|
1
|
Li J, Zhang Y, Hu L, Ye H, Yan X, Li X, Li Y, Ye S, Wu B, Li Z. T-cell Receptor Repertoire Analysis in the Context of Transarterial Chemoembolization Synergy with Systemic Therapy for Hepatocellular Carcinoma. J Clin Transl Hepatol 2025; 13:69-83. [PMID: 39801788 PMCID: PMC11712086 DOI: 10.14218/jcth.2024.00238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 10/03/2024] [Accepted: 10/25/2024] [Indexed: 01/16/2025] Open
Abstract
T-cell receptor (TCR) sequencing provides a novel platform for insight into and characterization of intricate T-cell profiles, advancing the understanding of tumor immune heterogeneity. Recently, transarterial chemoembolization (TACE) combined with systemic therapy has become the recommended regimen for advanced hepatocellular carcinoma. The regulation of the immune microenvironment after TACE and its impact on tumor progression and recurrence has been a focus of research. By examining and tracking fluctuations in the TCR repertoire following combination treatment, novel perspectives on the modulation of the tumor microenvironment post-TACE and the underlying mechanisms governing tumor progression and recurrence can be gained. Clarifying the distinctive metrics and dynamic alterations of the TCR repertoire within the context of combination therapy is imperative for understanding the mechanisms of anti-tumor immunity, assessing efficacy, exploiting novel treatments, and further advancing precision oncology in the treatment of hepatocellular carcinoma. In this review, we initially summarized the fundamental characteristics of TCR repertoire and depicted immune microenvironment remodeling after TACE. Ultimately, we illustrated the prospective applications of TCR repertoires in TACE combined with systemic therapy.
Collapse
Affiliation(s)
- Jie Li
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Engineering Technology Research Center for Minimally Invasive Interventional Tumors of Henan Province, Zhengzhou, Henan, China
| | - Yuyuan Zhang
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Engineering Technology Research Center for Minimally Invasive Interventional Tumors of Henan Province, Zhengzhou, Henan, China
| | - Luqi Hu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Engineering Technology Research Center for Minimally Invasive Interventional Tumors of Henan Province, Zhengzhou, Henan, China
| | - Heqing Ye
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Engineering Technology Research Center for Minimally Invasive Interventional Tumors of Henan Province, Zhengzhou, Henan, China
| | - Xingli Yan
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Engineering Technology Research Center for Minimally Invasive Interventional Tumors of Henan Province, Zhengzhou, Henan, China
| | - Xin Li
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Engineering Technology Research Center for Minimally Invasive Interventional Tumors of Henan Province, Zhengzhou, Henan, China
| | - Yifan Li
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Engineering Technology Research Center for Minimally Invasive Interventional Tumors of Henan Province, Zhengzhou, Henan, China
| | - Shuwen Ye
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Engineering Technology Research Center for Minimally Invasive Interventional Tumors of Henan Province, Zhengzhou, Henan, China
| | - Bailu Wu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Engineering Technology Research Center for Minimally Invasive Interventional Tumors of Henan Province, Zhengzhou, Henan, China
| | - Zhen Li
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Engineering Technology Research Center for Minimally Invasive Interventional Tumors of Henan Province, Zhengzhou, Henan, China
| |
Collapse
|
|
2
|
Zhang M, Huang K, Yin Q, Wu X, Zhu M, Li M. Spatial heterogeneity of the hepatocellular carcinoma microenvironment determines the efficacy of immunotherapy. Discov Oncol 2025; 16:15. [PMID: 39775241 PMCID: PMC11706828 DOI: 10.1007/s12672-025-01747-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Accepted: 01/02/2025] [Indexed: 01/11/2025] Open
Abstract
Hepatocellular carcinoma (HCC) remains a global health challenge owing to its widespread incidence and high mortality. HCC has a specific immune tolerance function because of its unique physiological structure, which limits the efficacy of chemotherapy, radiotherapy, and molecular targeting. In recent years, new immune approaches, including adoptive cell therapy, tumor vaccines, and oncolytic virus therapy, have shown great potential. As the efficacy of immunotherapy mainly depends on the spatial heterogeneity of the tumor immune microenvironment, it is necessary to elucidate the crosstalk between the composition of the liver cancer immune environment, from which potential therapeutic targets can be selected to provide more appropriate individualized treatment programs. The role of spatial heterogeneity of immune cells in the microenvironment of HCC in the progression and influence of immunotherapy on improving the treatment and prognosis of HCC were comprehensively analyzed, providing new inspiration for the subsequent clinical treatment of liver cancer.
Collapse
Affiliation(s)
- Minni Zhang
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou, 571199, Hainan, People's Republic of China
- The First Affiliated Hospital, Key Laboratory of Emergency and Trauma of Ministry of Education, Engineering Research Center for Hainan Biological Sample Resources of Major Diseases, The Hainan Branch of National Clinical Research Center for Cancer, Hainan Medical University, Haikou, 570102, Hainan, People's Republic of China
| | - Kailin Huang
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou, 571199, Hainan, People's Republic of China
| | - Qiushi Yin
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou, 571199, Hainan, People's Republic of China
| | - Xueqin Wu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou, 571199, Hainan, People's Republic of China
| | - Mingyue Zhu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou, 571199, Hainan, People's Republic of China.
| | - Mengsen Li
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou, 571199, Hainan, People's Republic of China.
- Department of Medical Oncology, Second Affiliated Hospital, Hainan Medical University, Haikou, 570023, Hainan, People's Republic of China.
- Key Laboratory of Tropical Translational Medicine, Ministry of Education, Hainan Medical University, Haikou, 571199, Hainan, People's Republic of China.
| |
Collapse
|
|
3
|
Shi Y, Wang Z, Xu J, Niu W, Wu Y, Guo H, Shi J, Li Z, Fu B, Hong Y, Wang Z, Guo W, Chen D, Li X, Li Q, Wang S, Gao J, Sun A, Xiao Y, Cao J, Fu L, Wu Y, Zhang T, Xia N, Yuan Q. TCR-like bispecific antibodies toward eliminating infected hepatocytes in HBV mouse models. Emerg Microbes Infect 2024; 13:2387448. [PMID: 39109538 PMCID: PMC11313007 DOI: 10.1080/22221751.2024.2387448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 07/19/2024] [Accepted: 07/30/2024] [Indexed: 08/10/2024]
Abstract
Therapeutics for eradicating hepatitis B virus (HBV) infection are still limited and current nucleos(t)ide analogs (NAs) and interferon are effective in controlling viral replication and improving liver health, but they cannot completely eradicate the hepatitis B virus and only a very small number of patients are cured of it. The TCR-like antibodies recognizing viral peptides presented on human leukocyte antigens (HLA) provide possible tools for targeting and eliminating HBV-infected hepatocytes. Here, we generated three TCR-like antibodies targeting three different HLA-A2.1-presented peptides derived from HBV core and surface proteins. Bispecific antibodies (BsAbs) were developed by fuzing variable fragments of these TCR-like mAbs with an anti-CD3ϵ antibody. Our data demonstrate that the BsAbs could act as T cell engagers, effectively redirecting and activating T cells to target HBV-infected hepatocytes in vitro and in vivo. In HBV-persistent mice expressing human HLA-A2.1, two infusions of BsAbs induced marked and sustained suppression in serum HBsAg levels and also reduced the numbers of HBV-positive hepatocytes. These findings highlighted the therapeutic potential of TCR-like BsAbs as a new strategy to cure hepatitis B.
