascular leak syndrome. To overcome the limitation of the current IL-2 therapy, a number of pharmaceutical companies have developed CD25 binding attenuated IL-2 muteins via various platform technology. These physical changes, however, accompanied a decrease in CD122-mediated signaling which was associated with cytotoxic lymphocytes expansion, leading to unsatisfied clinical consequences. In this context, we developed HM16390, a long-acting IL-2 analog with enhanced CD122 binding affinity to elicit potent anti-tumor efficacy. Furthermore, optimal binding affinity to CD25 was incorporated to prevent from unwanted toxicity. The pharmacokinetics in mice after single subcutaneous administration of HM16390 supported an extended duration of action (t1/2= 24.5 hr, bioavailability= 43.0%). To further investigate anti-tumor effect on various immunological conditions, syngeneic tumor mouse models, which are representing highly immunogenic colon cancer (CT26) and poorly immunogenic melanoma (B1F10), were chosen. After two weeks treatment in CT26 mice, complete response (CR) was observed in 89% and 100% of the mice by once weekly treatment of HM16390 at 2.1 and 8.5 mg/kg respectively, while only 22% of the mice showed CR by 5 consecutive day treatment per week of aldesleukin at 3.0 mg/kg. The cured mice had no evidence of relapse after tumor re-challenges at days 50 and 152. This immunological memory response against the CT26 tumor was demonstrated by significant increase in tumor-specific memory T cells in lymphoid organ and blood. Next, after four weeks treatment in B16F10 mice, once weekly treatment of HM16390 was well tolerated up to 42 mg/kg, and led to significant and dose-dependent retardation in tumor growth (vs syngeneic tumor vehicle) from 62.9% to 96.4% as well as dose-dependently prolonged median overall survival from 15 to 38 days (14 days in syngeneic tumor vehicle) at the dose range of 0.34 to 42 mg/kg. Of note, at doses ≥17 mg/kg, CR was observed in up to 22% of the mice. To sum up with the results, HM16390 has a dose-dependent and potent anti-tumor efficacy in murine models with the broad range of the immunogenic condition via CD122-enhanced IL-2 agonism. Citation Format: Jinyoung Kim, Jaehyuk Choi, Yu Yon Kim, Seongju Jeong, Sang Hyun Park, Sungmin Bae, Daejin Kim, In Young Choi. A long-acting and CD122-enhanced IL-2 analog, HM16390, shows a potent and durable anti-tumor effect in both syngeneic B16F10 or CT26 mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1814.
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- 2023
15. Abstract 1831: A long-acting and CD122-enhanced IL-2 analog, HM16390, synergizes with immune checkpoint inhibitor by remodeling an immune cell profile in tumor microenvironment
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Jaehyuk Choi, Jinyoung Kim, Yu Yon Kim, Seongju Jeong, Sungmin Bae, Daejin Kim, and In Young Choi
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Cancer Research ,Oncology - Abstract
Immune checkpoint inhibitors (CPI) are widely used for cancer immunotherapy. However, the response to CPIs is dependent on phenotype of tumor microenvironment (TME). A cold tumor known as immune-excluded or -desert has shown poor response to CPIs due to an absence of effector T cells in TME. IL-2 analog, which is immune stimulator and able to recruit cancer-fighting cells into TME, may be promising therapeutic partner for overcoming a limitation of CPIs. Previously, HM16390, a long-acting CD-122-enhanced IL-2 analog, exerted dose-dependent anti-tumor activity in low immunogenic B16F10 melanoma mice. Here, we further investigated the immune cells composition in TME following HM16390 treatment and synergistic anti-tumor effect after combination with CPI. B16F10 mice were sacrificed at days 1, 3, and 8 following single subcutaneous administration of HM16390 or 5 consecutive daily administrations of aldesleukin. According to the result, HM16390 transiently increased peripheral cytokines (IFNγ and TNFα) more than aldesleukin. In line with this, we observed that the tumor-infiltrating NK/Treg ratio was significantly increased approximately 19 by treatment of HM16390 while showing 4.2 in aldesleukin treated group at Day 3. Furthermore, tumor-infiltrating CD8+/Treg ratio was also upregulated approximately 74 by treatment of HM16390 while only showing 6.1 in aldesleukin treated group at Day 8. Significantly increased pro-inflammatory molecules such as GrzB and IFNγ were also observed in HM16390 treated group compared to aldesleukin (p Citation Format: Jaehyuk Choi, Jinyoung Kim, Yu Yon Kim, Seongju Jeong, Sungmin Bae, Daejin Kim, In Young Choi. A long-acting and CD122-enhanced IL-2 analog, HM16390, synergizes with immune checkpoint inhibitor by remodeling an immune cell profile in tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1831.
