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Review Article
Applicability of Spatial Technology in Cancer Research
Sangjeong Ahn, Hye Seung Lee
Cancer Res Treat. 2024;56(2):343-356.   Published online January 30, 2024
DOI: https://doi.org/10.4143/crt.2023.1302
AbstractAbstract PDFPubReaderePub
This review explores spatial mapping technologies in cancer research, highlighting their crucial role in understanding the complexities of the tumor microenvironment (TME). The TME, which is an intricate ecosystem of diverse cell types, has a significant impact on tumor dynamics and treatment outcomes. This review closely examines cutting-edge spatial mapping technologies, categorizing them into capture-, imaging-, and antibody-based approaches. Each technology was scrutinized for its advantages and disadvantages, factoring in aspects such as spatial profiling area, multiplexing capabilities, and resolution. Additionally, we draw attention to the nuanced choices researchers face, with capture-based methods lending themselves to hypothesis generation, and imaging/antibody-based methods that fit neatly into hypothesis testing. Looking ahead, we anticipate a scenario in which multi-omics data are seamlessly integrated, artificial intelligence enhances data analysis, and spatiotemporal profiling opens up new dimensions.

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  • Distinctive Phenotypic and Microenvironmental Characteristics of Neuroendocrine Carcinoma and Adenocarcinoma Components in Gastric Mixed Adenoneuroendocrine Carcinoma
    Yoonjin Kwak, Soo Kyung Nam, Yujun Park, Yun-Suhk Suh, Sang-Hoon Ahn, Seong-Ho Kong, Do Joong Park, Hyuk-Joon Lee, Hyung-Ho Kim, Han-Kwang Yang, Hye Seung Lee
    Modern Pathology.2024; 37(10): 100568.     CrossRef
  • Effector Function Characteristics of Exhausted CD8+ T-Cell in Microsatellite Stable and Unstable Gastric Cancer
    Dong-Seok Han, Yoonjin Kwak, Seungho Lee, Soo Kyung Nam, Seong-Ho Kong, Do Joong Park, Hyuk-Joon Lee, Nak-Jung Kwon, Hye Seung Lee, Han-Kwang Yang
    Cancer Research and Treatment.2024; 56(4): 1146.     CrossRef
  • 3,692 View
  • 233 Download
  • 1 Web of Science
  • 2 Crossref
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Original Articles
Gastrointestinal cancer
A Single-Arm Phase II Study of Nab-Paclitaxel Plus Gemcitabine and Cisplatin for Locally Advanced or Metastatic Biliary Tract Cancer
Ting Liu, Qing Li, Zhen Lin, Chunhua Liu, Wei Pu, Shasha Zeng, Jun Lai, Xuebin Cai, Lisha Zhang, Shuyang Wang, Miao Chen, Wei Cao, Hongfeng Gou, Qing Zhu
Cancer Res Treat. 2024;56(2):602-615.   Published online October 12, 2023
DOI: https://doi.org/10.4143/crt.2023.726
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Patients with advanced biliary tract cancer (BTC) have a poor survival. We aim to evaluate the efficacy and safety of nab-paclitaxel plus gemcitabine and cisplatin regimen in Chinese advanced BTC patients.
Materials and Methods
Eligible patients with locally advanced or metastatic BTC administrated intravenous 100 mg/m2 nab-paclitaxel, 800 mg/m2 gemcitabine, and 25 mg/m2 cisplatin every 3 weeks. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS) and adverse events, while exploratory endpoint was the association of biomarkers with efficacy.
Results
After the median follow-up of 25.0 months, the median PFS and OS of 34 enrolled patients were 7.1 months (95% confidence interval [CI], 5.4 to 13.7) and 16.4 months (95% CI, 10.9 to 23.6), respectively. The most common treatment-related adverse events at ≥ 3 grade were neutropenia (26.5%) and leukopenia (26.5%). Survival analyses demonstrated that carcinoembryonic antigen (CEA) levels could monitor patients’ survival outcomes. A significant increase in the number of infiltrating CD4+ cells (p=0.008) and a decrease in programmed death-1–positive (PD-1+) cells (p=0.032) were observed in the response patients.