Collapse
Affiliation(s)
- Yang Shi
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, People’s Republic of China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostic, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, People’s Republic of China
| | - Zihan Wang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, People’s Republic of China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostic, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, People’s Republic of China
| | - Jingjing Xu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, People’s Republic of China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostic, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, People’s Republic of China
| | - Wenxia Niu
- Department of Infectious Disease, Xiang’an Hospital of Xiamen University, Xiamen University, Xiamen, People’s Republic of China
| | - Yubin Wu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, People’s Republic of China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostic, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, People’s Republic of China
| | - Huiyu Guo
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, People’s Republic of China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostic, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, People’s Republic of China
| | - Jinmiao Shi
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, People’s Republic of China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostic, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, People’s Republic of China
| | - Zonglin Li
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, People’s Republic of China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostic, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, People’s Republic of China
| | - Baorong Fu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, People’s Republic of China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostic, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, People’s Republic of China
| | - Yunda Hong
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, People’s Republic of China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostic, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, People’s Republic of China
| | - Zikang Wang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, People’s Republic of China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostic, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, People’s Republic of China
| | - Wenjie Guo
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, People’s Republic of China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostic, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, People’s Republic of China
| | - Dabing Chen
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, People’s Republic of China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostic, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, People’s Republic of China
| | - Xingling Li
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, People’s Republic of China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostic, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, People’s Republic of China
| | - Qian Li
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, People’s Republic of China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostic, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, People’s Republic of China
| | - Shaojuan Wang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, People’s Republic of China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostic, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, People’s Republic of China
| | - Jiahua Gao
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, People’s Republic of China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostic, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, People’s Republic of China
| | - Aling Sun
- Department of Infectious Disease, Xiang’an Hospital of Xiamen University, Xiamen University, Xiamen, People’s Republic of China
| | - Yaosheng Xiao
- Department of Infectious Disease, Xiang’an Hospital of Xiamen University, Xiamen University, Xiamen, People’s Republic of China
| | - Jiali Cao
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, People’s Republic of China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostic, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, People’s Republic of China
- Department of Clinical Laboratory, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen, People’s Republic of China
| | - Lijuan Fu
- Department of Infectious Disease, Xiang’an Hospital of Xiamen University, Xiamen University, Xiamen, People’s Republic of China
| | - Yangtao Wu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, People’s Republic of China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostic, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, People’s Republic of China
| | - Tianying Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, People’s Republic of China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostic, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, People’s Republic of China
| | - Ningshao Xia
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, People’s Republic of China
| | - Quan Yuan
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, People’s Republic of China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostic, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, People’s Republic of China
| |
Collapse
|
|
4
|
Murugesan G, Paterson RL, Kulkarni R, Ilkow V, Suckling RJ, Connolly MM, Karuppiah V, Pengelly R, Jadhav A, Donoso J, Heunis T, Bunjobpol W, Philips G, Ololade K, Kay D, Sarkar A, Barber C, Raj R, Perot C, Grant T, Treveil A, Walker A, Dembek M, Gibbs-Howe D, Hock M, Carreira RJ, Atkin KE, Dorrell L, Knox A, Leonard S, Salio M, Godinho LF. Viral sequence determines HLA-E-restricted T cell recognition of hepatitis B surface antigen. Nat Commun 2024; 15:10126. [PMID: 39578466 PMCID: PMC11584656 DOI: 10.1038/s41467-024-54378-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 11/08/2024] [Indexed: 11/24/2024] Open
Abstract
The non-polymorphic HLA-E molecule offers opportunities for new universal immunotherapeutic approaches to chronic infectious diseases. Chronic Hepatitis B virus (HBV) infection is driven in part by T cell dysfunction due to elevated levels of the HBV envelope (Env) protein hepatitis B surface antigen (HBsAg). Here we report the characterization of three genotypic variants of an HLA-E-binding HBsAg peptide, Env371-379, identified through bioinformatic predictions and verified by biochemical and cellular assays. Using a soluble affinity-enhanced T cell receptor (TCR) (a09b08)-anti-CD3 bispecific molecule to probe HLA-E presentation of the Env371-379 peptides, we demonstrate that only the most stable Env371-379 variant, L6I, elicits functional responses to a09b08-anti-CD3-redirected polyclonal T cells co-cultured with targets expressing endogenous HBsAg. Furthermore, HLA-E-Env371-379 L6I-specific CD8+ T cells are detectable in HBV-naïve donors and people with chronic HBV after in vitro priming. In conclusion, we provide evidence for HLA-E-mediated HBV Env peptide presentation, and highlight the effect of viral mutations on the stability and targetability of pHLA-E molecules.
Collapse
Affiliation(s)
| | | | - Rakesh Kulkarni
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Veronica Ilkow
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | | | - Mary M Connolly
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | | | - Robert Pengelly
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Archana Jadhav
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Jose Donoso
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Tiaan Heunis
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | | | - Gwilym Philips
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Kafayat Ololade
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Daniel Kay
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Anshuk Sarkar
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Claire Barber
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Ritu Raj
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Carole Perot
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Tressan Grant
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Agatha Treveil
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Andrew Walker
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Marcin Dembek
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Dawn Gibbs-Howe
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Miriam Hock
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | | | - Kate E Atkin
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Lucy Dorrell
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Andrew Knox
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Sarah Leonard
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Mariolina Salio
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Luis F Godinho
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK.
| |
Collapse
|
|
5
|
Gong Q, Zhang L, Guo J, Zhao W, Zhou B, Yang C, Jiang N. FBXO family genes promotes hepatocellular carcinoma via ubiquitination of p53. J Cancer Res Clin Oncol 2024; 150:458. [PMID: 39397119 PMCID: PMC11471714 DOI: 10.1007/s00432-024-05948-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 09/10/2024] [Indexed: 10/15/2024]
Abstract
FBXO protein family plays an essential role in the ubiquitination process acting as E3 ligases, which may contribute to the progression of cancers. However, the molecular functions of FBXOs in hepatocellular carcinoma (HCC) remain incompletely understood. Here, we investigated the overlapping genes between the FBXOs and differentially expressed genes (DEGs) of HCC identified by utilizing The Cancer Genome Atlas (TCGA) dataset, then, a prognostic model with effective predictive capacity was constructed based on the uni-cox and LASSO regression analyses. To elucidate the underlying mechanism of the FBXO model genes, KEGG analysis was carried out. Drug metabolism-cytochrome P450 and retinol metabolism were revealed as the potential pathway, which Increased the credibility of subsequent drug prediction research. Meanwhile, patients divided by the prognostic model showed a different immune infiltrating status and we also found FBXO model genes may ubiquitinate P53, inducing TP53 more prone to mutations, thereby promoting the occurrence and development of tumors. Consistent with these findings, the result of immunohistochemistry (IHC) validated an elevated expression of these model genes in HCC tissues than in the adjacent tissues. The primary aim of this investigation is to formulate a prognostic model while exploring the underlying mechanisms associated with FBXO genes in HCC. These findings offer initial research perspectives on the involvement of FBXO genes in HCC and contribute to the discovery of dependable biomarkers for the management, prognostication, and early detection of HCC in patients.
Collapse
Affiliation(s)
- Qingge Gong
- Chongqing Medical University, Chongqing, China
| | - La Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jiao Guo
- School of Basic Medical Science, Chongqing Medical University, Chongqing, China
| | - Wei Zhao
- School of Basic Medical Science, Chongqing Medical University, Chongqing, China
| | - Baoyong Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Changhong Yang
- Department of Bioinformatics, Chongqing Medical University, Chongqing, People's Republic of China.
| | - Ning Jiang
- Department of Pathology, Chongqing Medical University, Chongqing, China.
- Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, Chongqing, China.
- Department of Pathology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| |
Collapse
|
|
6
|
Yue B, Gao Y, Hu Y, Zhan M, Wu Y, Lu L. Harnessing CD8 + T cell dynamics in hepatitis B virus-associated liver diseases: Insights, therapies and future directions. Clin Transl Med 2024; 14:e1731. [PMID: 38935536 PMCID: PMC11210506 DOI: 10.1002/ctm2.1731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 05/16/2024] [Accepted: 05/21/2024] [Indexed: 06/29/2024] Open
Abstract
Hepatitis B virus (HBV) infection playsa significant role in the etiology and progression of liver-relatedpathologies, encompassing chronic hepatitis, fibrosis, cirrhosis, and eventual hepatocellularcarcinoma (HCC). Notably, HBV infection stands as the primary etiologicalfactor driving the development of HCC. Given the significant contribution ofHBV infection to liver diseases, a comprehensive understanding of immunedynamics in the liver microenvironment, spanning chronic HBV infection,fibrosis, cirrhosis, and HCC, is essential. In this review, we focused on thefunctional alterations of CD8+ T cells within the pathogenic livermicroenvironment from HBV infection to HCC. We thoroughly reviewed the roles ofhypoxia, acidic pH, metabolic reprogramming, amino acid deficiency, inhibitory checkpointmolecules, immunosuppressive cytokines, and the gut-liver communication in shapingthe dysfunction of CD8+ T cells in the liver microenvironment. Thesefactors significantly impact the clinical prognosis. Furthermore, we comprehensivelyreviewed CD8+ T cell-based therapy strategies for liver diseases,encompassing HBV infection, fibrosis, cirrhosis, and HCC. Strategies includeimmune checkpoint blockades, metabolic T-cell targeting therapy, therapeuticT-cell vaccination, and adoptive transfer of genetically engineered CD8+ T cells, along with the combined usage of programmed cell death protein-1/programmeddeath ligand-1 (PD-1/PD-L1) inhibitors with mitochondria-targeted antioxidants.Given that targeting CD8+ T cells at various stages of hepatitis Bvirus-induced hepatocellular carcinoma (HBV + HCC) shows promise, we reviewedthe ongoing need for research to elucidate the complex interplay between CD8+ T cells and the liver microenvironment in the progression of HBV infection toHCC. We also discussed personalized treatment regimens, combining therapeuticstrategies and harnessing gut microbiota modulation, which holds potential forenhanced clinical benefits. In conclusion, this review delves into the immunedynamics of CD8+ T cells, microenvironment changes, and therapeuticstrategies within the liver during chronic HBV infection, HCC progression, andrelated liver diseases.
