دورية أكاديمية
The TOPK Inhibitor HI-TOPK-032 Enhances CAR T-cell Therapy of Hepatocellular Carcinoma by Upregulating Memory T Cells.
| العنوان: | The TOPK Inhibitor HI-TOPK-032 Enhances CAR T-cell Therapy of Hepatocellular Carcinoma by Upregulating Memory T Cells. |
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| المؤلفون: | Zhang Q; Section of Immunology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, P.R. China., Zheng F; Section of Immunology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, P.R. China., Chen Y; Section of Immunology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, P.R. China., Liang CL; Section of Immunology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, P.R. China., Liu H; Section of Immunology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, P.R. China., Qiu F; Section of Immunology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, P.R. China., Liu Y; Department of Medicine, Emory University School of Medicine, Atlanta, Georgia., Huang H; Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China., Lu W; Section of Immunology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, P.R. China., Dai Z; Section of Immunology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, P.R. China. |
| المصدر: | Cancer immunology research [Cancer Immunol Res] 2024 May 02; Vol. 12 (5), pp. 631-643. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 101614637 Publication Model: Print Cited Medium: Internet ISSN: 2326-6074 (Electronic) Linking ISSN: 23266066 NLM ISO Abbreviation: Cancer Immunol Res Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Philadelphia, PA : American Association for Cancer Research, [2013]- |
| مواضيع طبية MeSH: | Carcinoma, Hepatocellular*/therapy , Carcinoma, Hepatocellular*/immunology , Carcinoma, Hepatocellular*/pathology , Immunotherapy, Adoptive*/methods , Liver Neoplasms*/immunology , Liver Neoplasms*/therapy , Liver Neoplasms*/pathology , Memory T Cells*/drug effects , Memory T Cells*/immunology , Indolizines*/pharmacology , Indolizines*/therapeutic use , Quinoxalines*/pharmacology , Quinoxalines*/therapeutic use, Animals ; Humans ; Mice ; CD8-Positive T-Lymphocytes/immunology ; Cell Line, Tumor ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Receptors, Chimeric Antigen/immunology ; Tumor Microenvironment/immunology ; Xenograft Model Antitumor Assays |
| مستخلص: | Chimeric antigen receptor (CAR) T cells are emerging as an effective antitumoral therapy. However, their therapeutic effects on solid tumors are limited because of their short survival time and the immunosuppressive tumor microenvironment. Memory T cells respond more vigorously and persist longer than their naïve/effector counterparts. Therefore, promoting CAR T-cell development into memory T cells could further enhance their antitumoral effects. HI-TOPK-032 is a T-LAK cell-originated protein kinase (TOPK)-specific inhibitor that moderately represses some types of tumors. However, it is unknown whether HI-TOPK-032 works on hepatocellular carcinoma (HCC) and whether it impacts antitumoral immunity. Using both subcutaneous and orthotopic xenograft tumor models of two human HCC cell lines, Huh-7 and HepG2, we found that HI-TOPK-032 significantly improved proliferation/persistence of CD8+ CAR T cells, as evidenced by an increase in CAR T-cell counts or frequency of Ki-67+CD8+ cells and a decrease in PD-1+LAG-3+TIM-3+CD8+ CAR T cells in vivo. Although HI-TOPK-032 did not significantly suppress HCC growth, it enhanced the capacity of CAR T cells to inhibit tumor growth. Moreover, HI-TOPK-032 augmented central memory CD8+ T cell (TCM) frequency while increasing eomesodermin expression in CD8+ CAR T cells in tumor-bearing mice. Moreover, it augmented CD8+ CAR TCM cells in vitro and reduced their expression of immune checkpoint molecules. Finally, HI-TOPK-032 inhibited mTOR activation in CAR T cells in vitro and in tumors, whereas overactivation of mTOR reversed the effects of HI-TOPK-032 on CD8+ TCM cells and tumor growth. Thus, our studies have revealed mechanisms underlying the antitumoral effects of HI-TOPK-032 while advancing CAR T-cell immunotherapy. (©2024 American Association for Cancer Research.) |
| معلومات مُعتمدة: | 82104605 National Natural Science Foundation of China (NSFC); 2019A1515110741 Natural Science Foundation of Guangdong Province (); 202201020347 Guangzhou Municipal Science and Technology Bureau (GZST) |
| المشرفين على المادة: | 0 (N-(12-cyanoindolizino(2,3-b)quinoxalin-2-yl)thiophene-2-carboxamide) |
| تواريخ الأحداث: | Date Created: 20240226 Date Completed: 20240502 Latest Revision: 20240516 |
| رمز التحديث: | 20240516 |
| DOI: | 10.1158/2326-6066.CIR-23-0587 |
| PMID: | 38407902 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 2326-6074 |
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| DOI: | 10.1158/2326-6066.CIR-23-0587 |