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Liu M, Tang Y, Yan M, Zhang J, Chen H, Zhang Q. Self-regulating immunosuppressive tumor microenvironment by NIR-II photothermal agent with anti-inflammatory activity for self-reinforcing immunotherapy synergy with cancer photothermal ablation. Biomaterials 2025; 318:123187. [PMID: 39965425 DOI: 10.1016/j.biomaterials.2025.123187] [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: 11/01/2024] [Revised: 01/14/2025] [Accepted: 02/11/2025] [Indexed: 02/20/2025]
Abstract
Cancer thermal immunotherapeutic strategy has garnered tremendous attention in nanomedicine frontier. Photothermal therapy (PTT) within the second near-infrared (NIR-II) window is popular hyperthermia technique, but the effect of NIR-II PTT on antitumor immunity remains extensive exploration. Here, we first reveal the inflammatory immunosuppressive tumor microenvironment (TME) characterized by high-influx of myeloid-derived suppressor cells (MDSCs) following NIR-II PTT. For this issue, we develop biomineralized copper sulfide nanoparticles (BCS NPs) as NIR-II photothermal agents (PTAs), and found for the first time that they are superior electron-donor antioxidants with pronounced anti-inflammatory activities. Impressively, the excessive inflammation triggered by BCS NPs-mediated NIR-II PTT can be self-alleviated to minimize the high-influx of MDSCs, and the immunosuppression-related reactive oxygen species produced by MDSCs can also be self-scavenged. Such reprogramming of TME facilitates the activation of systemic adaptive antitumor immunity and the strengthened tumour-infiltrating of cytotoxic T lymphocytes, thereby realizing self-reinforcing immunotherapy synergy with cancer NIR-II PTT. More importantly, a robust abscopal effect against distant tumors is also observed in bilateral tumor models. This work provides the first example to underscore the potential of PTAs with antioxidant and anti-inflammatory functions as innovative thermal immuno-nanomedicines.
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Affiliation(s)
- Min Liu
- School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-Lane Xiangshan, Hangzhou, 310024, China; State Key Laboratory of High-Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Ding-Xi Road, Shanghai, 200050, China; Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yiwen Tang
- School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-Lane Xiangshan, Hangzhou, 310024, China; Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Mijia Yan
- School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-Lane Xiangshan, Hangzhou, 310024, China; State Key Laboratory of High-Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Ding-Xi Road, Shanghai, 200050, China; Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jiale Zhang
- School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-Lane Xiangshan, Hangzhou, 310024, China; State Key Laboratory of High-Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Ding-Xi Road, Shanghai, 200050, China; Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Hangrong Chen
- School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-Lane Xiangshan, Hangzhou, 310024, China; State Key Laboratory of High-Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Ding-Xi Road, Shanghai, 200050, China; Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Qiuhong Zhang
- School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-Lane Xiangshan, Hangzhou, 310024, China; Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China.
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2
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Weissenstein U, Tschumi S, Leonhard B, Baumgartner S. A fermented Mistletoe (Viscum album L.) extract elicits markers characteristic for immunogenic cell death driven by endoplasmic reticulum stress in vitro. BMC Complement Med Ther 2025; 25:175. [PMID: 40369535 PMCID: PMC12076857 DOI: 10.1186/s12906-025-04909-8] [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: 11/12/2024] [Accepted: 05/01/2025] [Indexed: 05/16/2025] Open
Abstract
BACKGROUND Immune evasion is a characteristic hallmark of cancer. Immunotherapies aim to activate and support the body's immune system to recognize and fight tumor cells. Induction of immunogenic cell death (ICD) and the associated activation of danger signaling pathways can increase the immunogenicity of tumor cells. Therapeutic ICD stimuli activate endoplasmic reticulum stress pathways and apoptosis leading to the cellular expression of damage-associated molecular patterns (DAMPs). The aim of our in vitro study was to investigate whether mistletoe extracts induce characteristics of immunogenic tumor cell death in cancer cell lines. METHODS Three human breast cancer cell lines and one murine melanoma cell line (SKBR3, MDA-MB-231, MCF-7, and B16F10) were treated with aqueous, fermented Viscum album extract (VAE: Iscador Qu spec.) and taxol or tunicamycin as positive controls, respectively. To investigate whether VAE induces ribotoxic stress, we measured the ER stress regulators p-eIF2a, ATF4, and CHOP by Western blot. Cell surface exposure of DAMPs (calreticulin, heat shock proteins hsp70 and hsp90), apoptosis and induction of mitochondrial reactive oxygen species (ROS) were assessed by flow cytometry. HMGB1 and ATP were quantified by ELISA and chemiluminescence assay, respectively. RESULTS Treatment with VAE resulted in phosphorylation of eIF2α in all cancer cell lines tested and increased calreticulin (CRT) exposure on the surface of pre-apoptotic SKBR3 breast cancer and B16F10 mouse melanoma cells. VAE exerted a concentration-dependent effect in all cell lines, resulting in a significantly increased exposure of three DAMPs (CRT, hsp70 and hsp90) on the surface of early apoptotic cells. Furthermore, VAE elevated mitochondrial ROS production and the release of ATP. HMGB1 release was not induced by VAE. CONCLUSIONS In this in vitro study, we demonstrated for the first time the potential of a mistletoe extract to induce surrogate markers of immunogenic cancer cell death. This is a primary step in investigating the potential of VAEs to contribute to ICD-induced tumor-specific immune activation.
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Affiliation(s)
| | | | | | - Stephan Baumgartner
- Society for Cancer Research, Arlesheim, Switzerland
- Institute of Integrative Medicine, Witten/Herdecke University, Herdecke, Germany
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Peng S, Hou X, Liu J, Huang F. Advances in polymer nanomaterials targeting cGAS-STING pathway for enhanced cancer immunotherapy. J Control Release 2025; 381:113560. [PMID: 40023225 DOI: 10.1016/j.jconrel.2025.02.056] [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: 09/13/2024] [Revised: 02/17/2025] [Accepted: 02/19/2025] [Indexed: 03/04/2025]
Abstract
Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway has been recognized as a promising target for cancer immunotherapy. Although various STING agonists have been developed, their clinical applications are still severely impeded by various issues, such as non-specific accumulation, adverse effects, rapid clearance, etc. In recent years, the emergence of nanomaterials has profoundly revolutionized STING agonists delivery, which promote tumor-targeted delivery, boost the immunotherapeutic effects and reduce systemic toxicity of STING agonists. In particular, polymer nanomaterials possess inherent advantages including controllable structure, tunable function and degradability. These properties afford them the capacity to serve as delivery vehicles for small-molecule STING agonists. Furthermore, the superior characteristics of polymer nanomaterials can enable their utilization as a novel STING agonist to stimulate anti-tumor immunity. In this review, the molecular mechanisms of cGAS-STING pathway activation are discussed. The recent development of small-molecules STING agonists is described. Then polymer nanomaterials are discussed as carriers for STING agonists in cancer immunotherapy, including polymersomes, polymer micelles, polymer capsules, and polymer nanogels. Additionally, polymer nanomaterials are identified as a novel class of STING agonists for efficient cancer immunotherapy, encompassing both polymer materials and polymer-STING agonists conjugates. The review also presents the combination of polymer-based cGAS-STING immunotherapy with chemotherapy, radiotherapy, phototherapy (both photodynamic and photothermal), chemodynamic therapy, and other therapeutic strategies. Furthermore, the discussion highlights recent advancements targeting the cGAS-STING pathway in clinically approved polymer nanomaterials and corresponding potent innovations. Finally, the potential challenges and perspectives of polymer nanomaterials for activating cGAS-STING pathway are outlined, emphasizing the critical scientific issue and hoping to offer guidance for their clinical translation.
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Affiliation(s)
- Shiyu Peng
- State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Key Laboratory of Radiopharmacokinetics for Innovative Drugs, Tianjin Institutes of Health Science, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China
| | - Xiaoxue Hou
- State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Key Laboratory of Radiopharmacokinetics for Innovative Drugs, Tianjin Institutes of Health Science, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China
| | - Jianfeng Liu
- State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Key Laboratory of Radiopharmacokinetics for Innovative Drugs, Tianjin Institutes of Health Science, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China.
| | - Fan Huang
- State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Key Laboratory of Radiopharmacokinetics for Innovative Drugs, Tianjin Institutes of Health Science, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China.
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4
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Naffaa MM, Al-Ewaidat OA, Gogia S, Begiashvili V. Neoantigen-based immunotherapy: advancing precision medicine in cancer and glioblastoma treatment through discovery and innovation. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2025; 6:1002313. [PMID: 40309350 PMCID: PMC12040680 DOI: 10.37349/etat.2025.1002313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Accepted: 04/07/2025] [Indexed: 05/02/2025] Open
Abstract
Neoantigen-based immunotherapy has emerged as a transformative approach in cancer treatment, offering precision medicine strategies that target tumor-specific antigens derived from genetic, transcriptomic, and proteomic alterations unique to cancer cells. These neoantigens serve as highly specific targets for personalized therapies, promising more effective and tailored treatments. The aim of this article is to explore the advances in neoantigen-based therapies, highlighting successful treatments such as vaccines, tumor-infiltrating lymphocyte (TIL) therapy, T-cell receptor-engineered T cells therapy (TCR-T), and chimeric antigen receptor T cells therapy (CAR-T), particularly in cancer types like glioblastoma (GBM). Advances in technologies such as next-generation sequencing, RNA-based platforms, and CRISPR gene editing have accelerated the identification and validation of neoantigens, moving them closer to clinical application. Despite promising results, challenges such as tumor heterogeneity, immune evasion, and resistance mechanisms persist. The integration of AI-driven tools and multi-omic data has refined neoantigen discovery, while combination therapies are being developed to address issues like immune suppression and scalability. Additionally, the article discusses the ongoing development of personalized immunotherapies targeting tumor mutations, emphasizing the need for continued collaboration between computational and experimental approaches. Ultimately, the integration of cutting-edge technologies in neoantigen research holds the potential to revolutionize cancer care, offering hope for more effective and targeted treatments.