Collapse
Affiliation(s)
- Bing Yue
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Jinan UniversityZhuhaiGuangdongChina
| | - Yuxia Gao
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Jinan UniversityZhuhaiGuangdongChina
| | - Yi Hu
- Microbiology and Immunology DepartmentSchool of MedicineFaculty of Medical ScienceJinan UniversityGuangzhouGuangdongChina
| | - Meixiao Zhan
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Jinan UniversityZhuhaiGuangdongChina
| | - Yangzhe Wu
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Jinan UniversityZhuhaiGuangdongChina
| | - Ligong Lu
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Jinan UniversityZhuhaiGuangdongChina
| |
Collapse
|
|
7
|
Zhao X, Shao S, Hu L. The recent advancement of TCR-T cell therapies for cancer treatment. Acta Biochim Biophys Sin (Shanghai) 2024; 56:663-674. [PMID: 38557898 PMCID: PMC11187488 DOI: 10.3724/abbs.2024034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Accepted: 03/06/2024] [Indexed: 04/04/2024] Open
Abstract
Adoptive cell therapies involve infusing engineered immune cells into cancer patients to recognize and eliminate tumor cells. Adoptive cell therapy, as a form of living drug, has undergone explosive growth over the past decade. The recognition of tumor antigens by the T-cell receptor (TCR) is one of the natural mechanisms that the immune system used to eliminate tumor cells. TCR-T cell therapy, which involves introducing exogenous TCRs into patients' T cells, is a novel cell therapy strategy. TCR-T cell therapy can target the entire proteome of cancer cells. Engineering T cells with exogenous TCRs to help patients combat cancer has achieved success in clinical trials, particularly in treating solid tumors. In this review, we examine the progress of TCR-T cell therapy over the past five years. This includes the discovery of new tumor antigens, protein engineering techniques for TCR, reprogramming strategies for TCR-T cell therapy, clinical studies on TCR-T cell therapy, and the advancement of TCR-T cell therapy in China. We also propose several potential directions for the future development of TCR-T cell therapy.
Collapse
Affiliation(s)
- Xiang Zhao
- />Key Laboratory of Multi-Cell SystemsShanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceChinese Academy of SciencesShanghai200031China
| | - Shuai Shao
- />Key Laboratory of Multi-Cell SystemsShanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceChinese Academy of SciencesShanghai200031China
| | - Lanxin Hu
- />Key Laboratory of Multi-Cell SystemsShanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceChinese Academy of SciencesShanghai200031China
| |
Collapse
|
|
8
|
Ali FEM, Ibrahim IM, Althagafy HS, Hassanein EHM. Role of immunotherapies and stem cell therapy in the management of liver cancer: A comprehensive review. Int Immunopharmacol 2024; 132:112011. [PMID: 38581991 DOI: 10.1016/j.intimp.2024.112011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 04/01/2024] [Accepted: 04/02/2024] [Indexed: 04/08/2024]
Abstract
Liver cancer (LC) is the sixth most common disease and the third most common cause of cancer-related mortality. The WHO predicts that more than 1 million deaths will occur from LC by 2030. Hepatocellular carcinoma (HCC) is a common form of primary LC. Today, the management of LC involves multiple disciplines, and multimodal therapy is typically selected on an individual basis, considering the intricate interactions between the patient's overall health, the stage of the tumor, and the degree of underlying liver disease. Currently, the treatment of cancers, including LC, has undergone a paradigm shift in the last ten years because of immuno-oncology. To treat HCC, immune therapy approaches have been developed to enhance or cause the body's natural immune response to specifically target tumor cells. In this context, immune checkpoint pathway inhibitors, engineered cytokines, adoptive cell therapy, immune cells modified with chimeric antigen receptors, and therapeutic cancer vaccines have advanced to clinical trials and offered new hope to cancer patients. The outcomes of these treatments are encouraging. Additionally, treatment using stem cells is a new approach for restoring deteriorated tissues because of their strong differentiation potential and capacity to release cytokines that encourage cell division and the formation of blood vessels. Although there is no proof that stem cell therapy works for many types of cancer, preclinical research on stem cells has shown promise in treating HCC. This review provides a recent update regarding the impact of immunotherapy and stem cells in HCC and promising outcomes.
Collapse
Affiliation(s)
- Fares E M Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut, 71524, Egypt; Michael Sayegh, Faculty of Pharmacy, Aqaba University of Technology, Aqaba 77110, Jordan.
| | - Islam M Ibrahim
- Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524, Egypt
| | - Hanan S Althagafy
- Department of Biochemistry, Faculty of Science, University of Jeddah, Jeddah, Saudi Arabia
| | - Emad H M Hassanein
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut, 71524, Egypt
| |
Collapse
|
|
9
|
Amissah OB, Basnet R, Chen W, Habimana JDD, Baiden BE, Owusu OA, Saeed BJ, Li Z. Enhancing antitumor response by efficiently generating large-scale TCR-T cells targeting a single epitope across multiple cancer antigens. Cell Immunol 2024; 399-400:104827. [PMID: 38733699 DOI: 10.1016/j.cellimm.2024.104827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 04/26/2024] [Accepted: 05/07/2024] [Indexed: 05/13/2024]
Abstract
The need to contrive interventions to curb the rise in cancer incidence and mortality is critical for improving patients' prognoses. Adoptive cell therapy is challenged with quality large-scale production, heightening its production cost. Several cancer types have been associated with the expression of highly-immunogenic CTAG1 and CTAG2 antigens, which share common epitopes. Targeting two antigens on the same cancer could improve the antitumor response of TCR-T cells. In this study, we exploited an efficient way to generate large-fold quality TCR-T cells and also demonstrated that the common epitopes of CTAG1 and CTAG2 antigens provide an avenue for improved cancer-killing via dual-antigen-epitope targeting. Our study revealed that xeno/sera-free medium could expand TCR-T cells to over 500-fold, posing as a better replacement for FBS-supplemented media. Human AB serum was also shown to be a good alternative in the absence of xeno/sera-free media. Furthermore, TCR-T cells stimulated with beads-coated T-activator showed a better effector function than soluble T-activator stimulated TCR-T cells. Additionally, TCR-T cells that target multiple antigens in the same cancer yield better anticancer activity than those targeting a single antigen. This showed that targeting multiple antigens with a common epitope may enhance the antitumor response efficacy of T cell therapies.
Collapse
Affiliation(s)
- Obed Boadi Amissah
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Shijingshan District, Beijing 100049, China
| | - Rajesh Basnet
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Shijingshan District, Beijing 100049, China
| | - Wenfang Chen
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Shijingshan District, Beijing 100049, China
| | - Jean de Dieu Habimana
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Belinda Edwina Baiden
- College of Health Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Osei Asibey Owusu
- Department of Clinical and Medical Sciences, University of Exeter, Exeter, UK
| | - Babangida Jabir Saeed
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Zhiyuan Li
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Shijingshan District, Beijing 100049, China; GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha 410013, China.
| |
Collapse
|
|
10
|
Wang L, Liang Z, Guo Y, Habimana JDD, Ren Y, Amissah OB, Mukama O, Peng S, Ding X, Lv L, Li J, Chen M, Liu Z, Huang R, Zhang Y, Li Y, Li Z, Sun Y. STING agonist diABZI enhances the cytotoxicity of T cell towards cancer cells. Cell Death Dis 2024; 15:265. [PMID: 38615022 PMCID: PMC11016101 DOI: 10.1038/s41419-024-06638-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 03/28/2024] [Accepted: 04/02/2024] [Indexed: 04/15/2024]
Abstract
Antigen-specific T cell receptor-engineered T cell (TCR-T) based immunotherapy has proven to be an effective method to combat cancer. In recent years, cross-talk between the innate and adaptive immune systems may be requisite to optimize sustained antigen-specific immunity, and the stimulator of interferon genes (STING) is a promising therapeutic target for cancer immunotherapy. The level of expression or presentation of antigen in tumor cells affects the recognition and killing of tumor cells by TCR-T. This study aimed at investigating the potential of innate immune stimulation of T cells and engineered T cells to enhance immunotherapy for low-expression antigen cancer cells. We systematically investigated the function and mechanism of cross-talk between STING agonist diABZI and adaptive immune systems. We established NY-ESO-1 full knockout Mel526 cells for this research and found that diABZI activated STING media and TCR signaling pathways. In addition, the results of flow cytometry showed that antigens presentation from cancer cells induced by STING agonist diABZI also improved the affinity of TCR-T cells function against tumor cells in vitro and in vivo. Our findings revealed that diABZI enhanced the immunotherapy efficacy of TCR-T by activating STING media and TCR signaling pathways, improving interferon-γ expression, and increasing antigens presentation of tumor cells. This indicates that STING agonist could be used as a strategy to promote TCR-T cancer immunotherapy.