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- 2023
16. Spectral Characteristics of Ground Motion from Induced Earthquakes in the Fort Worth Basin, Texas, Using the Generalized Inversion Technique
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Heather R. DeShon, SeongJu Jeong, and Brian W. Stump
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Ground motion ,Geophysics ,010504 meteorology & atmospheric sciences ,Geochemistry and Petrology ,Inversion (geology) ,Structural basin ,010502 geochemistry & geophysics ,01 natural sciences ,Geology ,Seismology ,0105 earth and related environmental sciences - Abstract
A generalized inversion technique (GIT) is applied to local seismic data from 90 induced earthquakes (ML 2.0–3.9) in the Fort Worth Basin (FWB) of north Texas to separate path, site, and source characteristics and to improve local seismic hazard assessment. Seismograms from three earthquake sequences on spatially separated basement faults are recorded on 66 temporary stations. Because of the lack of hard-rock recording sites within the sedimentary basin, we developed a site correction method for the appropriate GIT process. At about 30 km distance from the hypocenters, we observed a change in spectral attenuation and thus focus data analysis within this distance range. The estimated quality factors for S and P waves result in a QS that is larger than QP which we interpret as a result of concentrations of crustal pore fluids or partial fluid-saturated material along the path; an interpretation consistent with fluid-rich sedimentary rocks in the FWB. Strong site amplifications as much as five times on horizontal components reflect the thick sediments in the basin. A limited number of sites exhibit amplification or deamplification on the vertical component that limits the use of horizontal-to-vertical spectral ratio methods for characterizing the site effect relative to the site effects estimated by GIT. Stress drops for all earthquakes range from 1.18 and 21.73 MPa with a mean of 4.46 MPa, similar to values reported for tectonic intraplate events. The stress-drop values suggest that strong motion and seismic hazard from the injection-induced earthquake in the FWB are comparable to those for tectonic earthquakes. The strong site amplification and fluid effects on propagation attenuation may be crucial factors to take into account for estimating seismic hazards of induced earthquakes in sedimentary basins.
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- 2020
17. IFITM3 Is Upregulated Characteristically in IL-15-Mediated Bystander-Activated CD8
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Seongju, Jeong, Minwoo, Jeon, Hoyoung, Lee, So-Young, Kim, Su-Hyung, Park, and Eui-Cheol, Shin
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Interleukin-15 ,Mice, Inbred C57BL ,Mice ,Influenza, Human ,Receptors, Antigen, T-Cell ,Animals ,Cytokines ,Humans ,Membrane Proteins ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,Immunologic Memory - Abstract
In bystander activation, pre-existing memory CD8
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- 2021
18. Abnormality in the NK cell population is prolonged in severe COVID-19 patients
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Yeon Sook Kim, Seongjin Choi, Ho-Young Lee, Shinhye Cheon, Hye Won Jeong, Su-Hyung Park, Hyeongseok Jeong, Seongju Jeong, Eui-Soon Kim, Eui-Cheol Shin, and Galam Leem
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Male ,IL-1, interleukin-1 ,STAT3, signal transducer and activator of transcription 3 ,PID, pathway interaction database ,cCD56dim, conventional CD56dimCD16pos ,Cell ,NK cells ,Lymphocyte Activation ,GSVA, gene set variation analysis ,GSEA, gene set enrichment analysis ,Immunology and Allergy ,Longitudinal Studies ,Prospective Studies ,RNA-Seq ,Cytotoxicity ,innate immunity ,COVID-19, coronavirus disease 2019 ,education.field_of_study ,EBV, Epstein-Barr virus ,tp53, tumor protein p53 ,TCPTP, T-cell protein tyrosine phosphatase ,Middle Aged ,Killer Cells, Natural ,medicine.anatomical_structure ,TNFA, tumor necrosis factor alpha ,CRP, C-reactive protein ,cytotoxicity ,KIRs, inhibitory killer-cell immunoglobulin-like receptors ,NK, natural killer ,WBC, white blood cell ,Adult ,PBMC, peripheral blood mononuclear cell ,TIGIT, T cell immunoglobulin and ITIM domain ,uCD56dim, unconventional CD56dimCD16neg ,Immunology ,Population ,HLH, hemophagocytic lymphohistiocytosis ,Peripheral blood mononuclear cell ,SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 ,KEGG, Kyoto Encyclopedia of Genes and Genomes ,Article ,Proinflammatory cytokine ,PPI, protein-protein interaction ,Immune system ,medicine ,Humans ,IFN, interferon ,cCD56bright, conventional CD56brightCD16neg ,education ,ARDS, acute respiratory distress syndrome ,GO, gene ontology ,Hemophagocytic lymphohistiocytosis ,Innate immune system ,business.industry ,SARS-CoV-2 ,ILC, innate lymphoid cells ,RNA-seq, RNA sequencing ,COVID-19 ,medicine.disease ,unconventional CD56dimCD16neg NK cells ,business ,NFKB1, nuclear factor kappa B subunit 1 - Abstract
Background Our understanding of adaptive immune responses in COVID-19 patients is rapidly evolving, but information on the innate immune responses by natural killer (NK) cells is still insufficient. Objective We aimed to examine the phenotypic and functional status of NK cells and their changes during the course of mild and severe COVID-19. Methods We performed RNA sequencing (RNA-seq) and flow cytometric analysis of NK cells from patients with mild and severe COVID-19 at multiple time points in the course of the disease using cryopreserved peripheral blood mononuclear cells (PBMCs). Results In RNA-seq analysis, the NK cells exhibited distinctive features compared to healthy donors, with significant enrichment of pro-inflammatory cytokine-mediated signaling pathways. Intriguingly, we found that the unconventional CD56dimCD16neg (uCD56dim) NK cell population expanded in cryopreserved PBMCs from COVID-19 patients regardless of disease severity, accompanied by decreased NK cell cytotoxicity. The NK cell population was rapidly normalized alongside the disappearance of uCD56dim NK cells and the recovery of NK cell cytotoxicity in mild COVID-19 patients, but this occurred slowly in severe COVID-19 patients. Conclusion The current longitudinal study provides a deep understanding of the NK cell biology in COVID-19., Graphical abstract
- Published
- 2021
19. Tracking Induced Seismicity in the Fort Worth Basin: A Summary of the 2008–2018 North Texas Earthquake Study Catalog
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Monique M. Holt, SeongJu Jeong, P. Ogwari, L. Quinones, Heather R. DeShon, K. B. Kwong, and O. Sufri
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Geophysics ,010504 meteorology & atmospheric sciences ,Geochemistry and Petrology ,Structural basin ,Induced seismicity ,010502 geochemistry & geophysics ,Tracking (particle physics) ,01 natural sciences ,Seismology ,Geology ,0105 earth and related environmental sciences - Abstract
Since 2008, earthquake sequences within the Fort Worth basin (FWB), north Texas, have been linked to wastewater disposal activities related to unconventional shale‐gas production. The North Texas Earthquake Study (NTXES) catalog (2008–2018), described and included herein, uses a combination of local and regional seismic networks to track significant seismic sequences in the basin. The FWB earthquakes occur along discrete faults that are relatively far apart (>30 km), allowing for more detailed study of individual sequence development. The three largest sequences (magnitude 3.6+) are monitored by local seismic networks (10 km) over time, implying that far‐field stress changes associated with fluid injection activities may be an important component to understanding the seismic hazard of induced seismicity sequences.