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Affiliation(s)
- Moawiah M Naffaa
- Department of Psychology and Neuroscience, Duke University, Durham, NC 27708, USA
- Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Ola A Al-Ewaidat
- Department of Internal Medicine, Ascension Saint Francis Hospital, Evanston, IL 60202, USA
| | - Sopiko Gogia
- Department of Internal Medicine, Ascension Saint Francis Hospital, Evanston, IL 60202, USA
| | - Valiko Begiashvili
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66103, USA
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Arai M, Hanada M, Taniguchi H, Nakajima F, Ohmoto H, Inoue T, Naka K, Sawa M. Discovery of HM-279, a Potent Inhibitor of ALK5 for Improving Therapeutic Efficacy of Cancer Immunotherapy. J Med Chem 2025; 68:7106-7118. [PMID: 40108955 DOI: 10.1021/acs.jmedchem.4c02293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/22/2025]
Abstract
Activin receptor-like kinase 5 (ALK5) is a type I receptor serine/threonine kinase and responsible for the TGF-β signaling pathway. ALK5 is thought to be a key player in the tumor microenvironment to promote tumor progression by affecting the anticancer immunity. Therefore, ALK5 is an attractive drug target for modulating TGF-β signaling pathways to improve the therapeutic efficacy of cancer immunotherapy. We report the optimization of a series of thiazole analogues starting from lead compound 6, focusing on improving off-target selectivity. Compound 19f (HM-279) was identified as a potent ALK5 inhibitor with an acceptable off-target selectivity and favorable ADME/PK properties. Oral administration of HM-279 demonstrated antitumor activity in a CT26.WT colon carcinoma syngeneic mouse model as a single agent and in combination with the anti-PD-1 antibody through CD8+ T cell immunity.
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Affiliation(s)
- Mai Arai
- Research and Development, Carna Biosciences, Inc., BMA 3F, 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan
| | - Mitsuharu Hanada
- Research and Development, Carna Biosciences, Inc., BMA 3F, 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan
| | - Haruka Taniguchi
- Research and Development, Carna Biosciences, Inc., BMA 3F, 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan
| | - Fumio Nakajima
- Research and Development, Carna Biosciences, Inc., BMA 3F, 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan
| | - Hiroshi Ohmoto
- Research and Development, Carna Biosciences, Inc., BMA 3F, 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan
| | - Tsuyoshi Inoue
- Graduate School of Pharmaceutical Sciences, Osaka University, Yamada-oka 1-6, Suita, Osaka 565-0871, Japan
| | - Kazuhito Naka
- Department of Stem Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan
| | - Masaaki Sawa
- Research and Development, Carna Biosciences, Inc., BMA 3F, 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan
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Zhang J, Liu J, Zhang H, Liu B, Li L, Li Y, Pei J, Lin Q, Chen Q, Lin J. Lymph node-targeted delivery of Lonicera japonica thunb. polysaccharides for enhancing antitumor immunotherapy. Mater Today Bio 2025; 31:101559. [PMID: 40026631 PMCID: PMC11871467 DOI: 10.1016/j.mtbio.2025.101559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 01/15/2025] [Accepted: 02/04/2025] [Indexed: 03/05/2025] Open
Abstract
Dendritic cells (DCs) are crucial for the initiation and regulation of innate and adaptive immunity. Their maturity and infiltration in the tumor largely determine the efficiency of antigen presentation, the CTL responses, and the prognosis of tumors. However, the application of common immunoregulatory plant polysaccharides to DCs in vivo still represents major challenges due to the off-target effect and short biological lifespan. Lonicera japonica Thunb. polysaccharides (LJP) were found to exert benign immunoregulatory ability, but the effectiveness of utilizing LJP alone is unsatisfactory. As a result, we innovatively encapsulated LJP in into the exosomes derived from mouse bone mesenchymal stem cells (BMSCs) to form a DC-activated inducer (LJP-exosome). LJP-exosomes possessed a profound ability to target lymph nodes and the co-stimulatory capability of DCs compared with the application of LJP alone. Adequate results have shown that DCs primed by LJP-exosomes enhanced the tumor-reactive CD8+ T cell responses, leading to prophylactic tumor inhibition in an immunologically ignorant tumor model. The study proposed offers a promising strategy for enhancing the immune activation efficacy of extracted polysaccharides of traditional Chinese medicine by building the patients' immunity, thus consolidating the overall prognosis.
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Affiliation(s)
- Jiatong Zhang
- The Clinical Department, College of Veterinary Medicine, China Agricultural University, No. 2, Yuanmingyuan West Road, Haidian District, Beijing 100193, China
| | - Jintong Liu
- The Clinical Department, College of Veterinary Medicine, China Agricultural University, No. 2, Yuanmingyuan West Road, Haidian District, Beijing 100193, China
| | - Hong Zhang
- The Eighth Medical Center of the Chinese People's Liberation Army General Hospital, Beijing, China
| | - Biao Liu
- The Clinical Department, College of Veterinary Medicine, China Agricultural University, No. 2, Yuanmingyuan West Road, Haidian District, Beijing 100193, China
| | - Lujie Li
- The Clinical Department, College of Veterinary Medicine, China Agricultural University, No. 2, Yuanmingyuan West Road, Haidian District, Beijing 100193, China
| | - Yifan Li
- The Clinical Department, College of Veterinary Medicine, China Agricultural University, No. 2, Yuanmingyuan West Road, Haidian District, Beijing 100193, China
| | - Jingrou Pei
- The Clinical Department, College of Veterinary Medicine, China Agricultural University, No. 2, Yuanmingyuan West Road, Haidian District, Beijing 100193, China
| | - Qiao Lin
- The Clinical Department, College of Veterinary Medicine, China Agricultural University, No. 2, Yuanmingyuan West Road, Haidian District, Beijing 100193, China
| | - Qi Chen
- Molecular and Nanoscale Physics Group, School of Physics and Astronomy, University of Leeds, Leeds LS2 9JT, UK
| | - Jiahao Lin
- The Clinical Department, College of Veterinary Medicine, China Agricultural University, No. 2, Yuanmingyuan West Road, Haidian District, Beijing 100193, China
- Center of Research and Innovation of Chinese Traditional Veterinary Medicine, China Agricultural University, Beijing, China
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Wang Y, Zhou H, Ju S, Dong X, Zheng C. The solid tumor microenvironment and related targeting strategies: a concise review. Front Immunol 2025; 16:1563858. [PMID: 40207238 PMCID: PMC11979131 DOI: 10.3389/fimmu.2025.1563858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Accepted: 03/12/2025] [Indexed: 04/11/2025] Open
Abstract
The malignant tumor is a serious disease threatening human life. Increasing studies have confirmed that the tumor microenvironment (TME) is composed of a variety of complex components that precisely regulate the interaction of tumor cells with other components, allowing tumor cells to continue to proliferate, resist apoptosis, evade immune surveillance and clearance, and metastasis. However, the characteristics of each component and their interrelationships remain to be deeply understood. To target TME, it is necessary to deeply understand the role of various components of TME in tumor growth and search for potential therapeutic targets. Herein, we innovatively classify the TME into physical microenvironment (such as oxygen, pH, etc.), mechanical microenvironment (such as extracellular matrix, blood vessels, etc.), metabolic microenvironment (such as glucose, lipids, etc.), inflammatory microenvironment and immune microenvironment. We introduce a concise but comprehensive classification of the TME; depict the characteristics of each component in TME; summarize the existing methods for detecting each component in TME; highlight the current strategies and potential therapeutic targets for TME; discuss current challenges in presenting TME and its clinical applications; and provide our prospect on the future research direction and clinical benefits of TME.
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Affiliation(s)
- Yingliang Wang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, China
- Hubei Provincial Clinical Research Center for Precision Radiology & Interventional Medicine, Wuhan, China
| | - Huimin Zhou
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuguang Ju
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, China
- Hubei Provincial Clinical Research Center for Precision Radiology & Interventional Medicine, Wuhan, China
| | - Xiangjun Dong
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, China
- Hubei Provincial Clinical Research Center for Precision Radiology & Interventional Medicine, Wuhan, China
| | - Chuansheng Zheng
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, China
- Hubei Provincial Clinical Research Center for Precision Radiology & Interventional Medicine, Wuhan, China
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8
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Bayat M, Nahand JS. Battlegrounds of treatment resistance: decoding the tumor microenvironment. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04055-5. [PMID: 40131387 DOI: 10.1007/s00210-025-04055-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Accepted: 03/12/2025] [Indexed: 03/27/2025]
Abstract
The tumor microenvironment (TME) emerges as a formidable actor in the cancer treatment landscape, wielding the power to thwart therapeutic efficacy across various modalities, including chemotherapy, radiotherapy, immunotherapy, targeted therapy, and hormonal therapy. This intricate ecosystem comprising diverse cellular constituents, signaling molecules, and the extracellular matrix fosters a dynamic interplay that profoundly influences tumor behavior and treatment outcomes. This review explores the mechanisms through which the TME drives resistance to standard therapies, emphasizing key factors such as hypoxia, immune evasion, and metabolic reprogramming. Furthermore, we illuminate innovative strategies aimed at reprogramming this hostile environment, including the application of therapeutic vaccines, CAR T cell therapy, and combination immunotherapies designed to enhance anti-tumor responses. By advocating for multidimensional approaches that dismantle the TME's barriers to effective treatment, this review calls for a transformative shift in cancer treatment paradigms. By bridging the gap between the TME's complexities and targeted therapeutic strategies, we pave the way for targeted interventions that promise to enhance clinical outcomes and improve patient prognosis in the relentless battle against cancer.