Collapse
Affiliation(s)
- Ling Wang
- Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Zhaoduan Liang
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health GuangDong Laboratory), Guangzhou, 510005, China
| | - Yunzhuo Guo
- Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Jean de Dieu Habimana
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Yuefei Ren
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Obed Boadi Amissah
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Omar Mukama
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- Department of Biology, College of Science and Technology, University of Rwanda, Kigali, 3900, Rwanda
| | - Siqi Peng
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong, China
| | - Xuanyan Ding
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Linshuang Lv
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Junyi Li
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Min Chen
- Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Zhaoming Liu
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Rongqi Huang
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Yinchao Zhang
- Department of Breast Surgery, Second Hospital of Jilin University, Changchun, 130022, China
| | - Yi Li
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong, China.
| | - Zhiyuan Li
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
- GZMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, 510530, China.
| | - Yirong Sun
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
| |
Collapse
|
|
11
|
Kamiya H, Komatsu S, Takashima Y, Ishida R, Arakawa H, Nishibeppu K, Kiuchi J, Imamura T, Ohashi T, Shimizu H, Arita T, Konishi H, Shiozaki A, Kubota T, Fujiwara H, Yagyu S, Iehara T, Otsuji E. Low blood level of tumour suppressor miR-5193 as a target of immunotherapy to PD-L1 in gastric cancer. Br J Cancer 2024; 130:671-681. [PMID: 38148376 PMCID: PMC10876550 DOI: 10.1038/s41416-023-02532-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 11/19/2023] [Accepted: 11/30/2023] [Indexed: 12/28/2023] Open
Abstract
BACKGROUND Recent studies have identified that low levels of some tumour suppressor microRNAs (miRNAs) in the blood contribute to tumour progression and poor outcomes in various cancers. However, no study has proved these miRNAs are associated with cancer immune mechanisms. METHODS From a systematic review of the NCBI and miRNA databases, four tumour suppressor miRNA candidates were selected (miR-5193, miR-4443, miR-520h, miR-496) that putatively target programmed cell death ligand 1 (PD-L1). RESULTS Test-scale and large-scale analyses revealed that plasma levels of miR-5193 were significantly lower in gastric cancer (GC) patients than in healthy volunteers (HVs). Low plasma levels of miR-5193 were associated with advanced pathological stages and were an independent prognostic factor. Overexpression of miR-5193 in GC cells suppressed PD-L1 on the surface of GC cells, even with IFN-γ stimulation. In the coculture model of GC cells and T cells stimulated by anti-CD3/anti-CD28 beads, overexpression of miR-5193 increased anti-tumour activity of T cells by suppressing PD-L1 expression. Subcutaneous injection of miR-5193 also significantly enhanced the tumour-killing activity and trafficking of T cells in mice. CONCLUSIONS Low blood levels of miR-5193 are associated with GC progression and poor outcomes and could be a target of nucleic acid immunotherapy in GC patients.
Collapse
Affiliation(s)
- Hajime Kamiya
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Shuhei Komatsu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.
| | - Yusuke Takashima
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Ryo Ishida
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hiroshi Arakawa
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Keiji Nishibeppu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Jun Kiuchi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Taisuke Imamura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Takuma Ohashi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hiroki Shimizu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Tomohiro Arita
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Takeshi Kubota
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hitoshi Fujiwara
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Shigeki Yagyu
- Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
- Center for Advanced Research of Gene and Cell Therapy in Shinshu University (CARS), Shinshu University School of Medicine, Matsumoto, Japan
| | - Tomoko Iehara
- Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| |
Collapse
|
|
12
|
Ge J, Chen J, Shen Q, Zheng X, Chen X, Shi L, Chen L, Xu B. Comprehensive Analysis of the Immunosuppressive Function of Regulatory T Cells in Human Hepatocellular Carcinoma Tissues. Cancer Control 2024; 31:10732748241251580. [PMID: 38712609 DOI: 10.1177/10732748241251580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/08/2024] Open
Abstract
BACKGROUND Immune-based therapies are commonly employed to combat hepatocellular carcinoma (HCC). However, the presence of immune-regulating elements, especially regulatory T cells (Tregs), can dramatically impact the treatment efficacy. A deeper examination of the immune-regulation mechanisms linked to these inhibitory factors and their impact on HCC patient outcomes is warranted. METHODS We employed multicolor fluorescence immunohistochemistry (mIHC) to stain Foxp3, cytokeratin, and nuclei on an HCC tissue microarray (TMA). Leveraging liver cancer transcriptome data from TCGA, we built a prognostic model focused on Treg-associated gene sets and represented it with a nomogram. We then sourced liver cancer single-cell RNA sequencing data (GSE140228) from the GEO database, selectively focusing on Treg subsets, and conducted further analyses, including cell-to-cell communication and pseudo-time trajectory examination. RESULTS Our mIHC results revealed a more substantial presence of Foxp3+Tregs in HCC samples than in adjacent normal tissue samples (P < .001). An increased presence of Foxp3+Tregs in HCC samples correlated with unfavorable patient outcomes (HR = 1.722, 95% CI:1.023-2.899, P = .041). The multi-factorial prognosis model we built from TCGA liver cancer data highlighted Tregs as a standalone risk determinant for predicting outcomes (HR = 3.84, 95% CI:2.52-5.83, P < .001). Re-analyzing the scRNA-seq dataset (GSE140228) showcased distinctive gene expression patterns in Tregs from varying tissues. Interactions between Tregs and other CD4+T cell types were predominantly governed by the CXCL13/CXCR3 signaling pathway. Communication pathways between Tregs and macrophages primarily involved MIF-CD74/CXCR4, LGALS9/CD45, and PTPRC/MRC1. Additionally, macrophages could influence Tregs via HLA-class II and CD4 interactions. CONCLUSION An elevated presence of Tregs in HCC samples correlated with negative patient outcomes. Elucidating the interplay between Tregs and other immune cells in HCC could provide insights into the modulatory role of Tregs within HCC tissues.
Collapse
Affiliation(s)
- Junwei Ge
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, China
- Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Junjun Chen
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, China
- Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Qiong Shen
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, China
- Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Xiao Zheng
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, China
- Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Xuemin Chen
- Radiological Intervention Center, Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Liangrong Shi
- Radiological Intervention Center, Department of Radiology, Xiangya Hospital, Central South University, Changsha, China
| | - Lujun Chen
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, China
- Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Bin Xu
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, China
- Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, China
| |
Collapse
|
|
13
|
Wu D, Li Y. Application of adoptive cell therapy in hepatocellular carcinoma. Immunology 2023; 170:453-469. [PMID: 37435926 DOI: 10.1111/imm.13677] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 06/20/2023] [Indexed: 07/13/2023] Open
Abstract
Hepatocellular carcinoma (HCC) remains a global health challenge. Novel treatment modalities are urgently needed to extend the overall survival of patients. The liver plays an immunomodulatory function due to its unique physiological structural characteristics. Therefore, following surgical resection and radiotherapy, immunotherapy regimens have shown great potential in the treatment of hepatocellular carcinoma. Adoptive cell immunotherapy is rapidly developing in the treatment of hepatocellular carcinoma. In this review, we summarize the latest research on adoptive immunotherapy for hepatocellular carcinoma. The focus is on chimeric antigen receptor (CAR)-T cells and T cell receptor (TCR) engineered T cells. Then tumour-infiltrating lymphocytes (TILs), natural killer (NK) cells, cytokine-induced killer (CIK) cells, and macrophages are briefly discussed. The main overview of the application and challenges of adoptive immunotherapy in hepatocellular carcinoma. It aims to provide the reader with a comprehensive understanding of the current status of HCC adoptive immunotherapy and offers some strategies. We hope to provide new ideas for the clinical treatment of hepatocellular carcinoma.
Collapse
Affiliation(s)
- Dengqiang Wu
- Department of Clinical Laboratory, Ningbo No. 6 Hospital, Ningbo, China
| | - Yujie Li
- Clinical Laboratory of Ningbo Medical Centre Lihuili Hospital, Ningbo University, Zhejiang, Ningbo, China
| |
Collapse
|
|
14
|
Li J, Xiao Z, Wang D, Jia L, Nie S, Zeng X, Hu W. The screening, identification, design and clinical application of tumor-specific neoantigens for TCR-T cells. Mol Cancer 2023; 22:141. [PMID: 37649123 PMCID: PMC10466891 DOI: 10.1186/s12943-023-01844-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 08/16/2023] [Indexed: 09/01/2023] Open
Abstract
Recent advances in neoantigen research have accelerated the development of tumor immunotherapies, including adoptive cell therapies (ACTs), cancer vaccines and antibody-based therapies, particularly for solid tumors. With the development of next-generation sequencing and bioinformatics technology, the rapid identification and prediction of tumor-specific antigens (TSAs) has become possible. Compared with tumor-associated antigens (TAAs), highly immunogenic TSAs provide new targets for personalized tumor immunotherapy and can be used as prospective indicators for predicting tumor patient survival, prognosis, and immune checkpoint blockade response. Here, the identification and characterization of neoantigens and the clinical application of neoantigen-based TCR-T immunotherapy strategies are summarized, and the current status, inherent challenges, and clinical translational potential of these strategies are discussed.
Collapse
Affiliation(s)
- Jiangping Li
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.
| | - Zhiwen Xiao
- Department of Otolaryngology Head and Neck Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, People's Republic of China
| | - Donghui Wang
- Department of Radiation Oncology, The Third Affiliated Hospital Sun Yat-Sen University, Guangzhou, 510630, People's Republic of China
| | - Lei Jia
- International Health Medicine Innovation Center, Shenzhen University, Shenzhen, 518060, People's Republic of China
| | - Shihong Nie
- Department of Radiation Oncology, West China Hospital, Sichuan University, Cancer Center, Chengdu, 610041, People's Republic of China
| | - Xingda Zeng
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Wei Hu
- Division of Vascular Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, People's Republic of China
| |
Collapse
|
|
15
|
Zhang Z, Gao W, Liu Z, Yu S, Jian H, Hou Z, Zeng P. Comprehensive analysis of m6A regulators associated with immune infiltration in Hepatitis B virus-related hepatocellular carcinoma. BMC Gastroenterol 2023; 23:259. [PMID: 37507670 PMCID: PMC10385918 DOI: 10.1186/s12876-023-02873-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 07/05/2023] [Indexed: 07/30/2023] Open
Abstract
BACKGROUND N6A methylation (m6A) is a significant epigenetic modification that critically impacts post-transcriptional regulation and tumor occurrence and development. While previous studies have identified a role for epigenetic regulation in hepatocellular carcinoma (HCC), the potential function of the m6A cluster in Hepatitis B virus (HBV)-related HCC remains unclear. METHODS The related information was downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Based on the expression of 20 m6A regulators, we comprehensively evaluated the m6A clusters and systematically explored the correlation between these clusters and immune cell infiltration characteristics of the tumor microenvironment (TME). The patients were divided into low- and high-m6A score groups. Then, the immune cell infiltration, chemokines, and cytokines levels, and drug sensitivity were further explored between the two groups. RESULTS The m6A cluster predicted a better prognosis that was accompanied by increased immune cell infiltration. Using these results, an m6A score was established that could predict overall survival, immune checkpoints, and clinical treatments for patients with HBV-related HCC. This study demonstrated that m6A modifications affected tumorigenesis, TME, and the prognosis of patients with HBV-related HCC. CONCLUSION A comprehensive assessment of m6A patterns could improve the current understanding of immune cell infiltration patterns and inform the development of individualized cancer treatments.