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- 2019
20. Significance of bystander T cell activation in microbial infection
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Ho-Young Lee, Eui-Cheol Shin, and Seongju Jeong
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Inflammation ,Effector ,T cell ,Microbiota ,Immunology ,Disease ,Bystander Effect ,Biology ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,medicine.anatomical_structure ,Antigen ,Bystander effect ,medicine ,Immunology and Allergy ,Animals ,Cytokines ,Humans ,Antigens ,Immunologic Memory ,CD8 - Abstract
During microbial infection, pre-existing memory CD8+ T cells that are not specific for the infecting pathogens can be activated by cytokines without cognate antigens, termed bystander activation. Studies in mouse models and human patients demonstrate bystander activation of memory CD8+ T cells, which exerts either protective or detrimental effects on the host, depending on the infection model or disease. Research has elucidated mechanisms underlying the bystander activation of CD8+ T cells in terms of the responsible cytokines and the effector mechanisms of bystander-activated CD8+ T cells. In this Review, we describe the history of research on bystander CD8+ T cell activation as well as evidence of bystander activation. We also discuss the mechanisms and immunopathological roles of bystander activation in various microbial infections.
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- 2021
21. Tumour-infiltrating bystander CD8
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Galam, Leem, Minwoo, Jeon, Kun Woo, Kim, Seongju, Jeong, Seong Jin, Choi, Yong Joon, Lee, Eui-Soon, Kim, Jae-Ik, Lee, Seung Yeon, Ha, Su-Hyung, Park, Hyo Sup, Shim, Jin Gu, Lee, Shin Myung, Kang, and Eui-Cheol, Shin
- Subjects
Interleukin-15 ,Interferon-gamma ,Mice ,Lung Neoplasms ,NK Cell Lectin-Like Receptor Subfamily K ,Carcinoma, Non-Small-Cell Lung ,Tumor Microenvironment ,Animals ,Humans ,CD8-Positive T-Lymphocytes - Abstract
Tumour-unrelated, virus-specific bystander CD8We studied the characteristics of bystander CD8We show that bystander CD8Thus, the study demonstrates that bystander CD8
- Published
- 2021
22. Tumour-infiltrating bystander CD8+ T cells activated by IL-15 contribute to tumour control in non-small cell lung cancer.
- Author
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Leem, Galam, Jeon, Minwoo, Kun Woo Kim, Seongju Jeong, Seong Jin Choi, Yong Joon Lee, Eui-Soon, Jae-Ik Lee, Seung Yeon Ha, Su-Hyung Park, Hyo Sup Shim, Jin Gu Lee, Shin Myung Kang, Eui-Cheol Shin, Kim, Kun Woo, Jeong, Seongju, Choi, Seong Jin, Lee, Yong Joon, Kim, Eui-Soon, and Lee, Jae-Ik
- Subjects
LUNG cancer ,INTERLEUKINS ,RESEARCH ,ANIMAL experimentation ,RESEARCH methodology ,LUNG tumors ,CELL physiology ,CELL receptors ,EVALUATION research ,INTERFERONS ,COMPARATIVE studies ,T cells ,MICE - Abstract
Background: Tumour-unrelated, virus-specific bystander CD8+ T cells were recently shown to be abundant among tumour-infiltrating lymphocytes (TILs). However, their roles in tumour immunity have not been elucidated yet.Methods: We studied the characteristics of bystander CD8+ TILs from non-small cell lung cancer (NSCLC) tissues (N=66) and their activation by interleukin (IL)-15 to repurpose them for tumour immunotherapy.Results: We show that bystander CD8+ TILs specific to various viruses are present in human NSCLC tissues. We stimulated CD8+ TILs ex vivo using IL-15 without cognate antigens and found that IL-15 treatment upregulated NKG2D expression on CD8+ TILs, resulting in NKG2D-dependent production of interferon (IFN)-γ (p=0.0006). Finally, we tested whether IL-15 treatment can control tumour growth in a murine NSCLC model with or without a history of murine cytomegalovirus (MCMV) infection. IL-15 treatment reduced the number of tumour nodules in the lung only in mice with MCMV infection (p=0.0037). We confirmed that MCMV-specific bystander CD8+ TILs produced interferon (IFN)-γ after IL-15 treatment, and that IL-15 treatment in MCMV-infected mice upregulated tumour necrosis factor-α and IFN-γ responsive genes in tumour microenvironment.Conclusion: Thus, the study demonstrates that bystander CD8+ TILs can be repurposed by IL-15 for tumour immunotherapy. [ABSTRACT FROM AUTHOR]- Published
- 2022
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23. Stress Drop Variations of Induced Earthquakes at the Dallas-Fort Worth Airport, Texas
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SeongJu Jeong, Brian William Stump, and Heather R. DeShon
- Published
- 2021
24. Implication of CD69
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Hyung-Don, Kim, Seongju, Jeong, Seongyeol, Park, Yong Joon, Lee, Young Seok, Ju, Danbee, Kim, Gi-Won, Song, Jae Hoon, Lee, Sang-Yeob, Kim, Jaehoon, Shin, Eui-Cheol, Shin, Shin, Hwang, Changhoon, Yoo, and Su-Hyung, Park
- Subjects