Conclusion
In advanced BTC patients, nab-paclitaxel plus gemcitabine and cisplatin regimen showed therapeutic potential. Potential prognostic factors of CEA levels, number of CD4+ cells and PD-1+ cells may help us maximize the efficacy benefit.

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  • Efficacy and biomarker analysis of second‐line nab‐paclitaxel plus sintilimab in patients with advanced biliary tract cancer
    Xiaofen Li, Nan Zhou, Yu Yang, Zijian Lu, Hongfeng Gou
    Cancer Science.2024; 115(7): 2371.     CrossRef
  • 3,274 View
  • 152 Download
  • 1 Web of Science
  • 1 Crossref
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Lung and Thoracic cancer
Histone Deacetylase as a Valuable Predictive Biomarker and Therapeutic Target in Immunotherapy for Non-Small Cell Lung Cancer
Hyun-Seock Shin, Juwhan Choi, Jinhwan Lee, Sung Yong Lee
Cancer Res Treat. 2022;54(2):458-468.   Published online September 10, 2021
DOI: https://doi.org/10.4143/crt.2021.425
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Histone deacetylase inhibitors (HDACis) are epigenetic regulators and used clinically for hematopoietic malignancies. Recently, HDACis have received attention as a factor that modulates the immune system. In this study, the role of histone deacetylase (HDAC) expression as a predictive marker in lung cancer patients who were treated with immune checkpoint inhibitors (ICIs) and the role of HDACi and ICI combination treatment in the mouse tumor model were analyzed.
Materials and Methods
The overall response rate (ORR) and progression-free survival (PFS) were analyzed by the expression of HDAC. In vitro assay, the mRNA and protein expression levels of cytokines and programmed death-ligand 1 (PD-L1) were analyzed after HDACi treatment. In vivo assay, TC-1 tumor-bearing mice were treated with HDACi and mouse programmed cell death 1 (PD-1) inhibitor.
Results
The HDAC6 low expression group showed high ORR and prolonged PFS. When the selective HDAC6 inhibitor was administered to the A549 cell line, the levels of interleukin-1β and interleukin-6 decreased and the expression of PD-L1 was reduced. Mice that received both the mouse PD-1 inhibitor and pan-HDACi had a smaller tumor size than that of the mice from the control group. Moreover, mice treated with the mouse PD-1 inhibitor and pan-HDACi generated greater numbers of E7-specific CD8+ T cells.
Conclusion
HDAC6 expression can predict the prognosis of non–small cell lung cancerpatients who were treated with ICIs. Furthermore, co-treatment with HDACi and PD-1 inhibitor was shown to decrease the tumor growth rate and create a favorable tumor microenvironment for cytotoxic T lymphocytes in the TC-1 mouse model.