Collapse
Affiliation(s)
- Zhen Zhang
- Department of Oncology, Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine, Changsha, 410006, P.R. China
| | - Wenhui Gao
- School of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410208, P.R. China
| | - Zhuo Liu
- Department of Oncology, Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine, Changsha, 410006, P.R. China
| | - Shuxian Yu
- Department of Oncology, Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine, Changsha, 410006, P.R. China
| | - Huiying Jian
- Department of Oncology, Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine, Changsha, 410006, P.R. China
| | - Zongwei Hou
- Department of Oncology, Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine, Changsha, 410006, P.R. China
| | - Puhua Zeng
- Department of Oncology, Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine, Changsha, 410006, P.R. China.
| |
Collapse
|
|
16
|
Norberg SM, Hinrichs CS. Engineered T cell therapy for viral and non-viral epithelial cancers. Cancer Cell 2023; 41:58-69. [PMID: 36400016 PMCID: PMC9839504 DOI: 10.1016/j.ccell.2022.10.016] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 09/13/2022] [Accepted: 10/17/2022] [Indexed: 11/18/2022]
Abstract
Engineered T cell therapy has shown remarkable efficacy in hematologic malignancies and has the potential for application to common epithelial cancers. Diverse T cell therapy strategies including adoptive transfer of tumor-infiltrating lymphocytes, chimeric antigen receptor (CAR)-T cells, and T cell receptor (TCR)-T cells have been studied in clinical trials. Recent research has established treatment of human papillomavirus (HPV)-associated cancers with TCR-T cells as a model for proof-of-principle studies in epithelial cancers. These studies and others have provided critical insight into mechanisms of tumor regression, therapeutic targets, treatment safety, treatment design, and barriers to curative cell therapies for common types of cancer. This perspective will review and consolidate understanding gained from clinical trials to treat viral and non-viral epithelial cancers with cell and gene therapy and will examine how past experience may guide future strategy in treatment and biomarker discovery.
Collapse
Affiliation(s)
- Scott M Norberg
- National Cancer Institute, Center for Immuno-Oncology, Bethesda, MD 20892, USA
| | - Christian S Hinrichs
- Rutgers Cancer Institute of New Jersey, Duncan and Nancy MacMillan Cancer Immunology and Metabolism Center of Excellence, New Brunswick, NJ 08901, USA.
| |
Collapse
|
|
17
|
Sarantis P, Trifylli EM, Koustas E, Papavassiliou KA, Karamouzis MV, Papavassiliou AG. Immune Microenvironment and Immunotherapeutic Management in Virus-Associated Digestive System Tumors. Int J Mol Sci 2022; 23:13612. [PMID: 36362398 PMCID: PMC9655697 DOI: 10.3390/ijms232113612] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 10/31/2022] [Accepted: 11/04/2022] [Indexed: 08/29/2023] Open
Abstract
The development of cancer is a multifactorial phenomenon, while it constitutes a major global health problem. Viruses are an important factor that is involved in tumorigenesis and is associated with 12.1% of all cancer cases. Major examples of oncogenic viruses which are closely associated with the digestive system are HBV, HCV, EBV, HPV, JCV, and CMV. EBV, HPV, JCV, and CMV directly cause oncogenesis by expressing oncogenic proteins that are encoded in their genome. In contrast, HBV and HCV are correlated indirectly with carcinogenesis by causing chronic inflammation in the infected organs. In addition, the tumor microenvironment contains various immune cells, endothelial cells, and fibroblasts, as well as several growth factors, cytokines, and other tumor-secreted molecules that play a key role in tumor growth, progression, and migration, while they are closely interrelated with the virus. The presence of T-regulatory and B-regulatory cells in the tumor microenvironment plays an important role in the anti-tumor immune reaction. The tumor immune microenvironments differ in each type of cancer and depend on viral infection. The alterations in the immune microenvironment caused by viruses are also reflected in the effectiveness of immunotherapy. The present review aims at shedding light on the association between viruses and digestive system malignancies, the characteristics of the tumor immune microenvironment that develop, and the possible treatments that can be administered.
Collapse
Affiliation(s)
- Panagiotis Sarantis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Eleni-Myrto Trifylli
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece
| | - Evangelos Koustas
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece
| | - Kostas A. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Michalis V. Karamouzis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Athanasios G. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| |
Collapse
|
|
18
|
Xue JN, Wang YY, Wang YC, Zhang N, Zhang LH, Lu ZH, Zhao LJ, Zhao HT. Novel cellular therapies for hepatobiliary malignancies. Hepatobiliary Pancreat Dis Int 2022; 21:450-454. [PMID: 36100543 DOI: 10.1016/j.hbpd.2022.08.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 08/30/2022] [Indexed: 02/05/2023]
Abstract
BACKGROUND The mortalities of hepatobiliary malignancies are high. With the failure of conventional chemotherapy and unsatisfactory outcome of molecular targeted drugs, immune-based therapy has become a new focus of research in hepatobiliary cancers treatment. DATA SOURCES We performed a PubMed search with relevant articles published up to May 2022 and the following keywords: cellular immunotherapy, hepatobiliary cancer, antigen receptor T cell therapy, and receptor-engineered T cell. Information of clinical trials was obtained from https://clinicaltrials.gov/. RESULTS Cell therapies for hepatobiliary malignancies are at early stage of development. The current review showed that cellular therapies are safe and feasible in patients. These findings provide an important platform for future lager scale clinical trials on immunotherapy in patients with hepatobiliary malignancies. CONCLUSIONS With the continuous advances of cellular immunotherapy, the combination of cellular immunotherapy with surgery, chemotherapy and radiotherapy will be new therapeutic strategies for patients with hepatobiliary cancer.
Collapse
Affiliation(s)
- Jing-Nan Xue
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Yan-Yu Wang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Yun-Chao Wang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Nan Zhang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Long-Hao Zhang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Zheng-Hui Lu
- Hepatobiliary and Pancreatic Surgery, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen 518000, China
| | - Li-Jin Zhao
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Hai-Tao Zhao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
| |
Collapse
|
|
19
|
Jiang J, Xia M, Zhang L, Chen X, Zhao Y, Zeng C, Yang H, Liang P, Li G, Li N, Qi H, Wei T, Ren L. Rapid generation of genetically engineered T cells for the treatment of virus-related cancers. Cancer Sci 2022; 113:3686-3697. [PMID: 35950597 DOI: 10.1111/cas.15528] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 07/31/2022] [Accepted: 08/04/2022] [Indexed: 11/28/2022] Open
Abstract
Adoptive transfer of T cell receptor (TCR) engineered T cells targeting viral epitopes represents a promising approach for treating virus-related cancers. However, efficient identification of epitopes for T cells and corresponding TCR remains challenging. Here, we report a workflow permitting rapid generation of human papillomavirus (HPV)-specific TCR-T cells. Six epitopes of viral proteins belonged to HPV16 or HPV18 were predicted of high affinity to A11:01 according to bioinformatic analysis. Subsequently, cytotoxic T cells (CTLs) induction were performed with these six antigen peptides separately, and antigen-specific T cells were sorted by FACS. TCR clonotypes of these virus-specific T cells were determined by next-generation sequencing. To improve the efficiency of TCRαβ pairs validation, a lentiviral vector library containing 116 TCR constructs was generated, which was consisted of predominant TCRs according to TCR repoertire analysis. Later, TCR library transduced T cells were simulated with peptide pool-pulsed antigen presenting cells, then CD137-positive cells were sorted and subjected to TCR repoertire analysis. The top-hit TCRs and corresponding antigen peptides were deduced and validated. Through this workflow, a TCR targeting the E692-101 of HPV16 was identified. This HPV16-specific TCR-T cells showed high activities to HPV16-positive human cervical cancer cells in vitro and efficiently repressed tumor growth in murine model. This study provides a HPV16-specific TCR fitted to HLA-A11:01 population, and exemplifies an efficient approach which can be applied in large-scale screen of virus-specific TCRs, further encouraging researchers to exploit the therapeutic potential of TCR-T cell technique in treating virus-related cancers.