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Affiliation(s)
- Mobina Bayat
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javid Sadri Nahand
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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9
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Shah DD, Chorawala MR, Raghani NR, Patel R, Fareed M, Kashid VA, Prajapati BG. Tumor microenvironment: recent advances in understanding and its role in modulating cancer therapies. Med Oncol 2025; 42:117. [PMID: 40102282 DOI: 10.1007/s12032-025-02641-4] [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: 01/06/2025] [Accepted: 02/24/2025] [Indexed: 03/20/2025]
Abstract
Tumor microenvironment (TME) denotes the non-cancerous cells and components presented in the tumor, including molecules produced and released by them. Interactions between cancer cells, immune cells, stromal cells, and the extracellular matrix within the TME create a dynamic ecosystem that can either promote or hinder tumor growth and spread. The TME plays a pivotal role in either promoting or inhibiting tumor growth and dissemination, making it a critical factor to consider in the development of effective cancer therapies. Understanding the intricate interplay within the TME is crucial for devising effective cancer therapies. Combination therapies involving inhibitors of immune checkpoint blockade (ICB), and/or chemotherapy now offer new approaches for cancer therapy. However, it remains uncertain how to best utilize these strategies in the context of the complex tumor microenvironment. Oncogene-driven changes in tumor cell metabolism can impact the TME to limit immune responses and present barriers to cancer therapy. Cellular and acellular components in tumor microenvironment can reprogram tumor initiation, growth, invasion, metastasis, and response to therapies. Components in the TME can reprogram tumor behavior and influence responses to treatments, facilitating immune evasion, nutrient deprivation, and therapeutic resistance. Moreover, the TME can influence angiogenesis, promoting the formation of blood vessels that sustain tumor growth. Notably, the TME facilitates immune evasion, establishes a nutrient-deprived milieu, and induces therapeutic resistance, hindering treatment efficacy. A paradigm shift from a cancer-centric model to a TME-centric one has revolutionized cancer research and treatment. However, effectively targeting specific cells or pathways within the TME remains a challenge, as the complexity of the TME poses hurdles in designing precise and effective therapies. This review highlights challenges in targeting the tumor microenvironment to achieve therapeutic efficacy; explore new approaches and technologies to better decipher the tumor microenvironment; and discuss strategies to intervene in the tumor microenvironment and maximize therapeutic benefits.
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Affiliation(s)
- Disha D Shah
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad, Gujarat, 380009, India
| | - Mehul R Chorawala
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad, Gujarat, 380009, India.
| | - Neha R Raghani
- Department of Pharmacology and Pharmacy Practice, Saraswati Institute of Pharmaceutical Sciences, Gandhinagar, Gujarat, 382355, India
| | - Rajanikant Patel
- Department of Product Development, Granules Pharmaceuticals Inc., 3701 Concorde Parkway, Chantilly, VA, 20151, USA
| | - Mohammad Fareed
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, P.O. Box 71666, 13713, Riyadh, Saudi Arabia
| | - Vivekanand A Kashid
- MABD Institute of Pharmaceutical Education and Research, Babhulgaon, Yeola, Nashik, India
| | - Bhupendra G Prajapati
- Department of Pharmaceutics and Pharmaceutical Technology, Shree S. K. Patel College of Pharmaceutical Education & Research, Ganpat University, Kherva, Mehsana, Gujarat, 384012, India.
- Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, 73000, Thailand.
- Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India.
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10
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Jiang R, Fang Q, Liu W, Chen L, Yang H. Recent Progress in Radiosensitive Nanomaterials for Radiotherapy-Triggered Drug Release. ACS APPLIED MATERIALS & INTERFACES 2025; 17:14801-14821. [PMID: 40014050 DOI: 10.1021/acsami.4c23023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/28/2025]
Abstract
Benefiting from the unique properties of ionizing radiation, such as high tissue penetration, spatiotemporal resolution, and clinical relevance compared with other external stimuli, radiotherapy-induced drug release strategies are showing great promise in developing effective and personalized cancer treatments. However, the requirement of high doses of X-ray irradiation to break chemical bonds for drug release limits the application of radiotherapy-induced prodrug activation in clinics. Recent advances in nanomaterials offer a promising approach for radiotherapy sensitization as well as integrating multiple modalities for improved therapy outcomes. In particular, the catalytic radiosensitization that utilizes electrons and energy generated by nanomaterials upon X-ray irradiation has demonstrated excellent potential for enhanced radiotherapy. In this Review, we summarize the design principles of X-ray-responsive chemical bonds for controlled drug release, strategies for catalytic radiosensitization, and recent progress of X-ray-responsive nanoradiosensitizers for enhanced radiotherapy by integration with chemotherapy, chemodynamic therapy, photodynamic therapy, photothermal therapy, gas therapy, and immunotherapy. Finally, we discuss the challenges of X-ray-responsive nanoradiosensitizers heading toward possible clinical translation. We expect that emerging strategies based on radiotherapy-triggered drug release will facilitate a frontier in accurate and effective cancer therapy in the near future.
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Affiliation(s)
- Renfeng Jiang
- New Cornerstone Science Laboratory, MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry, Fuzhou University, Fuzhou 350108, China
| | - Qiong Fang
- New Cornerstone Science Laboratory, MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry, Fuzhou University, Fuzhou 350108, China
| | - Wenjun Liu
- New Cornerstone Science Laboratory, MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry, Fuzhou University, Fuzhou 350108, China
| | - Lanlan Chen
- New Cornerstone Science Laboratory, MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry, Fuzhou University, Fuzhou 350108, China
| | - Huanghao Yang
- New Cornerstone Science Laboratory, MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry, Fuzhou University, Fuzhou 350108, China
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11
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Zhang YZ, Ma Y, Ma E, Chen X, Zhang Y, Yin B, Zhao J. Sophisticated roles of tumor microenvironment in resistance to immune checkpoint blockade therapy in hepatocellular carcinoma. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2025; 8:10. [PMID: 40051497 PMCID: PMC11883234 DOI: 10.20517/cdr.2024.165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 01/13/2025] [Accepted: 02/21/2025] [Indexed: 03/09/2025]
Abstract
Hepatocellular carcinoma (HCC) remains a serious threat to global health, with rising incidence and mortality rates. Therapeutic options for advanced HCC are quite limited, and the overall prognosis remains poor. Recent advancements in immunotherapy, particularly immune-checkpoint blockade (ICB) targeting anti-PD1/PD-L1 and anti-CTLA4, have facilitated a paradigm shift in cancer treatment, demonstrating substantial survival benefits across various cancer types, including HCC. However, only a subset of HCC patients exhibit a favorable response to ICB therapy, and its efficacy is often hindered by the development of resistance. There are many studies to explore the underlying mechanisms of ICB response. In this review, we compiled the latest progression in immunotherapies for HCC and systematically summarized the sophisticated mechanisms by which components of the tumor microenvironment (TME) regulate resistance to ICB therapy. Additionally, we also outlined some scientific rationale strategies to boost antitumor immunity and enhance the efficacy of ICB in HCC. These insights may serve as a roadmap for future research and help improve outcomes for HCC patients.
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Affiliation(s)
- Yi-Zhe Zhang
- Hepatobiliary Surgery Center, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Authors contributed equally
| | - Yunshu Ma
- Hepatobiliary Surgery Center, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Authors contributed equally
| | - Ensi Ma
- Liver Transplantation Center, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Institute of Organ Transplantation, Fudan University, Shanghai 200040, China
| | - Xizhi Chen
- Hepatobiliary Surgery Center, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Yue Zhang
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang, China
| | - Baobing Yin
- Hepatobiliary Surgery Center, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Department of Hepatobiliary surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, Fujian, China
| | - Jing Zhao
- Hepatobiliary Surgery Center, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Department of Hepatobiliary surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, Fujian, China
- Cancer Metastasis Institute, Fudan University, Shanghai 201206, China
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12
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Jin K, Chu X, Qian J. Arginine and colorectal cancer: Exploring arginine-related therapeutic strategies and novel insights into cancer immunotherapies. Int Immunopharmacol 2025; 148:114146. [PMID: 39879835 DOI: 10.1016/j.intimp.2025.114146] [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: 05/05/2024] [Revised: 01/02/2025] [Accepted: 01/21/2025] [Indexed: 01/31/2025]
Abstract
Concerning the progression of societies and the evolution of lifestyle and dietary habits, the potential for the development of human malignancies, particularly colorectal cancer (CRC), has markedly escalated, positioning it as one of the most prevalent and lethal forms of cancer globally. Empirical evidence indicates that the metabolic processes of cancerous and healthy cells can significantly impact immune responses and the fate of tumors. Arginine, a multifaceted amino acid, assumes a crucial and paradoxical role in various metabolic pathways, as certain tumors exhibit arginine auxotrophy while others do not. Notably, CRC is classified as arginine non-auxotrophic, possessing the ability to synthesize arginine from citrulline. Systemic arginine deprivation and the inhibition of arginine uptake represent two prevalent therapeutic strategies in oncological treatment. However, given the divergent behaviors of tumors concerning the metabolism and synthesis of arginine, one of these therapeutic approaches-namely systemic arginine deprivation-does not apply to CRC. This review elucidates the characteristics of arginine uptake inhibition and systemic arginine deprivation alongside their respective benefits and limitations in CRC. Furthermore, the involvement of arginine in immunotherapeutic strategies is examined in light of the most recent discoveries on various human malignancies.
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Affiliation(s)
- Ketao Jin
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310003, China.
| | - Xiufeng Chu
- Department of General Surgery, Shaoxing Central Hospital, Shaoxing, Zhejiang 312030, China
| | - Jun Qian
- Department of Colorectal Surgery, Xinchang People's Hospital, Affiliated Xinchang Hospital, Wenzhou Medical University, Xinchang, Zhejiang 312500, China.