Cholangiocarcinoma ,Lymphocytes, Tumor-Infiltrating ,Humans ,Immunotherapy ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,Immunologic Memory - Abstract
The heterogeneous immune landscapes of intrahepatic cholangiocarcinoma (ICC) remain largely unknown. Here we aimed to investigate the implications of tissue-resident memory (TRM)-related features of tumour-infiltrating CD8From ICC patients, we obtained blood samples and ICC surgical specimens (n = 33). We performed multicolour flow cytometry, multiplexed immunohistochemistry and RNA sequencing.When compared to peripheral CD8CD69
- Published
- 2020
25. IL-15 enhances CCR5-mediated migration of memory CD8
- Author
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In-Ho, Seo, Hyuk Soo, Eun, Ja Kyung, Kim, Hoyoung, Lee, Seongju, Jeong, Seong Jin, Choi, Jeewon, Lee, Byung Seok, Lee, Seok Hyun, Kim, Woo Sun, Rou, Dong Hyeon, Lee, Won, Kim, Su-Hyung, Park, and Eui-Cheol, Shin
- Subjects
Adult ,Inflammation ,Interleukin-15 ,Male ,Receptors, CCR7 ,Cell Death ,Receptors, CCR5 ,MAP Kinase Signaling System ,Receptors, Antigen, T-Cell ,CD8-Positive T-Lymphocytes ,Hepatitis A ,Middle Aged ,Up-Regulation ,Mice, Inbred C57BL ,Young Adult ,Cell Movement ,Acute Disease ,Animals ,Humans ,Female ,Immunologic Memory ,Cell Proliferation - Abstract
During microbial infection, bystander CD8
- Published
- 2020
26. TOX-expressing terminally exhausted tumor-infiltrating CD8
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Hye Sook, Han, Seongju, Jeong, Hyunglae, Kim, Hyung-Don, Kim, A Reum, Kim, Minsuk, Kwon, Su-Hyung, Park, Chang Gok, Woo, Hee Kyung, Kim, Ki Hyeong, Lee, Sung Pil, Seo, Ho Won, Kang, Won Tae, Kim, Wun-Jae, Kim, Seok Joong, Yun, and Eui-Cheol, Shin
- Subjects
Adult ,Aged, 80 and over ,Male ,Carcinoma, Transitional Cell ,Primary Cell Culture ,Programmed Cell Death 1 Receptor ,Urinary Bladder ,High Mobility Group Proteins ,Drug Synergism ,CD8-Positive T-Lymphocytes ,Middle Aged ,Cystectomy ,Lymphocyte Activation ,Lymphocytes, Tumor-Infiltrating ,Urinary Bladder Neoplasms ,Chemotherapy, Adjuvant ,Antineoplastic Combined Chemotherapy Protocols ,Tumor Cells, Cultured ,Tumor Microenvironment ,Humans ,Female ,Prospective Studies ,Receptors, Immunologic ,Immune Checkpoint Inhibitors ,Aged - Abstract
Exhausted T cells in the tumor microenvironment are major targets of immunotherapies. However, the exhaustion status of CD8
- Published
- 2020
27. PD-1 blockade-unresponsive human tumor-infiltrating CD8(+) T cells are marked by loss of CD28 expression and rescued by IL-15
- Author
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Bo Mi Ku, Ho-Young Lee, Su-Hyung Park, Ji Won Han, Seongju Jeong, Myung-Ju Ahn, Seongjin Choi, Chang Gon Kim, Jiae Koh, Hyung-Lae Kim, Hyung-Don Kim, Minwoo Jeon, Hong Kwan Kim, Kyung Hwan Kim, and Eui-Cheol Shin
- Subjects
0301 basic medicine ,Lung Neoplasms ,T cell ,Immunology ,Programmed Cell Death 1 Receptor ,chemical and pharmacologic phenomena ,CD8-Positive T-Lymphocytes ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Lymphocytes, Tumor-Infiltrating ,CD28 Antigens ,Carcinoma, Non-Small-Cell Lung ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Animals ,Humans ,Immune Checkpoint Inhibitors ,Interleukin-15 ,biology ,Chemistry ,Cancer ,CD28 ,hemic and immune systems ,medicine.disease ,Blockade ,Mice, Inbred C57BL ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,Interleukin 15 ,Cancer research ,biology.protein ,Female ,Antibody ,CD8 ,030215 immunology - Abstract
Blockade of programmed death-1 (PD-1) reinvigorates exhausted CD8(+) T cells, resulting in tumor regression in cancer patients. Recently, reinvigoration of exhausted CD8(+) T cells following PD-1 blockade was shown to be CD28-dependent in mouse models. Herein, we examined the role of CD28 in anti-PD-1 antibody-induced human T cell reinvigoration using tumor-infiltrating CD8(+) T cells (CD8(+) TILs) obtained from non-small-cell lung cancer patients. Single-cell analysis demonstrated a distinct expression pattern of CD28 between mouse and human CD8(+) TILs. Furthermore, we found that human CD28(+)CD8(+) but not CD28(–)CD8(+) TILs responded to PD-1 blockade irrespective of B7/CD28 blockade, indicating that CD28 costimulation in human CD8(+) TILs is dispensable for PD-1 blockade-induced reinvigoration and that loss of CD28 expression serves as a marker of anti-PD-1 antibody-unresponsive CD8(+) TILs. Transcriptionally and phenotypically, PD-1 blockade-unresponsive human CD28(–)PD-1(+)CD8(+) TILs exhibited characteristics of terminally exhausted CD8(+) T cells with low TCF1 expression. Notably, CD28(–)PD-1(+)CD8(+) TILs had preserved machinery to respond to IL-15, and IL-15 treatment enhanced the proliferation of CD28(–)PD-1(+)CD8(+) TILs as well as CD28(+)PD-1(+)CD8(+) TILs. Taken together, these results show that loss of CD28 expression is a marker of PD-1 blockade-unresponsive human CD8(+) TILs with a TCF1(–) signature and provide mechanistic insights into combining IL-15 with anti-PD-1 antibodies.