Citations

Citations to this article as recorded by  
  • Immunomodulatory properties of HDAC6 inhibitors in cancer diseases: New chances for sophisticated drug design and treatment optimization
    Bernhard Biersack, Bianca Nitzsche, Michael Höpfner
    Seminars in Cell & Developmental Biology.2024; 154: 286.     CrossRef
  • Regulation of PD-L1 Expression by YY1 in Cancer: Therapeutic Efficacy of Targeting YY1
    Ana Dillen, Indy Bui, Megan Jung, Stephanie Agioti, Apostolos Zaravinos, Benjamin Bonavida
    Cancers.2024; 16(6): 1237.     CrossRef
  • Reducing PD-L1 Expression by Degraders and Downregulators as a Novel Strategy to Target the PD-1/PD-L1 Pathway
    Zhijie Wang, Lin Yuan, Xiaotong Liao, Xia Guo, Jianjun Chen
    Journal of Medicinal Chemistry.2024; 67(8): 6027.     CrossRef
  • Dual molecule targeting HDAC6 leads to intratumoral CD4+ cytotoxic lymphocytes recruitment through MHC-II upregulation on lung cancer cells
    Sarah Ducellier, Mélanie Demeules, Boris Letribot, Massimiliano Gaetani, Chloé Michaudel, Harry Sokol, Abdallah Hamze, Mouad Alami, Mégane Nascimento, Sébastien Apcher
    Journal for ImmunoTherapy of Cancer.2024; 12(4): e007588.     CrossRef
  • Selective HDAC6 Inhibition Has the Potential for Anti-Cancer Effect in Renal Cell Carcinoma
    Tsutomu Anraku, Masaki Murata, Hiroo Kuroki, Akira Kazama, Yuko Shirono, Masayuki Tasaki, Vladimir Bilim, Yoshihiko Tomita
    Journal of Personalized Medicine.2024; 14(7): 704.     CrossRef
  • Epigenetic Modification of PD-1/PD-L1-Mediated Cancer Immunotherapy against Melanoma
    Hikaru Nanamori, Yu Sawada
    International Journal of Molecular Sciences.2022; 23(3): 1119.     CrossRef
  • Epigenetic Alterations and Inflammation as Emerging Use for the Advancement of Treatment in Non-Small Cell Lung Cancer
    Shuo Yang, Yang Huang, Qi Zhao
    Frontiers in Immunology.2022;[Epub]     CrossRef
  • Targeting HDAC6 to Overcome Autophagy-Promoted Anti-Cancer Drug Resistance
    Hyein Jo, Kyeonghee Shim, Dooil Jeoung
    International Journal of Molecular Sciences.2022; 23(17): 9592.     CrossRef
  • Epigenetic modifications: Critical participants of the PD‑L1 regulatory mechanism in solid tumors (Review)
    Xiaoran Ma, Jibiao Wu, Bin Wang, Cun Liu, Lijuan Liu, Changgang Sun
    International Journal of Oncology.2022;[Epub]     CrossRef
  • 6,736 View
  • 206 Download
  • 9 Web of Science
  • 9 Crossref
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Lymphoma
Forkhead Box C1 (FOXC1) Expression in Stromal Cells within the Microenvironment of T and NK Cell Lymphomas: Association with Tumor Dormancy and Activation
Ji Hae Nahm, Woo Ick Yang, Sun Och Yoon
Cancer Res Treat. 2020;52(4):1273-1282.   Published online July 3, 2020
DOI: https://doi.org/10.4143/crt.2020.032
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Forkhead box C1 (FOXC1) is critical for maintaining bone marrow microenvironments during hematopoiesis, but its role in hematological malignancies remains obscure. Here, we investigated whether FOXC1 regulates tumor dormancy and activation in the microenvironments of T and natural killer (NK) cell lymphomas.
Materials and Methods
One hundred and twenty cases of T and NK cell lymphomas were included; the immunohistochemical expression of FOXC1 was investigated in stromal cells, and numbers of FOXC1+ stromal cells were counted. Furthermore, the expression of phosphorylated p38 (p-p38) and phosphorylated ERK1/2 (p-ERK1/2) in tumor cells was investigated using immunohistochemistry.
Results
FOXC1 was variably expressed in C-X-C motif chemokine 12–associated reticular stromal cells, histiocytes, (myo)fibroblasts, and endothelial cells. The phenotypes of cases were categorized as dormant (high p-p38/low p-ERK1/2; n=30, 25.0%), active (high p-ERK1/2/low p-p38; n=25, 20.8%), or intermediate (others; n=65, 54.2%). Lower FOXC1+ stromal cell infiltration was associated with the dormant phenotype, the precursor T lymphoblastic leukemia/lymphoma subtype, and inferior overall survival rates, whereas higher FOXC1+ stromal cell infiltration was associated with the active phenotype and favorable patient prognosis (p < 0.05 for all).
Conclusion
These results suggested that FOXC1+ stromal cells within the microenvironments of T and NK cell lymphomas might be related to tumor phenotypes.