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13
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Hosseini SA, Nasab NK, Kargozar S, Wang AZ. Advanced biomaterials and scaffolds for cancer immunotherapy. BIOMATERIALS FOR PRECISION CANCER MEDICINE 2025:377-424. [DOI: 10.1016/b978-0-323-85661-4.00016-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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14
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Rosenthal I, Padler-Karavani V. Current Landscape of Therapeutic Cancer Vaccines. Methods Mol Biol 2025; 2926:1-14. [PMID: 40266513 DOI: 10.1007/978-1-0716-4542-0_1] [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: 04/24/2025]
Abstract
Cancer vaccines aim to harness the immune system for prevention or treatment of the disease. This is achieved by immunizing against target antigens that are specific/associated with cancer. Myriad of particulate materials or cell-based strategies have been developed to induce immune responses against cancer antigens, using protein/peptide antigens, DNA or RNA, viral antigens, viral or bacterial vectors, embryonic material, whole tumor lysate, dendritic cells, red blood cells, exosomes, liposomes, engineered bioinspired and biomimetic vaccines and glycosylation-based vaccines. Several key factors affect the safety and efficacy of therapeutic cancer vaccines, including identification of potent neoantigens, dosage, adjuvant and regimen of immunization, route of administration and delivery methods, as well as overcoming intrinsic and extrinsic resistance mechanisms. More recently, novel approaches for improving cancer vaccines have been explored, such as intratumoral vaccinations, oncolytic viruses, and combination immunotherapies. This chapter aims to provide a glimpse into some of the most common approaches for therapeutic cancer vaccines.
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Affiliation(s)
- Inbal Rosenthal
- Department of Cell Research and Immunology, The Shmunis School of Biomedicine and Cancer Research, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Vered Padler-Karavani
- Department of Cell Research and Immunology, The Shmunis School of Biomedicine and Cancer Research, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
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15
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Au KM, Swinnea JS, Wang AZ. Intratumoral Injectable Redox-Responsive Immune Niche Improves the Abscopal Effect in Radiotherapy. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2025; 37:e2411330. [PMID: 39501983 PMCID: PMC11710980 DOI: 10.1002/adma.202411330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 10/03/2024] [Indexed: 01/11/2025]
Abstract
Radiotherapy (XRT) is often utilized to improve the immune checkpoint blockade response in cancer management. Such combination treatment can enhance the abscopal effect, facilitating a prolonged and durable systemic response. However, despite intense research efforts, only a minority of patients respond to this approach, and novel strategies to increase the abscopal effect are urgently needed. Here, the development of an intratumoral (i.t.) injectable nanofiber (NF)-based tumor immune niche (TIN) that converts XRT-treated tumors into an in situ cancer vaccine, eliciting robust systemic antitumor immunity, is reported. This NF-based immune niche incorporates redox-degradable anti-CTLA-4 (α-CTLA-4) nanogels (NGs) and interleukin-2 (IL-2) NGs for controlled release in hypoxic irradiated tumors, reversing the immunosuppressive tumor microenvironment into a pro-inflammatory microenvironment, and expanding the tumor-infiltrating CD8+ T cell population. Additionally, it is functionalized with polyinosinic-polycytidylic acid (poly(I:C)) to promote antigen-presenting cell maturation and prime neoantigen-specific CD8+ T cells. In vitro studies demonstrate TIN's ability to prime antigen-specific CD8+ T cells and increase antigen-specific cell-killing efficiency under in vitro immunosuppressive conditions. In vivo studies confirm TIN's ability to elicit robust systemic anticancer activity in mouse melanoma and colorectal cancer models without inducing severe immune-related adverse events.
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Affiliation(s)
- Kin Man Au
- Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75230, USA
| | - J. Steven Swinnea
- Department of Chemical Engineering, University of Texas at Austin, 200 E Dean Keeton St, Austin, TX 78712, USA
| | - Andrew Z. Wang
- Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75230, USA
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16
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Shi R, Ran L, Tian Y, Guo W, Zhao L, Jin S, Cheng J, Zhang Z, Ma Y. Prospects and challenges of neoantigen applications in oncology. Int Immunopharmacol 2024; 143:113329. [PMID: 39405926 DOI: 10.1016/j.intimp.2024.113329] [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: 07/23/2024] [Revised: 09/11/2024] [Accepted: 10/02/2024] [Indexed: 10/30/2024]
Abstract
Neoantigen, unique peptides resulting from tumor-specific mutations, represent a promising frontier in oncology for personalized cancer immunotherapy. Their unique features allow for the development of highly specific and effective cancer treatments, which can potentially overcome the limitations of conventional therapies. This paper explores the current prospects and challenges associated with the application of neoantigens in oncology. We examine the latest advances in neoantigen identification, vaccine development, and adoptive T cell therapy. Additionally, we discuss the obstacles related to neoantigen heterogeneity, immunogenicity prediction, and the tumor microenvironment. Through a comprehensive analysis of current research and clinical trials, this paper aims to provide a detailed overview of how neoantigens could revolutionize cancer treatment and the hurdles that must be overcome to realize their full potential.
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Affiliation(s)
- Ranran Shi
- Department of Basic Medical Sciences, Luohe Medical College, Luohe 462000, China; Henan Province Engineering & Technology Research Center of Foods for Special Medical Purpose, Luohe Medical College, Luohe 462000, China
| | - Ling Ran
- Department of Basic Medical Sciences, Luohe Medical College, Luohe 462000, China; Henan Province Engineering & Technology Research Center of Foods for Special Medical Purpose, Luohe Medical College, Luohe 462000, China
| | - Yuan Tian
- Department of Basic Medical Sciences, Luohe Medical College, Luohe 462000, China; Henan Province Engineering & Technology Research Center of Foods for Special Medical Purpose, Luohe Medical College, Luohe 462000, China
| | - Wei Guo
- Department of Basic Medical Sciences, Luohe Medical College, Luohe 462000, China
| | - Lifang Zhao
- Department of Basic Medical Sciences, Luohe Medical College, Luohe 462000, China; Henan Province Engineering & Technology Research Center of Foods for Special Medical Purpose, Luohe Medical College, Luohe 462000, China
| | - Shaoju Jin
- Department of Basic Medical Sciences, Luohe Medical College, Luohe 462000, China; Henan Province Engineering & Technology Research Center of Foods for Special Medical Purpose, Luohe Medical College, Luohe 462000, China
| | - Jiang Cheng
- Department of Basic Medical Sciences, Luohe Medical College, Luohe 462000, China; Department of Neurology, General Hospital of Ningxia Medical University, Yinchuan 750000, China
| | - Zhe Zhang
- School of Sciences, Henan University of Technology, Zhengzhou 450001, China.
| | - Yongchao Ma
- Department of Basic Medical Sciences, Luohe Medical College, Luohe 462000, China.
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17
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Ma X, Mao M, Liu Z, Liang C, He J, Qu Y, Xu L, Cheng R, Zhuang W, Lei Y, Nie W, Yuan L, Pang DW, Xie HY. AND-Gate Logic Förster Resonance Energy Transfer/Magnetic Resonance Tuning Nanoprobe for Programmable Antitumor Immunity Imaging. J Am Chem Soc 2024; 146:31873-31884. [PMID: 39504515 DOI: 10.1021/jacs.4c11072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2024]
Abstract
Simultaneous detection of different biomarkers related to the spatiotemporally dynamic immune events is of particular importance for the accurate evaluation of antitumor immune effects. Here, we have developed an AND-gate logic dual resonance energy transfer nanoprobe (named DRET) for dynamic monitoring of programmed CD8+ T cell activation and tumor cell apoptosis. Immunotherapy-induced granzyme B secretion from CD8+ T cells and the subsequent caspase-3 release from apoptotic tumor cells individually activate one of the tiers of the "AND-gate" logic DRET. The resulting fluorescence recovery and magnetic resonance T1 enhancement can be used for precise immunomodulatory drug screening, early efficacy prediction, and immune stratification. Particularly, not only "Responders" can be distinguished from "Non-responders", but also "Acquired resistance" can be identified from "Maintain responders", providing a novel approach to put forward the accurate evaluation of antitumor immunity.