Collapse
Affiliation(s)
- Jinxing Jiang
- Cytotherapy Laboratory, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen Guangdong, China
| | - Ming Xia
- Cytotherapy Laboratory, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen Guangdong, China
| | - Lijie Zhang
- Department of Gynecology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen Guangdong, China
| | - Xi Chen
- RootPath, Inc. 65 Grove Street, Suite 203, 02472, Watertown, MA, USA
| | - Yue Zhao
- RootPath, Inc. 65 Grove Street, Suite 203, 02472, Watertown, MA, USA
| | - Chenquan Zeng
- Cytotherapy Laboratory, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen Guangdong, China
| | - Haiyan Yang
- RootPath, Inc. 65 Grove Street, Suite 203, 02472, Watertown, MA, USA
| | - Peng Liang
- RootPath, Inc. 65 Grove Street, Suite 203, 02472, Watertown, MA, USA
| | - Guanghe Li
- Department of Pharmacy, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen Guangdong, China
| | - Ning Li
- Cytotherapy Laboratory, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen Guangdong, China
| | - Hui Qi
- Cytotherapy Laboratory, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen Guangdong, China
| | - Teng Wei
- Cytotherapy Laboratory, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen Guangdong, China
| | - Lili Ren
- Cytotherapy Laboratory, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen Guangdong, China
| |
Collapse
|
|
20
|
Ding Y, Zhou Z, Li X, Zhao C, Jin X, Liu X, Wu Y, Mei X, Li J, Qiu J, Shen C. Screening and Identification of HBV Epitopes Restricted by Multiple Prevalent HLA-A Allotypes. Front Immunol 2022; 13:847105. [PMID: 35464415 PMCID: PMC9021956 DOI: 10.3389/fimmu.2022.847105] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Accepted: 03/15/2022] [Indexed: 12/21/2022] Open
Abstract
Although host T cell immune responses to hepatitis B virus (HBV) have been demonstrated to have important influences on the outcome of HBV infection, the development of T cell epitope-based vaccine and T cell therapy and the clinical evaluation of specific T cell function are currently hampered markedly by the lack of validated HBV T cell epitopes covering broad patients. This study aimed to screen T cell epitopes spanning overall HBsAg, HBeAg, HBx and HBpol proteins and presenting by thirteen prevalent human leukocyte antigen (HLA)-A allotypes which gather a total gene frequency of around 95% in China and Northeast Asia populations. 187 epitopes were in silico predicted. Of which, 62 epitopes were then functionally validated as real-world HBV T cell epitopes by ex vivo IFN-γ ELISPOT assay and in vitro co-cultures using peripheral blood mononuclear cells (PBMCs) from HBV infected patients. Furthermore, the HLA-A cross-restrictions of each epitope were identified by peptide competitive binding assay using transfected HMy2.CIR cell lines, and by HLA-A/peptide docking as well as molecular dynamic simulation. Finally, a peptide library containing 105 validated epitopes which cross-binding by 13 prevalent HLA-A allotypes were used in ELISPOT assay to enumerate HBV-specific T cells for 116 patients with HBV infection. The spot forming units (SFUs) was significantly correlated with serum HBsAg level as confirmed by multivariate linear regression analysis. This study functionally validated 62 T cell epitopes from HBV main proteins and elucidated their HLA-A restrictions and provided an alternative ELISPOT assay using validated epitope peptides rather than conventional overlapping peptides for the clinical evaluation of HBV-specific T cell responses.
Collapse
Affiliation(s)
- Yan Ding
- Department of Microbiology and Immunology, Medical School, Southeast University, Nanjing, China
| | - Zining Zhou
- Department of Microbiology and Immunology, Medical School, Southeast University, Nanjing, China
| | - Xingyu Li
- Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, School of Life Science and Technology, Southeast University, Nanjing, China
| | - Chen Zhao
- Department of Microbiology and Immunology, Medical School, Southeast University, Nanjing, China
| | - Xiaoxiao Jin
- Department of Microbiology and Immunology, Medical School, Southeast University, Nanjing, China
| | - Xiaotao Liu
- Department of Microbiology and Immunology, Medical School, Southeast University, Nanjing, China
| | - Yandan Wu
- Department of Microbiology and Immunology, Medical School, Southeast University, Nanjing, China
| | - Xueyin Mei
- Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, School of Life Science and Technology, Southeast University, Nanjing, China
| | - Jian Li
- Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, School of Life Science and Technology, Southeast University, Nanjing, China
| | - Jie Qiu
- Division of Hepatitis, Nanjing Second Hospital, Nanjing Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
| | - Chuanlai Shen
- Department of Microbiology and Immunology, Medical School, Southeast University, Nanjing, China
| |
Collapse
|
|
21
|
Zhang L, Meng Y, Feng X, Han Z. CAR-NK cells for cancer immunotherapy: from bench to bedside. Biomark Res 2022; 10:12. [PMID: 35303962 PMCID: PMC8932134 DOI: 10.1186/s40364-022-00364-6] [Citation(s) in RCA: 104] [Impact Index Per Article: 34.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 03/08/2022] [Indexed: 02/08/2023] Open
Abstract
Natural killer (NK) cells are unique innate immune cells and manifest rapid and potent cytotoxicity for cancer immunotherapy and pathogen removal without the requirement of prior sensitization or recognition of peptide antigens. Distinguish from the T lymphocyte-based cythotherapy with toxic side effects, chimeric antigen receptor-transduced NK (CAR-NK) cells are adequate to simultaneously improve efficacy and control adverse effects including acute cytokine release syndrome (CRS), neurotoxicity and graft-versus-host disease (GVHD). Moreover, considering the inherent properties of NK cells, the CAR-NK cells are “off-the-shelf” product satisfying the clinical demand for large-scale manufacture for cancer immunotherapy attribute to the cytotoxic effect via both NK cell receptor-dependent and CAR-dependent signaling cascades. In this review, we mainly focus on the latest updates of CAR-NK cell-based tactics, together with the opportunities and challenges for cancer immunotherapies, which represent the paradigm for boosting the immune system to enhance antitumor responses and ultimately eliminate malignancies. Collectively, we summarize and highlight the auspicious improvement in CAR-NK cells and will benefit the large-scale preclinical and clinical investigations in adoptive immunotherapy.
Collapse
Affiliation(s)
- Leisheng Zhang
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province & NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou, 730000, China. .,Center for Cellular Therapies, The First Affiliated Hospital of Shandong First Medical University, Ji-nan, 250014, China. .,Key Laboratory of Radiation Technology and Biophysics, Hefei Institute of Physical Science, Chinese Academy of Sciences, 350 Shushanhu Road, Shushan District, Hefei, 230031, Anhui Province, China. .,Institute of Stem Cells, Health-Biotech (Tianjin) Stem Cell Research Institute Co., Ltd, Tianjin, 301700, China. .,Jiangxi Research Center of Stem Cell Engineering, Jiangxi Health-Biotech Stem Cell Technology Co., Ltd., Shangrao, 334000, China. .,Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, 204 Donggangxi Road, Chengguan District, Lanzhou City, 730013, Gansu Province, China.
| | - Yuan Meng
- State Key Laboratory of Experimental Hematology & National Clinical Research Center for Blood Disease, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Xiaoming Feng
- State Key Laboratory of Experimental Hematology & National Clinical Research Center for Blood Disease, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.
| | - Zhongchao Han
- Institute of Stem Cells, Health-Biotech (Tianjin) Stem Cell Research Institute Co., Ltd, Tianjin, 301700, China. .,Jiangxi Research Center of Stem Cell Engineering, Jiangxi Health-Biotech Stem Cell Technology Co., Ltd., Shangrao, 334000, China. .,State Key Laboratory of Experimental Hematology & National Clinical Research Center for Blood Disease, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China. .,Stem Cell Bank of Guizhou Province, Guizhou Health-Biotech Biotechnology Co., Ltd., Guiyang, 550000, China.
| |
Collapse
|
|
22
|
A Systematic Review of T Cell Epitopes Defined from the Proteome of Hepatitis B Virus. Vaccines (Basel) 2022; 10:vaccines10020257. [PMID: 35214714 PMCID: PMC8878595 DOI: 10.3390/vaccines10020257] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 02/04/2022] [Accepted: 02/05/2022] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B virus (HBV) infection remains a worldwide health problem and no eradicative therapy is currently available. Host T cell immune responses have crucial influences on the outcome of HBV infection, however the development of therapeutic vaccines, T cell therapies and the clinical evaluation of HBV-specific T cell responses are hampered markedly by the lack of validated T cell epitopes. This review presented a map of T cell epitopes functionally validated from HBV antigens during the past 33 years; the human leukocyte antigen (HLA) supertypes to present these epitopes, and the methods to screen and identify T cell epitopes. To the best of our knowledge, a total of 205 CD8+ T cell epitopes and 79 CD4+ T cell epitopes have been defined from HBV antigens by cellular functional experiments thus far, but most are restricted to several common HLA supertypes, such as HLA-A0201, A2402, B0702, DR04, and DR12 molecules. Therefore, the currently defined T cell epitope repertoire cannot cover the major populations with HLA diversity in an indicated geographic region. More researches are needed to dissect a more comprehensive map of T cell epitopes, which covers overall HBV proteome and global patients.