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- 2020
28. 4-1BB Delineates Distinct Activation Status of Exhausted Tumor-Infiltrating CD8+ T Cells in Hepatocellular Carcinoma
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Seongju Jeong, Kyung Hwan Kim, Hong Kwan Kim, Byung Soh Min, Jung Yun Lee, Eui-Cheol Shin, Su-Hyung Park, Ho-Young Lee, Hyung-Don Kim, Jong Hee Chang, Seung-Mo Hong, Yong Joon Lee, Shin Hwang, Sunghoon Kim, Young Seok Ju, Seongyeol Park, Gi-Won Song, and Chang Gon Kim
- Subjects
0301 basic medicine ,Male ,medicine.medical_treatment ,Receptor expression ,Programmed Cell Death 1 Receptor ,Clinical Sciences ,Immunology ,Member 9 ,Biology ,CD8-Positive T-Lymphocytes ,Medical Biochemistry and Metabolomics ,Lymphocyte Activation ,03 medical and health sciences ,0302 clinical medicine ,Rare Diseases ,Cancer immunotherapy ,Co-stimulation ,medicine ,Cytotoxic T cell ,Humans ,2.1 Biological and endogenous factors ,Lymphocytes ,Tumor-Infiltrating ,Aetiology ,Aged ,Cancer ,Hepatology ,Gastroenterology & Hepatology ,Tumor-infiltrating lymphocytes ,Melanoma ,Tumor Necrosis Factor Receptor Superfamily ,CD137 ,Carcinoma ,Liver Neoplasms ,Hepatocellular ,Middle Aged ,medicine.disease ,030104 developmental biology ,Good Health and Well Being ,Cancer research ,030211 gastroenterology & hepatology ,Female ,Digestive Diseases ,CD8 - Abstract
Background and aims Targeting costimulatory receptors with agonistic antibodies is a promising cancer immunotherapy option. We aimed to investigate costimulatory receptor expression, particularly 4-1BB (CD137 or tumor necrosis factor receptor superfamily member 9), on tumor-infiltrating CD8+ T cells (CD8+ tumor-infiltrating lymphocytes [TILs]) and its association with distinct T-cell activation features among exhausted CD8+ TILs in hepatocellular carcinoma (HCC). Approach and results Tumor tissues, adjacent nontumor tissues, and peripheral blood were collected from HCC patients undergoing surgical resection (n = 79). Lymphocytes were isolated and used for multicolor flow cytometry, RNA-sequencing, and in vitro functional restoration assays. Among the examined costimulatory receptors, 4-1BB was most prominently expressed on CD8+ TILs. 4-1BB expression was almost exclusively detected on CD8+ T cells in the tumor-especially on programmed death 1 (PD-1)high cells and not PD-1int and PD-1neg cells. Compared to PD-1int and 4-1BBneg PD-1high CD8+ TILs, 4-1BBpos PD-1high CD8+ TILs exhibited higher levels of tumor reactivity and T-cell activation markers and significant enrichment for T-cell activation gene signatures. Per-patient analysis revealed positive correlations between percentages of 4-1BBpos cells among CD8+ TILs and levels of parameters of tumor reactivity and T-cell activation. Among highly exhausted PD-1high CD8+ TILs, 4-1BBpos cells harbored higher proportions of cells with proliferative and reinvigoration potential. Our 4-1BB-related gene signature predicted survival outcomes of HCC patients in the The Cancer Genome Atlas cohort. 4-1BB agonistic antibodies enhanced the function of CD8+ TILs and further enhanced the anti-PD-1-mediated reinvigoration of CD8+ TILs, especially in cases showing high levels of T-cell activation. Conclusion 4-1BB expression on CD8+ TILs represents a distinct activation state among highly exhausted CD8+ T cells in HCC. 4-1BB costimulation with agonistic antibodies may be a promising strategy for treating HCCs exhibiting prominent T-cell activation.