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Affiliation(s)
- Xianbin Ma
- School of Medical Technology, Beijing Institute of Technology, Beijing 100081, P. R. China
| | - Mingchuan Mao
- School of Medical Technology, Beijing Institute of Technology, Beijing 100081, P. R. China
| | - Zhenya Liu
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Frontiers Science Center for New Organic Matter, Research Center for Analytical Sciences, College of Chemistry, Nankai University, Tianjin 300071, P. R. China
| | - Chao Liang
- School of Life Science, Beijing Institute of Technology, Beijing 100081, P. R. China
| | - Jiaqi He
- School of Life Science, Beijing Institute of Technology, Beijing 100081, P. R. China
| | - Yun Qu
- School of Life Science, Beijing Institute of Technology, Beijing 100081, P. R. China
| | - Luzheng Xu
- Medical and Health Analysis Center, Peking University, Beijing 100191, P. R. China
| | - Ran Cheng
- School of Life Science, Beijing Institute of Technology, Beijing 100081, P. R. China
| | - Wanru Zhuang
- State Key Laboratory of Natural and Biomimetic Drugs, Chemical Biology Center, School of Pharmaceutical Sciences, Peking University, Beijing 100191, P. R. China
| | - Yao Lei
- State Key Laboratory of Natural and Biomimetic Drugs, Chemical Biology Center, School of Pharmaceutical Sciences, Peking University, Beijing 100191, P. R. China
| | - Weidong Nie
- School of Life Science, Beijing Institute of Technology, Beijing 100081, P. R. China
| | - Lan Yuan
- Medical and Health Analysis Center, Peking University, Beijing 100191, P. R. China
| | - Dai-Wen Pang
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Frontiers Science Center for New Organic Matter, Research Center for Analytical Sciences, College of Chemistry, Nankai University, Tianjin 300071, P. R. China
| | - Hai-Yan Xie
- State Key Laboratory of Natural and Biomimetic Drugs, Chemical Biology Center, School of Pharmaceutical Sciences, Peking University, Beijing 100191, P. R. China
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18
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Wu B, Zhang B, Li B, Wu H, Jiang M. Cold and hot tumors: from molecular mechanisms to targeted therapy. Signal Transduct Target Ther 2024; 9:274. [PMID: 39420203 PMCID: PMC11491057 DOI: 10.1038/s41392-024-01979-x] [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: 04/17/2024] [Revised: 08/20/2024] [Accepted: 09/12/2024] [Indexed: 10/19/2024] Open
Abstract
Immunotherapy has made significant strides in cancer treatment, particularly through immune checkpoint blockade (ICB), which has shown notable clinical benefits across various tumor types. Despite the transformative impact of ICB treatment in cancer therapy, only a minority of patients exhibit a positive response to it. In patients with solid tumors, those who respond well to ICB treatment typically demonstrate an active immune profile referred to as the "hot" (immune-inflamed) phenotype. On the other hand, non-responsive patients may exhibit a distinct "cold" (immune-desert) phenotype, differing from the features of "hot" tumors. Additionally, there is a more nuanced "excluded" immune phenotype, positioned between the "cold" and "hot" categories, known as the immune "excluded" type. Effective differentiation between "cold" and "hot" tumors, and understanding tumor intrinsic factors, immune characteristics, TME, and external factors are critical for predicting tumor response and treatment results. It is widely accepted that ICB therapy exerts a more profound effect on "hot" tumors, with limited efficacy against "cold" or "altered" tumors, necessitating combinations with other therapeutic modalities to enhance immune cell infiltration into tumor tissue and convert "cold" or "altered" tumors into "hot" ones. Therefore, aligning with the traits of "cold" and "hot" tumors, this review systematically delineates the respective immune characteristics, influencing factors, and extensively discusses varied treatment approaches and drug targets based on "cold" and "hot" tumors to assess clinical efficacy.
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Affiliation(s)
- Bo Wu
- Department of Neurology, The Fourth Affiliated Hospital, China Medical University, Shenyang, China
| | - Bo Zhang
- Department of Youth League Committee, The Fourth Affiliated Hospital, China Medical University, Shenyang, China
| | - Bowen Li
- Department of Pancreatic and Gastrointestinal Surgery, Ningbo No. 2 Hospital, Ningbo, China
| | - Haoqi Wu
- Department of Gynaecology and Obstetrics, The Second Hospital of Dalian Medical University, Dalian, China
| | - Meixi Jiang
- Department of Neurology, The Fourth Affiliated Hospital, China Medical University, Shenyang, China.
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19
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Han J, Sheng T, Zhang Y, Cheng H, Gao J, Yu J, Gu Z. Bioresponsive Immunotherapeutic Materials. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2209778. [PMID: 36639983 DOI: 10.1002/adma.202209778] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Revised: 12/31/2022] [Indexed: 06/17/2023]
Abstract
The human immune system is an interaction network of biological processes, and its dysfunction is closely associated with a wide array of diseases, such as cancer, infectious diseases, tissue damage, and autoimmune diseases. Manipulation of the immune response network in a desired and controlled fashion has been regarded as a promising strategy for maximizing immunotherapeutic efficacy and minimizing side effects. Integration of "smart" bioresponsive materials with immunoactive agents including small molecules, biomacromolecules, and cells can achieve on-demand release of agents at targeted sites to reduce overdose-related toxicity and alleviate off-target effects. This review highlights the design principles of bioresponsive immunotherapeutic materials and discusses the critical roles of controlled release of immunoactive agents from bioresponsive materials in recruiting, housing, and manipulating immune cells for evoking desired immune responses. Challenges and future directions from the perspective of clinical translation are also discussed.
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Affiliation(s)
- Jinpeng Han
- Zhejiang Provincial Key Laboratory for Advanced Drug Delivery Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Tao Sheng
- Zhejiang Provincial Key Laboratory for Advanced Drug Delivery Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Yuqi Zhang
- Zhejiang Provincial Key Laboratory for Advanced Drug Delivery Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
- Department of Burns and Wound Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Hao Cheng
- Department of Materials Science and Engineering, Drexel University, Philadelphia, PA, 19104, USA
| | - Jianqing Gao
- Zhejiang Provincial Key Laboratory for Advanced Drug Delivery Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
- Cancer Center, Zhejiang University, Hangzhou, 310058, China
- Jinhua Institute of Zhejiang University, Jinhua, 321299, China
| | - Jicheng Yu
- Zhejiang Provincial Key Laboratory for Advanced Drug Delivery Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
- Jinhua Institute of Zhejiang University, Jinhua, 321299, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
- Department of General Surgery, Sir Run Run Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China
| | - Zhen Gu
- Zhejiang Provincial Key Laboratory for Advanced Drug Delivery Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
- Jinhua Institute of Zhejiang University, Jinhua, 321299, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
- Department of General Surgery, Sir Run Run Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China
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20
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Fu M, Li J, Xuan Z, Zheng Z, Liu Y, Zhang Z, Zheng J, Zhong M, Liu B, Du Y, Zhang L, Sun H. NDR1 mediates PD-L1 deubiquitination to promote prostate cancer immune escape via USP10. Cell Commun Signal 2024; 22:429. [PMID: 39227807 PMCID: PMC11370014 DOI: 10.1186/s12964-024-01805-5] [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: 06/12/2024] [Accepted: 08/22/2024] [Indexed: 09/05/2024] Open
Abstract
Prostate cancer (PCa) is one of the most common male genitourinary system malignancies. Despite the significant benefits of anti-PD-L1 immune checkpoint inhibitor therapy in other cancers, the reasons for its poor therapeutic efficacy in prostate cancer (PCa) remain unclear.NDR1 plays an important role in innate immunity, but its role in tumor immunity and immunotherapy has not been investigated. The role of NDR1 in the immune microenvironment of PCa and the related mechanisms are unknown. Here, we found a positive correlation between NDR1 and PD-L1 expression in PCa. NDR1 significantly inhibits CD8 + T cell infiltration and function, thereby promoting immune escape in prostate cancer.More importantly, NDR1 inhibition significantly enhanced CD8 + T cell activation, which enhanced the therapeutic effect of anti-PD-L1. Mechanistic studies revealed that NDR1 inhibits ubiquitination-mediated PD-L1 degradation via the deubiquitinase USP10, upregulates PD-L1, and promotes PCa immune escape. Thus, our study suggests a unique PD-L1 regulatory mechanism underlying PCa immunotherapy failure. The significance of NDR1 in PCa immune escape and its mechanism of action were clarified, and combined NDR1/PD-L1 inhibition was suggested as an approach to boost PCa immunotherapy effectiveness.
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Affiliation(s)
- Meiling Fu
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Jinxin Li
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Zuodong Xuan
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Zeyuan Zheng
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Yankuo Liu
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Zeyi Zhang
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Jianzhong Zheng
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Min Zhong
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Bin Liu
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Yifan Du
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Lei Zhang
- School of Public Health, Xiamen University, Xiamen, 361101, China.
| | - Huimin Sun
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China.
- Central Laboratory, School of Medicine, Xiang'an Hospital of Xiamen University, Xiamen University, Xiamen, 361101, China.
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21
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Li Y, Tong F, Wang Y, Wang J, Wu M, Li H, Guo H, Gao H. I n situ tumor vaccine with optimized nanoadjuvants and lymph node targeting capacity to treat ovarian cancer and metastases. Acta Pharm Sin B 2024; 14:4102-4117. [PMID: 39309485 PMCID: PMC11413692 DOI: 10.1016/j.apsb.2024.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 04/17/2024] [Accepted: 04/20/2024] [Indexed: 09/25/2024] Open
Abstract
Tumor vaccine, a promising modality of tumor immunotherapy, needs to go through the process of tumor antigen generation and loading, antigen drainage to lymph nodes (LNs), antigen internalization by dendritic cells (DCs), DC maturation, and antigen cross-presentation to activate T-cells. However, tumor vaccines are often unable to satisfy all the steps, leading to the limitation of their application and efficacy. Herein, based on a smart nanogel system, an in situ nano-vaccine (CpG@Man-P/Tra/Gel) targeting LNs was constructed to induce potent anti-tumor immune effects and inhibit the recurrence and metastasis of ovarian cancer. The CpG@Man-P/Tra/Gel exhibited MMP-2-sensitive release of trametinib (Tra) and nano-adjuvant CPG@Man-P, which generated abundant in situ depot of whole-cell tumor antigens and formed in situ nano-vaccines with CpG@Man-P. Benefiting from mannose (Man) modification, the nano-vaccines targeted to LNs, promoted the uptake of antigens by DCs, further inducing the maturation of DCs and activation of T cells. Moreover, CpG@Man-P with different particle sizes were prepared and the effective size was selected to evaluate the antitumor effect and immune response in vivo. Notably, combined with PD-1 blocking, the vaccine effectively inhibited primary tumor growth and induced tumor-specific immune response against tumor recurrence and metastasis of ovarian cancer.