Collapse
|
|
23
|
Wang K, Wang C, Jiang H, Zhang Y, Lin W, Mo J, Jin C. Combination of Ablation and Immunotherapy for Hepatocellular Carcinoma: Where We Are and Where to Go. Front Immunol 2022; 12:792781. [PMID: 34975896 PMCID: PMC8714655 DOI: 10.3389/fimmu.2021.792781] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 11/25/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide and is increasing in incidence. Local ablative therapy plays a leading role in HCC treatment. Radiofrequency (RFA) is one of the first-line therapies for early local ablation. Other local ablation techniques (e.g., microwave ablation, cryoablation, irreversible electroporation, phototherapy.) have been extensively explored in clinical trials or cell/animal studies but have not yet been established as a standard treatment or applied clinically. On the one hand, single treatment may not meet the needs. On the other hand, ablative therapy can stimulate local and systemic immune effects. The combination strategy of immunotherapy and ablation is reasonable. In this review, we briefly summarized the current status and progress of ablation and immunotherapy for HCC. The immune effects of local ablation and the strategies of combination therapy, especially synergistic strategies based on biomedical materials, were discussed. This review is hoped to provide references for future researches on ablative immunotherapy to arrive to a promising new era of HCC treatment.
Collapse
Affiliation(s)
- Kunpeng Wang
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Cong Wang
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, China
| | - Hao Jiang
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Yaqiong Zhang
- Department of Clinical Laboratory, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Weidong Lin
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Jinggang Mo
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Chong Jin
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| |
Collapse
|
|
24
|
Yang Y, Bai H, Wu Y, Chen P, Zhou J, Lei J, Ye X, Brown AJ, Zhou X, Shu T, Chen Y, Wei P, Yin L. The Activating receptor KIR2DS2 bound to HLA-C1 reveals the novel recognition features of activating receptor. Immunology 2021; 165:341-354. [PMID: 34967442 DOI: 10.1111/imm.13439] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 11/30/2021] [Accepted: 12/15/2021] [Indexed: 11/05/2022] Open
Abstract
Killer cell immunoglobulin-like receptors (KIRs) are important receptors for regulating the killing of virus-infected or cancer cells of natural killer (NK) cells. KIR2DS2 can recognize peptides derived from hepatitis C virus (HCV) or global flaviviruses (such as dengue and Zika) presented by HLA-C*0102 to activate NK cells, and have shown promising results when used for cancer immunotherapy. Here, we present the complex structure of KIR2DS2 with HLA-C*0102 at a resolution of 2.5Å. Our structure reveals that KIR2DS2 can bind HLA-C*0102 and HLA-A*1101 in two different directions. Moreover, Tyr45 (in activating receptor KIR2DS2) and Phe45 (in inhibitory KIRs) distinguish the two different binding models and binding affinity between activating KIRs and inhibitory KIRs. The conserved "AT" motif of the peptide mediates recognition and determines the peptide specificity of recognition. These structural characteristic shed light on how KIRs activate NK cells and can provide a molecular basis for immunotherapy by NK cells.
Collapse
Affiliation(s)
- Yi Yang
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Hua Bai
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Yankang Wu
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Peng Chen
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Jin Zhou
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Jun Lei
- Department of Clinical Oncology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiang Ye
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Alex J Brown
- Department of Immunology and Genomic Medicine, National Jewish Health, Denver, CO, USA.,Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Xi Zhou
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, CAS, Wuhan, China
| | - Ting Shu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, CAS, Wuhan, China
| | - Yongshun Chen
- Department of Clinical Oncology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Pengcheng Wei
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China.,Department of Immunology and Genomic Medicine, National Jewish Health, Denver, CO, USA
| | - Lei Yin
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
| |
Collapse
|
|
25
|
Möller K, Fraune C, Blessin NC, Lennartz M, Kluth M, Hube-Magg C, Lindhorst L, Dahlem R, Fisch M, Eichenauer T, Riechardt S, Simon R, Sauter G, Büscheck F, Höppner W, Matthies C, Doh O, Krech T, Marx AH, Zecha H, Rink M, Steurer S, Clauditz TS. Tumor cell PD-L1 expression is a strong predictor of unfavorable prognosis in immune checkpoint therapy-naive clear cell renal cell cancer. Int Urol Nephrol 2021; 53:2493-2503. [PMID: 33797012 PMCID: PMC8599390 DOI: 10.1007/s11255-021-02841-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 03/17/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND PD-L1 expression predicts response to immune checkpoint inhibitors in renal cell carcinomas (RCC), but has also been suggested to be linked to poor patient outcome. METHODS We analyzed PD-L1 in > 1400 RCC in a tissue microarray format by immunohistochemistry. Results were compared with histological tumor type, parameters of cancer aggressiveness, and intratumoral CD8+ cytotoxic cells. RESULT At a cut-off level of 5% PD-L1 positive tumor cells, PD-L1 positivity was seen in 6.3% of 633 clear cell RCC (ccRCC), 18.2% of 165 papillary RCC, 18.8% of 64 chromophobe RCC, and 41.7% of 103 oncocytomas. In ccRCC, PD-L1 positivity was significantly linked to high ISUP (p < 0.0001), Fuhrman (p < 0.0001), Thoenes grade (p < 0.0001), distant metastasis (p = 0.0042), short recurrence-free (p < 0.0001), and overall survival (p = 0.0002). Intratumoral CD8+ lymphocytes were more frequent in PD-L1 positive (1055 ± 109) than in PD-L1 negative ccRCC (407 ± 28; p < 0.0001). PD-L positive immune cells were seen in 8.2% of all RCC and 13.9% of papillary RCC. In ccRCC, PD-L1 positive immune cells were linked to high numbers of tumor-infiltrating CD8+ cells (p < 0.0001), high ISUP (p < 0.0001), Fuhrman (p = 0.0027), and Thoenes grade (p < 0.0001), and poor tumor-specific survival (p = 0.0280). CONCLUSIONS These data suggest that PD-L1 expression in highly immunogenic RCCs facilitates immune evasion and contributes to cancer aggressiveness.
Collapse
Affiliation(s)
- Katharina Möller
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Christoph Fraune
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Niclas C Blessin
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Maximilian Lennartz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Martina Kluth
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Claudia Hube-Magg
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Linnea Lindhorst
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Roland Dahlem
- Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Margit Fisch
- Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Till Eichenauer
- Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Silke Riechardt
- Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Franziska Büscheck
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | | | - Cord Matthies
- Department of Urology, Bundeswehr Hospital Hamburg, Hamburg, Germany
| | - Ousman Doh
- Department of Urology, Regio Medical Center Elmshorn, Elmshorn, Germany
| | - Till Krech
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
- Institute of Pathology, Clinical Center Osnabrueck, Osnabrück, Germany
| | - Andreas H Marx
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
- Department of Pathology, Academic Hospital Fuerth, Fuerth, Germany
| | - Henrik Zecha
- Department of Urology, Albertinen Clinic, Hamburg, Germany
| | - Michael Rink
- Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stefan Steurer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Till S Clauditz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| |
Collapse
|
|
26
|
T Cell Bispecific Antibodies: An Antibody-Based Delivery System for Inducing Antitumor Immunity. Pharmaceuticals (Basel) 2021; 14:ph14111172. [PMID: 34832954 PMCID: PMC8619951 DOI: 10.3390/ph14111172] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 11/13/2021] [Accepted: 11/14/2021] [Indexed: 02/06/2023] Open
Abstract
As a breakthrough immunotherapy, T cell bispecific antibodies (T-BsAbs) are a promising antibody therapy for various kinds of cancer. In general, T-BsAbs have dual-binding specificity to a tumor-associated antigen and a CD3 subunit forming a complex with the TCR. This enables T-BsAbs to crosslink tumor cells and T cells, inducing T cell activation and subsequent tumor cell death. Unlike immune checkpoint inhibitors, which release the brake of the immune system, T-BsAbs serve as an accelerator of T cells by stimulating their immune response via CD3 engagement. Therefore, they can actively redirect host immunity toward tumors, including T cell recruitment from the periphery to the tumor site and immunological synapse formation between tumor cells and T cells. Although the low immunogenicity of solid tumors increases the challenge of cancer immunotherapy, T-BsAbs capable of immune redirection can greatly benefit patients with such tumors. To investigate the detailed relationship between T-BsAbs delivery and their T cell redirection activity, it is necessary to determine how T-BsAbs deliver antitumor immunity to the tumor site and bring about tumor cell death. This review article discusses T-BsAb properties, specifically their pharmacokinetics, redirection of anticancer immunity, and local mechanism of action within tumor tissues, and discuss further challenges to expediting T-BsAb development.