Citations

Citations to this article as recorded by  
  • Mechanisms of lymphoma-stromal interactions focusing on tumor-associated macrophages, fibroblastic reticular cells, and follicular dendritic cells
    Rintaro Ohe
    Journal of Clinical and Experimental Hematopathology.2024; 64(3): 166.     CrossRef
  • 6,542 View
  • 110 Download
  • 5 Web of Science
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High-Throughput Multiplex Immunohistochemical Imaging of the Tumor and Its Microenvironment
Jiwon Koh, Yoonjin Kwak, Jin Kim, Woo Ho Kim
Cancer Res Treat. 2020;52(1):98-108.   Published online May 27, 2019
DOI: https://doi.org/10.4143/crt.2019.195
AbstractAbstract PDFPubReaderePub
Purpose
The aim of this study was to develop a formalin-fixed paraffin-embedded (FFPE) tissue based multiplex immunochemistry (mIHC) method for high-throughput comprehensive tissue imaging and demonstrate its feasibility, validity, and usefulness.
Materials and Methods
The mIHC protocol was developed and tested on tissue microarray slides made from archived gastric cancer (GC) tissue samples. On a single FFPE slide, cyclic immunochemistry for multiple markers of immune cells and cytokeratin for tumor cells was performed; hematoxylin staining was used for demarcation of nuclei. Whole slides were digitally scanned after each cycle. For interpretation of mIHC results, we performed computer-assisted image analysis using publicly available software.
Results
Using mIHC, we were able to characterize the tumor microenvironment (TME) of GCs with accurate visualization of various immune cells harboring complex immunophenotypes. Spatial information regarding intratumoral and peritumoral TME could be demonstrated by digital segmentation of image guided by cytokeratin staining results. We further extended the application of mIHC by showing that subcellular localization of molecules can be achieved by image analysis of mIHC results.
Conclusion
We developed a robust method for high-throughput multiplex imaging of FFPE tissue slides. The feasibility and adaptability of mIHC suggest that it is an efficient method for in situ single-cell characterization and analysis.

Citations

Citations to this article as recorded by  
  • The immunologic phenotype of thrombi is associated with future vascular events after cerebral infarction
    Wookjin Yang, Soon Auck Hong, Jeong-Min Kim, Hae-Bong Jeong, Taek-Kyun Nam, Hyun Ho Choi, Suh Min Kim, Kwang-Yeol Park, Hye Ryoun Kim
    Journal of NeuroInterventional Surgery.2024; 16(4): 352.     CrossRef
  • The tumor immune microenvironment remodeling and response to HER2‐targeted therapy in HER2‐positive advanced gastric cancer
    Lei Jiang, Xingwang Zhao, Yilin Li, Yajie Hu, Yu Sun, Shengde Liu, Zizhen Zhang, Yanyan Li, Xujiao Feng, Jiajia Yuan, Jian Li, Xiaotian Zhang, Yang Chen, Lin Shen
    IUBMB Life.2024; 76(7): 420.     CrossRef
  • HCR spectral imaging: 10-plex, quantitative, high-resolution RNA and protein imaging in highly autofluorescent samples
    Samuel J. Schulte, Mark E. Fornace, John K. Hall, Grace J. Shin, Niles A. Pierce
    Development.2024;[Epub]     CrossRef
  • iRhom2 deficiency reduces sepsis-induced mortality associated with the attenuation of lung macrophages in mice
    Jihye Kim, Jee Hyun Kim, Younghoon Kim, Jooyoung Lee, Hyun Jung Lee, Seong-Joon Koh, Jong Pil Im, Joo Sung Kim
    Histochemistry and Cell Biology.2024; 162(5): 415.     CrossRef
  • Immunohistochemistry for assessing toxicity and mechanism of action of anticancer drugs during preclinical trials. From theory to practice