- Published
- 2020
29. A SUMMARY OF FORT WORTH BASIN INDUCED EARTHQUAKE SEQUENCES 2008-PRESENT
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M. Beatrice Magnani, SeongJu Jeong, L. Quinones, and Heather R. DeShon
- Subjects
Paleontology ,Structural basin ,Geology - Published
- 2020
30. IL-15 Enhances CCR5-Mediated Migration of Memory CD8+ T Cells by Upregulating CCR5 Expression in the Absence of TCR Stimulation
- Author
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Jeewon Lee, Ho-Young Lee, Hyuk Soo Eun, Dong Hyeon Lee, Ja Kyung Kim, Seong Jin Choi, Su-Hyung Park, Byung Seok Lee, Seongju Jeong, In Ho Seo, Seok Hyun Kim, Woo Sun Rou, Won Kim, and Eui-Cheol Shin
- Subjects
Chemokine receptor ,In vivo ,Interleukin 15 ,Chemistry ,T-cell receptor ,Cytotoxic T cell ,Stimulation ,CD8 ,In vitro ,Cell biology - Abstract
During microbial infection, bystander CD8+ T cells that are not specific to infecting pathogens can be activated by cytokines, such as IL-15. However, the tissue-homing properties of bystander-activated CD8+ T cells have not been elucidated. Here, we examined the effects of IL-15 on the expression of chemokine receptors on CD8+ T cells and their migration. We found that IL-15 up-regulates CCR5 in memory CD8+ T cells in the absence of TCR stimulation and enhances CCR5-dependent migration in vitro and in vivo. IL-15-induced CCR5 up-regulation was abrogated by concurrent TCR stimulation, indicating that CCR5 is up-regulated in bystander-activated CD8+ T cells. Moreover, CCR5 signals increased proliferation and cytotoxic protein expression in IL-15-treated memory CD8+ T cells. CCR5 up-regulation in bystander-activated CD8+ T cells was associated with severe liver injury in patients with acute hepatitis A. Taken together, the results indicate that CCR5 up-regulation by IL-15 mediates the migration of bystander-activated CD8+ T cells.
- Published
- 2020
31. Co-Stimulatory Receptors in Cancers and Their Implications for Cancer Immunotherapy
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Su-Hyung Park and Seongju Jeong
- Subjects
business.industry ,T-Lymphocytes ,medicine.medical_treatment ,Immune checkpoint inhibitors ,Immunology ,Cancer ,Review Article ,Immunotherapy ,Cancer, Immunotherapy ,medicine.disease ,Food and drug administration ,Infectious Diseases ,Cancer immunotherapy ,medicine ,Cancer research ,Immunology and Allergy ,Costimulatory T-cell receptors ,Effector functions ,business ,Receptor - Abstract
Immune checkpoint inhibitors (ICIs), including anti-PD-1 and anti-CTLA-4 therapeutic agents, are now approved by the Food and Drug Administration for treatment of various types of cancer. However, the therapeutic efficacy of ICIs varies among patients and cancer types. Moreover, most patients do not develop durable antitumor responses after ICI therapy due to an ephemeral reversal of T-cell dysfunction. As co-stimulatory receptors play key roles in regulating the effector functions of T cells, activating co-stimulatory pathways may improve checkpoint inhibition efficacy, and lead to durable antitumor responses. Here, we review recent advances in our understating of co-stimulatory receptors in cancers, providing the necessary groundwork for the rational design of cancer immunotherapy.
- Published
- 2020
32. Characteristics of infrasound signals from North Korean underground nuclear explosions on 2016 January 6 and September 9
- Author
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Brian W. Stump, SeongJu Jeong, Fransiska Dannemann, Harrison R. Oldham, Chris Hayward, Vanshan Wright, Il-Young Che, Junghyun Park, K. B. Kwong, Sarah McComas, and M. M. Scales
- Subjects
Geophysics ,010504 meteorology & atmospheric sciences ,Geochemistry and Petrology ,Wave propagation ,Infrasound ,Environmental science ,010502 geochemistry & geophysics ,01 natural sciences ,Seismology ,0105 earth and related environmental sciences - Published
- 2018
33. Novel anti-4-1BB×PD-L1 bispecific antibody augments anti-tumor immunity through tumor-directed T-cell activation and checkpoint blockade
- Author
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Minwoo Jeon, Han-Byul Lee, Seongju Jeong, Shin Hwang, Hyung-Don Kim, Zhengyi Wang, Hyunjoo Kim, Su-Hyung Park, Eun-Sil Sung, Jung Uijung, Jeon Jaehyoung, Eui-Cheol Shin, Yangmi Lim, Shinai Lee, Jiang Wenqing, Kim Youngkwang, Eunyoung Park, Youngeun Hong, Fang Lei, Son Yonggyu, Jonghwa Won, and Jaeho Jung
- Subjects
Male ,0301 basic medicine ,Cancer Research ,medicine.drug_class ,T cell ,medicine.medical_treatment ,Immunology ,Monoclonal antibody ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,PD-L1 ,Antibodies, Bispecific ,medicine ,Animals ,Humans ,Immunology and Allergy ,Immune Checkpoint Inhibitors ,T-lymphocytes ,RC254-282 ,Clinical/Translational Cancer Immunotherapy ,Pharmacology ,biology ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,adaptive immunity ,Immunotherapy ,Acquired immune system ,costimulatory and inhibitory T-cell receptors ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Monoclonal ,biology.protein ,Cancer research ,Molecular Medicine ,Antibody ,business ,CD8 - Abstract
BackgroundStimulation of 4-1BB with agonistic antibodies is a promising strategy for improving the therapeutic efficacy of immune checkpoint inhibitors (ICIs) or for overcoming resistance to ICIs. However, dose-dependent hepatotoxicity was observed in clinical trials with monoclonal anti-4-1BB agonistic antibodies due to the activation of 4-1BB signaling in liver resident Kupffer cells.MethodsTo avoid this on-target liver toxicity, we developed a novel bispecific antibody (4-1BB×PD-L1 bispecific antibody, termed “ABL503”) uniquely designed to activate 4-1BB signaling only in the context of PD-L1, while also blocking PD-1/PD-L1 signaling.ResultsFunctional evaluation using effector cells expressing both 4-1BB and PD-1 revealed superior biological activity of ABL503 compared with the combination of each monoclonal antibody. ABL503 also augmented T-cell activation in in vitro assays and further enhanced the anti-PD-L1-mediated reinvigoration of tumor-infiltrating CD8+ T cells from patients with cancer. Furthermore, in humanized PD-L1/4-1BB transgenic mice challenged with huPD-L1-expressing tumor cells, ABL503 induced superior anti-tumor activity and maintained an anti-tumor response against tumor rechallenge. ABL503 was well tolerated, with normal liver function in monkeys.ConclusionThe novel anti-4-1BB×PD-L1 bispecific antibody may exert a strong anti-tumor therapeutic efficacy with a low risk of liver toxicity through the restriction of 4-1BB stimulation in tumors.