Collapse
|
|
27
|
Lawal G, Xiao Y, Rahnemai-Azar AA, Tsilimigras DI, Kuang M, Bakopoulos A, Pawlik TM. The Immunology of Hepatocellular Carcinoma. Vaccines (Basel) 2021; 9:vaccines9101184. [PMID: 34696292 PMCID: PMC8538643 DOI: 10.3390/vaccines9101184] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/20/2021] [Accepted: 10/08/2021] [Indexed: 12/13/2022] Open
Abstract
Liver cancer is the third leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. Liver resection or transplantation offer the only potentially curative options for HCC; however, many patients are not candidates for surgical resection, either due to presentation at advanced stages or poor liver function and portal hypertension. Liver transplantation is also limited to patients with certain characteristics, such as those that meet the Milan criteria (one tumor ≤ 5 cm, or up to three tumors no larger than 3 cm, along with the absence of gross vascular invasion or extrahepatic spread). Locoregional therapies, such as ablation (radiofrequency, ethanol, cryoablation, microwave), trans-arterial therapies like chemoembolization (TACE) or radioembolization (TARE), and external beam radiation therapy, have been used mainly as palliative measures with poor prognosis. Therefore, emerging novel systemic treatments, such as immunotherapy, have increasingly become popular. HCC is immunogenic, containing infiltrating tumor-specific T-cell lymphocytes and other immune cells. Immunotherapy may provide a more effective and discriminatory targeting of tumor cells through induction of a tumor-specific immune response in cancer cells and can improve post-surgical recurrence-free survival in HCC. We herein review evidence supporting different immunomodulating cell-based technology relative to cancer therapy in vaccines and targeted therapies, such as immune checkpoint inhibitors, in the management of hepatocellular carcinoma among patients with advanced disease.
Collapse
Affiliation(s)
- Gbemisola Lawal
- Division of Surgical Oncology, Department of Surgery, Arrowhead Regional Cancer Center, California University of Science and Medicine, Colton, CA 92324, USA; (G.L.); (A.A.R.-A.)
| | - Yao Xiao
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; (Y.X.); (M.K.)
| | - Amir A. Rahnemai-Azar
- Division of Surgical Oncology, Department of Surgery, Arrowhead Regional Cancer Center, California University of Science and Medicine, Colton, CA 92324, USA; (G.L.); (A.A.R.-A.)
| | - Diamantis I. Tsilimigras
- Department of Surgery, The Ohio State Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH 43210, USA;
- Correspondence: ; Tel.: +1-215-987-9177
| | - Ming Kuang
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; (Y.X.); (M.K.)
| | - Anargyros Bakopoulos
- Department of Surgery, Attikon University Hospital, University of Athens, 12462 Athens, Greece;
| | - Timothy M. Pawlik
- Department of Surgery, The Ohio State Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH 43210, USA;
| |
Collapse
|
|
28
|
Zheng Y, Li Y, Feng J, Li J, Ji J, Wu L, Yu Q, Dai W, Wu J, Zhou Y, Guo C. Cellular based immunotherapy for primary liver cancer. J Exp Clin Cancer Res 2021; 40:250. [PMID: 34372912 PMCID: PMC8351445 DOI: 10.1186/s13046-021-02030-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 06/28/2021] [Indexed: 02/07/2023] Open
Abstract
Primary liver cancer (PLC) is a common malignancy with high morbidity and mortality. Poor prognosis and easy recurrence on PLC patients calls for optimizations of the current conventional treatments and the exploration of novel therapeutic strategies. For most malignancies, including PLC, immune cells play crucial roles in regulating tumor microenvironments and specifically recognizing tumor cells. Therefore, cellular based immunotherapy has its instinctive advantages in PLC therapy as a novel therapeutic strategy. From the active and passive immune perspectives, we introduced the cellular based immunotherapies for PLC in this review, covering both the lymphoid and myeloid cells. Then we briefly review the combined cellular immunotherapeutic approaches and the existing obstacles for PLC treatment.
Collapse
Affiliation(s)
- Yuanyuan Zheng
- Department of Gastroenterology, Putuo People's Hospital, Tongji University, Shanghai, 200060, China
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Yan Li
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Jiao Feng
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Jingjing Li
- Department of Gastroenterology, Putuo People's Hospital, Tongji University, Shanghai, 200060, China
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Jie Ji
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Liwei Wu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Qiang Yu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Weiqi Dai
- Department of Gastroenterology, Putuo People's Hospital, Tongji University, Shanghai, 200060, China
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Jianye Wu
- Department of Gastroenterology, Putuo People's Hospital, Tongji University, Shanghai, 200060, China.
| | - Yingqun Zhou
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
| | - Chuanyong Guo
- Department of Gastroenterology, Putuo People's Hospital, Tongji University, Shanghai, 200060, China.
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
| |
Collapse
|
|
29
|
Ye R, Zeng H, Liu Z, Jin K, Liu C, Yan S, Yu Y, You R, Zhang H, Chang Y, Wang Y, Liu L, Zhu Y, Xu J, Xu L, Wang Z. Latency-associated peptide identifies therapeutically resistant muscle-invasive bladder cancer with poor prognosis. Cancer Immunol Immunother 2021; 71:301-310. [PMID: 34152439 DOI: 10.1007/s00262-021-02987-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 06/11/2021] [Indexed: 01/05/2023]
Abstract
BACKGROUND Latency-associated peptide (LAP) was identified as crucial immune regulator in tumor microenvironment (TME) in recent researches. In this study, we aimed to estimate the predictive value of LAP expression for clinical survival and therapeutic response in muscle-invasive bladder cancer (MIBC). METHODS Our study encompassed 140 MIBC patients from Zhongshan Hospital (ZSHS cohort), 401 patients from The Cancer Genome Atlas (TCGA cohort) and 195 patients received PDL1 blockade from IMvigor210 trial. Survival analyses were conducted through Kaplan-Meier curve and Cox regression model. LAP expression and its association with immune contexture were evaluated in ZSHS and TCGA cohort. RESULTS We found that high intratumoral LAP+ cells infiltration anticipated inferior survival and adjuvant chemotherapy (ACT) response, and was closely related to an immunoevasive contexture with increased M2 macrophages, neutrophils and conspicuously a cluster of highly exhausted CD8+ T cells. The combinational analysis of LAP+ cells and CD8+ T cells infiltration stratified patients into distinct risk groups with implications for therapeutic sensitivity to PDL1 blockade and refinement of molecular classification in MIBC. CONCLUSIONS LAP expression was correlated with patients' inferior prognosis, ACT-tolerance and an immunoevasive TME with exhausted CD8+ T cell infiltration, suggesting that LAP could serve as a promising therapeutic target in MIBC. Simultaneously, our novel TME classification based on LAP+ cells and CD8+ T cells infiltration and its potential in appraising PDL1 blockade application for MIBC patients deserved further validation.
Collapse
Affiliation(s)
- Ruiting Ye
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Han Zeng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Zhaopei Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Kaifeng Jin
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Chunnan Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Sen Yan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Yanze Yu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Runze You
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Hongyi Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Yuan Chang
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
| | - Yiwei Wang
- Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li Liu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yu Zhu
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Jiejie Xu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
| | - Le Xu
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Zewei Wang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| |
Collapse
|
|
30
|
Liu J, Li Y, Li Q, Liang D, Wang Q, Liu Q. Biomarkers of response to camrelizumab combined with apatinib: an analysis from a phase II trial in advanced triple-negative breast cancer patients. Breast Cancer Res Treat 2021; 186:687-697. [PMID: 33634417 DOI: 10.1007/s10549-021-06128-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 02/03/2021] [Indexed: 02/05/2023]
Abstract
PURPOSE We recently reported results of a phase II trial that camrelizumab plus apatinib induced an objective response rate (ORR) at 43.3% in advanced triple-negative breast cancer (TNBC). This study presents analysis of potential biomarkers. METHODS TILs, CD8+ T cells and PD-1/PD-L1 expression were evaluated in tumor samples by immunohistochemistry. 59 Cytokines/chemokines, growth factors, or checkpoint-related proteins, blood immune cell subpopulations were analyzed in blood samples by multiplexed bead immunoassays or flow cytometry. Correlation between biomarkers and clinical outcomes including ORR, progression-free survival (PFS), and overall survival (OS) was analyzed. RESULTS 28 Patients had biopsies and blood collected. Baseline TILs were significantly associated with longer PFS (P = 0.035). An increase of tumor-infiltrating CD8+ T cells > 15% during therapy was associated with higher ORR (P = 0.040). Patients with lower baseline plasma levels of HGF or IL-8 were more likely to respond to treatment (P = 0.005 or 0.001, respectively), and showed a longer PFS and OS. Patients with a decrease of IL-8, or an increase of TIM-3 or CD152 during treatment responded more to treatment (P = 0.008, 0.040, or 0.014, respectively). Responders had a higher baseline CD4+ T cells and B cell proportions in blood than non-responders (P = 0.002 and 0.030, respectively). CONCLUSION Higher baseline TILs or a greater increase of tumor-infiltrating CD8+ T cells during therapy, lower baseline plasma HGF/IL-8, a decrease of plasma IL-8, an increase of plasma TIM-3/CD152 during therapy, higher baseline CD4+ T cells or B cells proportion in blood are potential biomarkers for combinational anti-angiogenesis and immunotherapy in advanced TNBC patients.
Collapse
Affiliation(s)
- Jieqiong Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Yanjiang West Road 107#, Guangzhou, 510120, China.
| | - Ying Li
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Yanjiang West Road 107#, Guangzhou, 510120, China
| | - Qian Li
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Yanjiang West Road 107#, Guangzhou, 510120, China
| | - Dandan Liang
- Genecast Precision Medicine Technology Institute, Beijing, China
| | - Quanren Wang
- Jiangsu Hengrui Medicine Co., Ltd., Lianyungang, Jiangsu, China
| | - Qiang Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Yanjiang West Road 107#, Guangzhou, 510120, China.
| |
Collapse
|