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Affiliation(s)
- Yuan Li
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China
| | - Fan Tong
- Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Yufan Wang
- Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Jing Wang
- Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Manqi Wu
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China
| | - Hanmei Li
- School of Food and Biological Engineering, Chengdu University, Chengdu 610106, China
| | - Hongyan Guo
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China
| | - Huile Gao
- Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
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22
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Li C, Wang M, Li PF, Sheng J, Fu Q. Construction of Smart DNA-Based Drug Delivery Systems for Cancer Therapy. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2306257. [PMID: 38377302 DOI: 10.1002/smll.202306257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 02/10/2024] [Indexed: 02/22/2024]
Abstract
Due to the disadvantages of poor targeting, slow action, and low effectiveness of current commonly used cancer treatments, including surgery, chemotherapy, and radiotherapy, researchers have turned to DNA as a biomaterial for constructing drug delivery nanocarriers. DNA is favored for its biocompatibility and programmability. In order to overcome the limitations associated with traditional drug delivery systems (DDSs), researchers have developed smart-responsive DNA DDSs that can control drug release in response to specific physical or chemical stimuli at targeted sites. In this review, a summary of multiple targeted ligand structures is provided, various shapes of stable DNA nanomaterials, and different stimuli-responsive drug release strategies in DNA DDSs. Specifically, targeted cell recognition, in vivo stable transport, and controlled drug release of smart DDSs are focused. Finally, the further development prospects and challenges of clinical application of DNA nanomaterials in the field of smart drug delivery are discussed. The objective of this review is to enhance researchers' comprehension regarding the potential application of DNA nanomaterials in precision drug delivery, with the aim of expediting the clinical implementation of intelligent DDSs.
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Affiliation(s)
- Congcong Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266021, China
| | - Mengzhen Wang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266021, China
| | - Pei-Feng Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266021, China
| | - Junyue Sheng
- Qingdao No.58 High School of Shandong Province, 20 Jiushui Road, Qingdao, 266100, China
| | - Qinrui Fu
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266021, China
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23
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Luo Y, Luo X, Ru Y, Zhou X, Liu D, Huang Q, Linghu M, Wu Y, Lv Z, Chen M, Ma Y, Huang Y, Wang J. Copper(II)-Based Nano-Regulator Correlates Cuproptosis Burst and Sequential Immunogenic Cell Death for Synergistic Cancer Immunotherapy. Biomater Res 2024; 28:0039. [PMID: 38938647 PMCID: PMC11208873 DOI: 10.34133/bmr.0039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 05/08/2024] [Indexed: 06/29/2024] Open
Abstract
Immunogenic cell death (ICD) of tumor cells serves as a crucial initial signal in the activation of anti-tumor immune responses, holding marked promise in the field of tumor immunotherapy. However, low immunogenicity tumors pose challenges in achieving complete induction of ICD, thereby limiting the response rates of immunotherapy in clinical patients. The emergence of cuproptosis as a new form of regulated cell death has presented a promising strategy for enhanced immunotherapy of low immunogenic tumors. To trigger cuproptosis, copper-ionophore elesclomol (ES) had to be employed for the copper-transporting-mediated process. Herein, we proposed a copper(II)-based metal-organic framework nanoplatform (Cu-MOF) to facilitate a cooperative delivery of encapsulated ES and copper (ES-Cu-MOF) to induce cuproptosis burst and enhance ICD of fibrosarcoma. Our results showed that the ES-Cu-MOF nano-regulator could effectively release Cu2+ and ES in response to the intracellular environment, resulting in elevated mitochondrial ROS generation and initiated cuproptosis of tumor cells. Furthermore, sequential ICDs were significantly triggered via the ES-Cu-MOF nano-regulator to activate the anti-tumor immune response. The results of tumor inhibition experiment indicated that the nano-regulator of ES-Cu-MOF obviously accumulated in the tumor site, inducing ICD for dendritic cell activation. This enabled an increased infiltration of cytotoxic CD8+ T cells and consequently enhanced antitumor immune responses for successfully suppressing fibrosarcoma growth. Thus, the copper(II)-based metal-organic framework nano-regulator offered a promising approach for inducing cuproptosis and cuproptosis-stimulated ICD for cancer immunotherapy.
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Affiliation(s)
- Yingli Luo
- Wuxi School of Medicine,
Jiangnan University, Wuxi, Jiangsu 214122, PR China
- Affiliated Hospital of Jiangnan University,
Jiangnan University, Wuxi, Jiangsu 214062, PR China
| | - Xianyu Luo
- Wuxi School of Medicine,
Jiangnan University, Wuxi, Jiangsu 214122, PR China
| | - Yi Ru
- Wuxi School of Medicine,
Jiangnan University, Wuxi, Jiangsu 214122, PR China
| | - Xinru Zhou
- Wuxi School of Medicine,
Jiangnan University, Wuxi, Jiangsu 214122, PR China
| | - Didi Liu
- Wuxi School of Medicine,
Jiangnan University, Wuxi, Jiangsu 214122, PR China
| | - Qian Huang
- Wuxi School of Medicine,
Jiangnan University, Wuxi, Jiangsu 214122, PR China
| | - Maoyuan Linghu
- Wuxi School of Medicine,
Jiangnan University, Wuxi, Jiangsu 214122, PR China
| | - Yuhang Wu
- Wuxi School of Medicine,
Jiangnan University, Wuxi, Jiangsu 214122, PR China
| | - Zicheng Lv
- Wuxi School of Medicine,
Jiangnan University, Wuxi, Jiangsu 214122, PR China
| | - Meimei Chen
- Wuxi School of Medicine,
Jiangnan University, Wuxi, Jiangsu 214122, PR China
| | - Yinchu Ma
- Wuxi School of Medicine,
Jiangnan University, Wuxi, Jiangsu 214122, PR China
- Affiliated Hospital of Jiangnan University,
Jiangnan University, Wuxi, Jiangsu 214062, PR China
| | - Yi Huang
- Wuxi School of Medicine,
Jiangnan University, Wuxi, Jiangsu 214122, PR China
- Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei 230601, China
| | - Jilong Wang
- Joint Centre of Translational Medicine, Wenzhou Institute,
University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, PR China
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24
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Arrizabalaga L, Russo-Cabrera JS, Belsúe V, Berraondo P, Melero I, Aranda F. Tumor slice culture system for ex vivo immunotherapy studies. Methods Cell Biol 2024; 189:55-69. [PMID: 39393886 DOI: 10.1016/bs.mcb.2024.05.007] [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: 10/13/2024]
Abstract
Personalized immunotherapy is emerging as a promising approach for cancer treatment, aiming to harness the patient's own immune system to target and eliminate tumor cells. One key aspect of developing effective personalized immunotherapies is the utilization of tumor slices derived from individual patient tumors. Tumor slice models retain the complexity and heterogeneity of the original tumor microenvironment, including interactions with immune cells, stromal elements, and vasculature. These ex vivo models serve as valuable tools for studying tumor-immune interactions and for testing the efficacy of immunotherapeutic agents tailored to the specific characteristics of each patient's tumor. In this chapter, we set up a protocol for immunotherapy strategies in mouse models highlighting their translational potential to guide treatment decisions and improve therapeutic outcomes in cancer patients.
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Affiliation(s)
- Leire Arrizabalaga
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Joan Salvador Russo-Cabrera
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Virginia Belsúe
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Pedro Berraondo
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Ignacio Melero
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; Department of Oncology and Department of Immunology and Immunotherapy, Clínica Universidad de Navarra, Pamplona, Spain; Nuffield Department of Medicine and Oxford Center for Immuno-Oncology, University of Oxford, Oxford, United Kingdom
| | - Fernando Aranda
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain.
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25
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Xu MY, Zeng N, Liu CQ, Sun JX, An Y, Zhang SH, Xu JZ, Zhong XY, Ma SY, He HD, Hu J, Xia QD, Wang SG. Enhanced cellular therapy: revolutionizing adoptive cellular therapy. Exp Hematol Oncol 2024; 13:47. [PMID: 38664743 PMCID: PMC11046957 DOI: 10.1186/s40164-024-00506-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 03/31/2024] [Indexed: 04/28/2024] Open
Abstract
Enhanced cellular therapy has emerged as a novel concept following the basis of cellular therapy. This treatment modality applied drugs or biotechnology to directly enhance or genetically modify cells to enhance the efficacy of adoptive cellular therapy (ACT). Drugs or biotechnology that enhance the killing ability of immune cells include immune checkpoint inhibitors (ICIs) / antibody drugs, small molecule inhibitors, immunomodulatory factors, proteolysis targeting chimera (PROTAC), oncolytic virus (OV), etc. Firstly, overcoming the inhibitory tumor microenvironment (TME) can enhance the efficacy of ACT, which can be achieved by blocking the immune checkpoint. Secondly, cytokines or cytokine receptors can be expressed by genetic engineering or added directly to adoptive cells to enhance the migration and infiltration of adoptive cells to tumor cells. Moreover, multi-antigen chimeric antigen receptors (CARs) can be designed to enhance the specific recognition of tumor cell-related antigens, and OVs can also stimulate antigen release. In addition to inserting suicide genes into adoptive cells, PROTAC technology can be used as a safety switch or degradation agent of immunosuppressive factors to enhance the safety and efficacy of adoptive cells. This article comprehensively summarizes the mechanism, current situation, and clinical application of enhanced cellular therapy, describing potential improvements to adoptive cellular therapy.
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Affiliation(s)
- Meng-Yao Xu
- Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, 430030, China
| | - Na Zeng
- Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, 430030, China
| | - Chen-Qian Liu
- Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, 430030, China
| | - Jian-Xuan Sun
- Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, 430030, China
| | - Ye An
- Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, 430030, China
| | - Si-Han Zhang
- Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, 430030, China
| | - Jin-Zhou Xu
- Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, 430030, China
| | - Xing-Yu Zhong
- Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, 430030, China
| | - Si-Yang Ma
- Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, 430030, China
| | - Hao-Dong He
- Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, 430030, China
| | - Jia Hu
- Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, 430030, China
| | - Qi-Dong Xia
- Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, 430030, China.
| | - Shao-Gang Wang
- Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, 430030, China.