- Published
- 2021
34. 4-1BB Delineates Distinct Activation Status of Exhausted Tumor-Infiltrating CD8
- Author
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Hyung-Don, Kim, Seongyeol, Park, Seongju, Jeong, Yong Joon, Lee, Hoyoung, Lee, Chang Gon, Kim, Kyung Hwan, Kim, Seung-Mo, Hong, Jung-Yun, Lee, Sunghoon, Kim, Hong Kwan, Kim, Byung Soh, Min, Jong Hee, Chang, Young Seok, Ju, Eui-Cheol, Shin, Gi-Won, Song, Shin, Hwang, and Su-Hyung, Park
- Subjects
Male ,Carcinoma, Hepatocellular ,Liver Neoplasms ,Programmed Cell Death 1 Receptor ,Original Articles ,CD8-Positive T-Lymphocytes ,Middle Aged ,Lymphocyte Activation ,Tumor Necrosis Factor Receptor Superfamily, Member 9 ,Lymphocytes, Tumor-Infiltrating ,Humans ,Hepatobiliary Malignancies ,Female ,Original Article ,Aged - Abstract
Background and Aims Targeting costimulatory receptors with agonistic antibodies is a promising cancer immunotherapy option. We aimed to investigate costimulatory receptor expression, particularly 4‐1BB (CD137 or tumor necrosis factor receptor superfamily member 9), on tumor‐infiltrating CD8+ T cells (CD8+ tumor‐infiltrating lymphocytes [TILs]) and its association with distinct T‐cell activation features among exhausted CD8+ TILs in hepatocellular carcinoma (HCC). Approach and Results Tumor tissues, adjacent nontumor tissues, and peripheral blood were collected from HCC patients undergoing surgical resection (n = 79). Lymphocytes were isolated and used for multicolor flow cytometry, RNA‐sequencing, and in vitro functional restoration assays. Among the examined costimulatory receptors, 4‐1BB was most prominently expressed on CD8+ TILs. 4‐1BB expression was almost exclusively detected on CD8+ T cells in the tumor—especially on programmed death 1 (PD‐1)high cells and not PD‐1int and PD‐1neg cells. Compared to PD‐1int and 4‐1BBnegPD‐1high CD8+ TILs, 4‐1BBposPD‐1high CD8+ TILs exhibited higher levels of tumor reactivity and T‐cell activation markers and significant enrichment for T‐cell activation gene signatures. Per‐patient analysis revealed positive correlations between percentages of 4‐1BBpos cells among CD8+ TILs and levels of parameters of tumor reactivity and T‐cell activation. Among highly exhausted PD‐1high CD8+ TILs, 4‐1BBpos cells harbored higher proportions of cells with proliferative and reinvigoration potential. Our 4‐1BB–related gene signature predicted survival outcomes of HCC patients in the The Cancer Genome Atlas cohort. 4‐1BB agonistic antibodies enhanced the function of CD8+ TILs and further enhanced the anti‐PD‐1–mediated reinvigoration of CD8+ TILs, especially in cases showing high levels of T‐cell activation. Conclusion 4‐1BB expression on CD8+ TILs represents a distinct activation state among highly exhausted CD8+ T cells in HCC. 4‐1BB costimulation with agonistic antibodies may be a promising strategy for treating HCCs exhibiting prominent T‐cell activation.