    M. A. Dodokhova, M. A. Akimenko, O. V. Voronova, M. S. Alkhusein-Kulyaginova, N. A. Kornienko, M. V. Gulyan, D. N. Gyulmamedov, M.-M. Kh. Alasheva, E. Sh. Kazimagomedova, D. B. Shpakovsky, E. R. Milaeva, I. M. Kotieva
    Fundamental and Clinical Medicine.2024; 9(3): 74.     CrossRef
  • Nontoxic Fluorescent Nanoprobes for Multiplexed Detection and 3D Imaging of Tumor Markers in Breast Cancer
    Pavel Sokolov, Galina Nifontova, Pavel Samokhvalov, Alexander Karaulov, Alyona Sukhanova, Igor Nabiev
    Pharmaceutics.2023; 15(3): 946.     CrossRef
  • Automatic generation of pathological benchmark dataset from hyperspectral images of double stained tissues
    Jiansheng Wang, Xintian Mao, Yan Wang, Xiang Tao, Junhao Chu, Qingli Li
    Optics & Laser Technology.2023; 163: 109331.     CrossRef
  • Heterogeneity of the Tumor Microenvironment Across Molecular Subtypes of Breast Cancer
    Dharambir Kashyap, Amanjit Bal, Santosh Irinike, Siddhant Khare, Shalmoli Bhattacharya, Ashim Das, Gurpreet Singh
    Applied Immunohistochemistry & Molecular Morphology.2023; 31(8): 533.     CrossRef
  • Exploring the Complex and Multifaceted Interplay between Melanoma Cells and the Tumor Microenvironment
    Magdalena Kuras
    International Journal of Molecular Sciences.2023; 24(18): 14403.     CrossRef
  • New insights into the tumour immune microenvironment of nasopharyngeal carcinoma
    Aisling Forder, Greg L. Stewart, Nikita Telkar, Wan L. Lam, Cathie Garnis
    Current Research in Immunology.2022; 3: 222.     CrossRef
  • Let us not forget about our past contributions to the field of prostatic neoplasms: To some extent what we value now was already there
    Rodolfo Montironi, Alessia Cimadamore, Marina Scarpelli, Liang Cheng, Antonio Lopez-Beltran, Gregor Mikuz
    Pathology - Research and Practice.2021; 219: 153377.     CrossRef
  • Programmed Death Ligand 1-Expressing Classical Dendritic Cells Mitigate -Induced Gastritis
    Du-Min Go, Seung Hyun Lee, Su-Hyung Lee, Sang-Ho Woo, Kibyeong Kim, Kyeongdae Kim, Kyu Seong Park, Jong-Hwan Park, Sang-Jun Ha, Woo Ho Kim, Jae-Hoon Choi, Dae-Yong Kim
    Cellular and Molecular Gastroenterology and Hepatology.2021; 12(2): 715.     CrossRef
  • Expression of the immune checkpoint receptors PD-1, LAG3, and TIM3 in the immune context of stage II and III gastric cancer by using single and chromogenic multiplex immunohistochemistry
    Yujun Park, An Na Seo, Jiwon Koh, Soo Kyoung Nam, Yoonjin Kwak, Sang-Hoon Ahn, Do Joong Park, Hyung-Ho Kim, Hye Seung Lee
    OncoImmunology.2021;[Epub]     CrossRef
  • Prognostic significance of natural killer cell-associated markers in gastric cancer: quantitative analysis using multiplex immunohistochemistry
    Hee Young Na, Yujun Park, Soo Kyung Nam, Jiwon Koh, Yoonjin Kwak, Sang-Hoon Ahn, Do Joong Park, Hyung-Ho Kim, Kyu Sang Lee, Hye Seung Lee
    Journal of Translational Medicine.2021;[Epub]     CrossRef
  • Cellular and Extracellular Components in Tumor Microenvironment and Their Application in Early Diagnosis of Cancers
    Rui Wei, Si Liu, Shutian Zhang, Li Min, Shengtao Zhu
    Analytical Cellular Pathology.2020; 2020: 1.     CrossRef
  • Towards a Systems Immunology Approach to Unravel Responses to Cancer Immunotherapy
    Laura Bracci, Alessandra Fragale, Lucia Gabriele, Federica Moschella
    Frontiers in Immunology.2020;[Epub]     CrossRef
  • 9,310 View
  • 490 Download
  • 16 Web of Science
  • 16 Crossref
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