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26
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Wang Y, Xu Y, Deng Y, Yang L, Wang D, Yang Z, Zhang Y. Computational identification and experimental verification of a novel signature based on SARS-CoV-2-related genes for predicting prognosis, immune microenvironment and therapeutic strategies in lung adenocarcinoma patients. Front Immunol 2024; 15:1366928. [PMID: 38601163 PMCID: PMC11004994 DOI: 10.3389/fimmu.2024.1366928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Accepted: 03/11/2024] [Indexed: 04/12/2024] Open
Abstract
Background Early research indicates that cancer patients are more vulnerable to adverse outcomes and mortality when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nonetheless, the specific attributes of SARS-CoV-2 in lung Adenocarcinoma (LUAD) have not been extensively and methodically examined. Methods We acquired 322 SARS-CoV-2 infection-related genes (CRGs) from the Human Protein Atlas database. Using an integrative machine learning approach with 10 algorithms, we developed a SARS-CoV-2 score (Cov-2S) signature across The Cancer Genome Atlas and datasets GSE72094, GSE68465, and GSE31210. Comprehensive multi-omics analysis, including assessments of genetic mutations and copy number variations, was conducted to deepen our understanding of the prognosis signature. We also analyzed the response of different Cov-2S subgroups to immunotherapy and identified targeted drugs for these subgroups, advancing personalized medicine strategies. The expression of Cov-2S genes was confirmed through qRT-PCR, with GGH emerging as a critical gene for further functional studies to elucidate its role in LUAD. Results Out of 34 differentially expressed CRGs identified, 16 correlated with overall survival. We utilized 10 machine learning algorithms, creating 101 combinations, and selected the RFS as the optimal algorithm for constructing a Cov-2S based on the average C-index across four cohorts. This was achieved after integrating several essential clinicopathological features and 58 established signatures. We observed significant differences in biological functions and immune cell statuses within the tumor microenvironments of high and low Cov-2S groups. Notably, patients with a lower Cov-2S showed enhanced sensitivity to immunotherapy. We also identified five potential drugs targeting Cov-2S. In vitro experiments revealed a significant upregulation of GGH in LUAD, and its knockdown markedly inhibited tumor cell proliferation, migration, and invasion. Conclusion Our research has pioneered the development of a consensus Cov-2S signature by employing an innovative approach with 10 machine learning algorithms for LUAD. Cov-2S reliably forecasts the prognosis, mirrors the tumor's local immune condition, and supports clinical decision-making in tumor therapies.
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Affiliation(s)
- Yuzhi Wang
- Department of Laboratory Medicine, Deyang People's Hospital, Deyang, Sichuan, China
- Pathogenic Microbiology and Clinical Immunology Key Laboratory of Deyang City, Deyang People's Hospital, Deyang, Sichuan, China
| | - Yunfei Xu
- Department of Laboratory Medicine, Chengdu Women's and Children's Central Hospital, Chengdu, Sichuan, China
| | - Yuqin Deng
- Department of Cardiology, Jianyang People's Hospital, Jianyang, China
| | - Liqiong Yang
- Department of Laboratory Medicine, Deyang People's Hospital, Deyang, Sichuan, China
- Pathogenic Microbiology and Clinical Immunology Key Laboratory of Deyang City, Deyang People's Hospital, Deyang, Sichuan, China
| | - Dengchao Wang
- Department of Laboratory Medicine, Deyang People's Hospital, Deyang, Sichuan, China
- Pathogenic Microbiology and Clinical Immunology Key Laboratory of Deyang City, Deyang People's Hospital, Deyang, Sichuan, China
| | - Zhizhen Yang
- College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Yi Zhang
- Department of Blood Transfusion, Deyang People's Hospital, Deyang, Sichuan, China
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27
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Zhu S, Li X, Luo Z, Ding M, Shi S, Zhang T. Combined immunochemotherapy achieving targeted co-delivery of chlorogenic acid and doxorubicin by sialic acid-modified liposomes enhances anti-cancer efficacy. Drug Deliv Transl Res 2024; 14:718-729. [PMID: 37679600 DOI: 10.1007/s13346-023-01426-4] [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] [Accepted: 08/25/2023] [Indexed: 09/09/2023]
Abstract
Malignant melanoma is a high-grade aggressive skin tumor with an increasing incidence and mortality rates worldwide. Chemotherapeutic drugs such as doxorubicin have limited efficacy against melanoma due to their poor sensitivity, severe side effects, and drug resistance. Recent studies have shown that combinations of immunotherapy and chemotherapy have a synergistic effect in enhancing the anti-tumor effect. Here, we have developed liposomes co-loaded with chlorogenic acid (CA) and doxorubicin (DOX), modified with sialic acid-octadecylamine conjugate (SA-ODA), designated CA-DOX-SAL, that facilitate drug delivery by recognizing Siglec-1 receptor on TAMs. The physicochemical studies revealed the particle size and zeta potential of CA-DOX-SAL as 128.3 ± 0.8 nm and - 4.33 ± 0.50 mV, respectively. In vitro, CA-DOX-SAL demonstrated robust cellular uptake through SA receptor-mediated tumor-associated macrophages (TAM) targeting and exerted greater cytotoxicity on tumor cells. In vivo, targeted liposomes were found to accumulate in the tumor area, leading to an improvement in anti-tumor efficacy. In addition, CA-DOX-SAL effectively inhibited B16F10 melanoma tumor growth by stimulating the transition from tumor-promoting M2-type to anti-tumor M1-type and directly killing tumor cells. Overall, the co-delivery of immunomodulatory CA and chemotherapeutic DOX presents a promising therapeutic strategy to enhance clinical outcomes in the treatment of melanoma.
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Affiliation(s)
- Shunyao Zhu
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Xixi Li
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Ziyi Luo
- Department of Pharmacy, School of Medicine, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310018, China
| | - Meihong Ding
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Senlin Shi
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
| | - Ting Zhang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
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28
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Sun X, Watanabe T, Oda Y, Shen W, Ahmad A, Ouda R, de Figueiredo P, Kitamura H, Tanaka S, Kobayashi KS. Targeted demethylation and activation of NLRC5 augment cancer immunogenicity through MHC class I. Proc Natl Acad Sci U S A 2024; 121:e2310821121. [PMID: 38300873 PMCID: PMC10861931 DOI: 10.1073/pnas.2310821121] [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: 06/29/2023] [Accepted: 12/30/2023] [Indexed: 02/03/2024] Open
Abstract
Impaired expression of MHC (major histocompatibility complex) class I in cancers constitutes a major mechanism of immune evasion. It has been well documented that the low level of MHC class I is associated with poor prognosis and resistance to checkpoint blockade therapies. However, there is lmited approaches to specifically induce MHC class I to date. Here, we show an approach for robust and specific induction of MHC class I by targeting an MHC class I transactivator (CITA)/NLRC5, using a CRISPR/Cas9-based gene-specific system, designated TRED-I (Targeted reactivation and demethylation for MHC-I). The TRED-I system specifically recruits a demethylating enzyme and transcriptional activators on the NLRC5 promoter, driving increased MHC class I antigen presentation and accelerated CD8+ T cell activation. Introduction of the TRED-I system in an animal cancer model exhibited tumor-suppressive effects accompanied with increased infiltration and activation of CD8+ T cells. Moreover, this approach boosted the efficacy of checkpoint blockade therapy using anti-PD1 (programmed cell death protein) antibody. Therefore, targeting NLRC5 by this strategy provides an attractive therapeutic approach for cancer.
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Affiliation(s)
- Xin Sun
- Department of Immunology, Graduate School of Medicine, Hokkaido University, Sapporo060-8638, Japan
| | - Toshiyuki Watanabe
- Department of Immunology, Graduate School of Medicine, Hokkaido University, Sapporo060-8638, Japan
| | - Yoshitaka Oda
- Department of Cancer Pathology, Graduate School of Medicine, Hokkaido University, Hokkaido, Sapporo060-8638, Japan
| | - Weidong Shen
- Division of Functional Immunology, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo060-8638, Japan
| | - Alaa Ahmad
- Department of Immunology, Graduate School of Medicine, Hokkaido University, Sapporo060-8638, Japan
| | - Ryota Ouda
- Department of Immunology, Graduate School of Medicine, Hokkaido University, Sapporo060-8638, Japan
| | - Paul de Figueiredo
- Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX77807
- Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO65211
- Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO65211
- Department of Veterinary Pathobiology, University of MissouriSchool of Veterinary Medicine, Columbia, MO65211
| | - Hidemitsu Kitamura
- Division of Functional Immunology, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo060-8638, Japan
- Department of Biomedical Engineering, Faculty of Science and Engineering, Toyo University, Kawagoe350-8585, Japan
| | - Shinya Tanaka
- Department of Cancer Pathology, Graduate School of Medicine, Hokkaido University, Hokkaido, Sapporo060-8638, Japan
- Institute for Chemical Reaction Design and Discovery, Hokkaido University, Sapporo001-0021, Japan
| | - Koichi S. Kobayashi
- Department of Immunology, Graduate School of Medicine, Hokkaido University, Sapporo060-8638, Japan
- Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX77807
- Institute for Vaccine Research and Development, Hokkaido University, Sapporo060-8638, Japan
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29
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Mandal AK. Recent insights into crosstalk between genetic parasites and their host genome. Brief Funct Genomics 2024; 23:15-23. [PMID: 36307128 PMCID: PMC10799329 DOI: 10.1093/bfgp/elac032] [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: 08/04/2022] [Revised: 09/14/2022] [Accepted: 09/21/2022] [Indexed: 01/21/2024] Open
Abstract
The bulk of higher order organismal genomes is comprised of transposable element (TE) copies, i.e. genetic parasites. The host-parasite relation is multi-faceted, varying across genomic region (genic versus intergenic), life-cycle stages, tissue-type and of course in health versus pathological state. The reach of functional genomics though, in investigating genotype-to-phenotype relations, has been limited when TEs are involved. The aim of this review is to highlight recent progress made in understanding how TE origin biochemical activity interacts with the central dogma stages of the host genome. Such interaction can also bring about modulation of the immune context and this could have important repercussions in disease state where immunity has a role to play. Thus, the review is to instigate ideas and action points around identifying evolutionary adaptations that the host genome and the genetic parasite have evolved and why they could be relevant.