- Published
- 2019
35. Hypoxia-inducible factor-1 (HIF-1) activation in myeloid cells accelerates DSS-induced colitis progression in mice
- Author
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Seongju Jeong, Sin-Hyeog Im, Sujin Yeo, Jeongwoo Kim, Hak Jae Kim, Young Eun Kim, Young-Chul Sung, G-One Ahn, Hyejung Gu, Irving L. Weissman, You Jeong Lee, and Minji Lee
- Subjects
0301 basic medicine ,Myeloid ,Neuroscience (miscellaneous) ,Medicine (miscellaneous) ,Inflammation ,medicine.disease_cause ,Inflammatory bowel disease ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Immunology and Microbiology (miscellaneous) ,medicine ,Colitis ,Chemistry ,Azoxymethane ,medicine.disease ,Intestinal epithelium ,digestive system diseases ,030104 developmental biology ,medicine.anatomical_structure ,Hypoxia-inducible factors ,030220 oncology & carcinogenesis ,Cancer research ,medicine.symptom ,Carcinogenesis - Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease, in which the intestinal epithelium loses its barrier function. Given the existence of the oxygen gradient in the intestinal epithelium and that inflammation further contributes to the tissue hypoxia, we investigated the role of hypoxia-inducible factor (HIF), a transcription factor activated under hypoxic conditions in myeloid cells, in the progression of IBD. To do this, we utilized myeloid-specific knockout (KO) mice targeting HIF pathways, created by a Cre-loxP system with human MRP8 (hMRP8), an intracellular calcium-binding protein, as the myeloid promoter. By feeding 5% dextran sodium sulfate (DSS) to hMRP8 von Hippel Lindau (Vhl) KO mice, in which HIF-1α and HIF-2α are constitutively activated in myeloid cells, we found that these mice were highly susceptible to DSS-induced colitis, demonstrating greater body weight loss, increased mortality, faster onset of rectal bleeding, shortened colon length, and increased CD11b- or Gr-1-positive myeloid cells in the colon compared with wild-type (WT) mice. These parameters were restored to, if not better than, the WT levels when we examined hMRP8 Hif-1a KO mice upon 5% DSS feeding. hMRP8 Hif-2a KO mice, on the other hand, exhibited a similar degree of DSS-induced colitis to that of WT mice. Lastly, when DSS was given together with azoxymethane to induce tumorigenesis in the colon, we found that hMRP8 Hif-1a KO mice exhibited comparable levels of colorectal tumors to those of WT mice, indicating that HIF-1α in myeloid cells is dispensable for tumorigenesis. Collectively, our results suggest that HIF-1α activation in myeloid cells critically regulates IBD progression.
- Published
- 2018
36. Spectral Characteristics of Ground Motion from Induced Earthquakes in the Fort Worth Basin, Texas, Using the Generalized Inversion Technique.
- Author
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SeongJu Jeong, Stump, Brian W., and DeShon, Heather R.
- Abstract
A generalized inversion technique (GIT) is applied to local seismic data from 90 induced earthquakes (M
L 2.0-3.9) in the Fort Worth Basin (FWB) of north Texas to separate path, site, and source characteristics and to improve local seismic hazard assessment. Seismograms from three earthquake sequences on spatially separated basement faults are recorded on 66 temporary stations. Because of the lack of hard-rock recording sites within the sedimentary basin, we developed a site correction method for the appropriate GIT process. At about 30 km distance from the hypocenters, we observed a change in spectral attenuation and thus focus data analysis within this distance range. The estimated quality factors for S and P waves result in a QS that is larger than QP which we interpret as a result of concentrations of crustal pore fluids or partial fluid-saturated material along the path; an interpretation consistent with fluid-rich sedimentary rocks in the FWB. Strong site amplifications as much as five times on horizontal components reflect the thick sediments in the basin. A limited number of sites exhibit amplification or deamplification on the vertical component that limits the use of horizontal-to-vertical spectral ratio methods for characterizing the site effect relative to the site effects estimated by GIT. Stress drops for all earthquakes range from 1.18 and 21.73 MPa with a mean of 4.46 MPa, similar to values reported for tectonic intraplate events. The stress-drop values suggest that strong motion and seismic hazard from the injection-induced earthquake in the FWB are comparable to those for tectonic earthquakes. The strong site amplification and fluid effects on propagation attenuation may be crucial factors to take into account for estimating seismic hazards of induced earthquakes in sedimentary basins. [ABSTRACT FROM AUTHOR]- Published
- 2020
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37. Tracking Induced Seismicity in the Fort Worth Basin: A Summary of the 2008-2018 North Texas Earthquake Study Catalog.
- Author
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Quinones, Louis, DeShon, Heather R., SeongJu Jeong, Ogwari, Paul, Sufri, Oner, Holt, Monique M., and Kwong, Kevin B.
- Abstract
Since 2008, earthquake sequences within the Fort Worth basin (FWB), north Texas, have been linked to wastewater disposal activities related to unconventional shale-gas production. The North Texas Earthquake Study (NTXES) catalog (2008-2018), described and included herein, uses a combination of local and regional seismic networks to track significant seismic sequences in the basin. The FWB earthquakes occur along discrete faults that are relatively far apart (>30 km), allowing for more detailed study of individual sequence development. The three largest sequences (magnitude 3.6+) are monitored by local seismic networks (<15 km epicentral distances), whereas basinwide seismicity outside these three sequences is monitored using regional distance stations. A regional 1D velocity model for the FWB reflects basinwide well log, receiver function, and regional crustal structure studies and is modified for the larger individual earthquake sequences using local well-log and geology data. Here, we present an m
b _Lg relationship appropriate for Texas and a basin-specific ML relationship, both calculated using attenuation curves developed with the NTXES catalog. Analysis of the catalog reveals that the earthquakes generally occur within the Precambrian basement formation along steeply dipping normal faults, and although overall seismicity rates have decreased since 2016, new faults have become active. Between 2006 and 2018, more than 2 billion barrels of fluids were injected into the Ellenburger formation within the FWB. We observe strong spatial and temporal correlations between the earthquake locations and wastewater disposal well locations and injection volumes, implying that fluid injection activities may be the main driving force of seismicity in the basin. In addition, we observe seismicity occurring at greater distances from injection wells (>10 km) over time, implying that far-field stress changes associated with fluid injection activities may be an important component to understanding the seismic hazard of induced seismicity sequences. [ABSTRACT FROM AUTHOR]- Published
- 2019
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