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Affiliation(s)
- Amit K Mandal
- Corresponding author: A.K. Mandal, Nuffield Department of Surgical Sciences (NDS), University of Oxford, Old Road Campus Research building (ORCRB), Oxford OX3 7DQ, UK. Tel: +44 (0)1865 617123; Fax: +44 (0)1865 768876; E-mail:
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30
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Hua Y, Yang S, Zhang Y, Li J, Wang M, Yeerkenbieke P, Liao Q, Liu Q. Modulating ferroptosis sensitivity: environmental and cellular targets within the tumor microenvironment. J Exp Clin Cancer Res 2024; 43:19. [PMID: 38217037 PMCID: PMC10787430 DOI: 10.1186/s13046-023-02925-5] [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: 09/11/2023] [Accepted: 12/06/2023] [Indexed: 01/14/2024] Open
Abstract
Ferroptosis, a novel form of cell death triggered by iron-dependent phospholipid peroxidation, presents significant therapeutic potential across diverse cancer types. Central to cellular metabolism, the metabolic pathways associated with ferroptosis are discernible in both cancerous and immune cells. This review begins by delving into the intricate reciprocal regulation of ferroptosis between cancer and immune cells. It subsequently details how factors within the tumor microenvironment (TME) such as nutrient scarcity, hypoxia, and cellular density modulate ferroptosis sensitivity. We conclude by offering a comprehensive examination of distinct immunophenotypes and environmental and metabolic targets geared towards enhancing ferroptosis responsiveness within the TME. In sum, tailoring precise ferroptosis interventions and combination strategies to suit the unique TME of specific cancers may herald improved patient outcomes.
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Affiliation(s)
- Yuze Hua
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 1# Shuaifuyuan, Dongcheng District, Beijing, 100730, China
| | - Sen Yang
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 1# Shuaifuyuan, Dongcheng District, Beijing, 100730, China
| | - Yalu Zhang
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 1# Shuaifuyuan, Dongcheng District, Beijing, 100730, China
- Department of General Surgery, Anhui Provincial Hospital, Division of Life Science and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, 230027, China
| | - Jiayi Li
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 1# Shuaifuyuan, Dongcheng District, Beijing, 100730, China
| | - Mengyi Wang
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 1# Shuaifuyuan, Dongcheng District, Beijing, 100730, China
| | - Palashate Yeerkenbieke
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 1# Shuaifuyuan, Dongcheng District, Beijing, 100730, China
- Department of General Surgery, Xinjiang Yili Kazak Autonomous Prefecture Friendship Hospital, Xinjiang, 835099, China
| | - Quan Liao
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 1# Shuaifuyuan, Dongcheng District, Beijing, 100730, China.
| | - Qiaofei Liu
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 1# Shuaifuyuan, Dongcheng District, Beijing, 100730, China.
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Feng S, Luo H, Li C, Geng Y, Yang Z, Zhao X, Wang L, Liu R, Zhang Y, Che T, Zhang Q, Wang X. Regulatory role of RGMb in lung injury promoted by the combination of carbon ion irradiation and anti-PD-1 antibody through Erk1/2 and p38 MAPK pathways. Biochem Biophys Res Commun 2024; 691:149334. [PMID: 38042034 DOI: 10.1016/j.bbrc.2023.149334] [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: 07/25/2023] [Revised: 11/17/2023] [Accepted: 11/23/2023] [Indexed: 12/04/2023]
Abstract
The combination of carbon ion radiotherapy and anti-PD-1 antibody represents a new approach to treating thoracic tumors. However, the lung damage caused by this combination therapy may limit its use, and the potential mechanisms for this are worthy of investigation. The objective of this research was to examine the potential involvement of repulsive guidance molecule b (RGMb) in lung damage promoted by the utilization of carbon ion irradiation combined with an anti-PD-1 antibody. The C57BL/6 mice have been randomly separated into four distinct groups: control, anti-PD-1, whole thorax carbon ion irradiation, and irradiation in combination with anti-PD-1 treatment groups (combination group). Detection of pathological changes in lung tissue using HE staining. Detection of pulmonary fibrosis by Masson staining and the hydroxyproline assay. ELISA to detect TNF-α, TGF-β, IL-6, and IL-1β expression levels within lung homogenates. The expression of RGMb, p38 MAPK, and Erk1/2 pathways was detected using a fully automated digital Western blotting system WES (ProteinSimple, USA). Flow cytometry was employed to analyze tissue-resident memory T cells (TRM) within the lung. Subsequently, the siRNA gene was employed to induce the downregulation of RGMb in mice in order to validate the involvement of RGMb in radiation-immune lung injury. The present study observed a significant increase in both inflammatory and fibrotic indicators within the mice group's lung tissue that received the combination treatment. The combination group exhibited elevated levels of TGF-β, TNF-α, IL-6, and IL-1β in lung homogenates. Anti-PD-1 antibody and carbon ion irradiation, upregulated RGMb, phospho-p38 MAPK and phospho-Erk1/2. The results obtained from the flow cytometry analysis indicated that the combination group was significantly higher in the number of clonal expansion TRMs, which were predominantly characterized by the expression of CD8+CD103+CD69-TRMs. The downregulate of RGMb via siRNA in mice resulted in a decrease in phospho-p38 MAPK and phospho-Erk1/2. The combination group exhibited a reduction in TNF-α, TGF-β, IL-6, and IL-1β in their lung tissues, and the number of CD8+CD103+CD69-TRM was significantly reduced. The combination group exhibited a significant improvement in inflammatory and fibrotic indicators within the lung tissues. Anti-PD-1 antibody and carbon ion irradiation synergistically regulate RGMb, leading to strong clonal expansion of lung TRM through the p38 MAPK and Erk1/2 pathways. The present study offers valuable insights into the treatment of lung injury due to the combined administration of carbon ion radiotherapy and anti-PD-1 antibody therapy.
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Affiliation(s)
- Shuangwu Feng
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China.
| | - Hongtao Luo
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, Gansu, China; University of Chinese Academy of Sciences, Beijing, China.
| | - Chengcheng Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China.
| | - Yichao Geng
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China.
| | - Zhen Yang
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, Gansu, China; Gansu University of Traditional Chinese Medicine, Lanzhou, Gansu, China.
| | - Xueshan Zhao
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China.
| | - Lina Wang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China.
| | - Ruifeng Liu
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, Gansu, China; University of Chinese Academy of Sciences, Beijing, China.
| | - Yanying Zhang
- Gansu University of Traditional Chinese Medicine, Lanzhou, Gansu, China.
| | - Tuanjie Che
- Key Laboratory of Functional Genomics and Molecular Diagnosis of Gansu Province, Lanzhou, Gansu, China.
| | - Qiuning Zhang
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, Gansu, China; University of Chinese Academy of Sciences, Beijing, China.
| | - Xiaohu Wang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China; Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, Gansu, China; University of Chinese Academy of Sciences, Beijing, China; Key Laboratory of Functional Genomics and Molecular Diagnosis of Gansu Province, Lanzhou, Gansu, China.
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Nathani A, Sun L, Khan I, Aare M, Bagde A, Li Y, Singh M. Combined Role of Interleukin-15 Stimulated Natural Killer Cell-Derived Extracellular Vesicles and Carboplatin in Osimertinib-Resistant H1975 Lung Cancer Cells with EGFR Mutations. Pharmaceutics 2024; 16:83. [PMID: 38258094 PMCID: PMC10821370 DOI: 10.3390/pharmaceutics16010083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 01/05/2024] [Accepted: 01/06/2024] [Indexed: 01/24/2024] Open
Abstract
In this study, we evaluated IL-15 stimulated natural killer cell-derived EVs (NK-EVs) as therapeutic agents in vitro and in vivo in Osimertinib-resistant lung cancer (H1975R) with EGFR mutations (L858R) in combination with carboplatin (CBP). NK-EVs were isolated by ultracentrifugation and characterized by nanoparticle tracking analysis, and atomic force microscopy imaging revealed vesicles with a spherical form and sizes meeting the criteria of exosomal EVs. Further, Western blot studies demonstrated the presence of regular EV markers along with specific NK markers (perforin and granzyme). EVs were also characterized by proteomic analysis, which demonstrated that EVs had proteins for natural killer cell-mediated cytotoxicity (Granzyme B) and T cell activation (perforin and plastin-2). Gene oncology analysis showed that these differentially expressed proteins are involved in programmed cell death and positive regulation of cell death. Further, isolated NK-EVs were cytotoxic to H1975R cells in vitro in 2D and 3D cell cultures. CBP's IC50 was reduced by approximately in 2D and 3D cell cultures when combined with NK-EVs. The EVs were then combined with CBP and administered by i.p. route to H1975R tumor xenografts, and a significant reduction in tumor volume in vivo was observed. Our findings show for the first time that NK-EVs target the PD-L1/PD-1 immunological checkpoint to induce apoptosis and anti-inflammatory response by downregulation of SOD2, PARP, BCL2, SET, NF-κB, and TGF-ß. The ability to isolate functional NK-EVs on a large scale and use them with platinum-based drugs may lead to new clinical applications. The results of the present study suggest the possibility of the combination of NK-cell-derived EVs and CBP as a viable immunochemotherapeutic strategy for resistant cancers.
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Affiliation(s)
- Aakash Nathani
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA; (A.N.); (I.K.); (M.A.); (A.B.)
| | - Li Sun
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL 32310, USA;
- Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32304, USA
| | - Islauddin Khan
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA; (A.N.); (I.K.); (M.A.); (A.B.)
| | - Mounika Aare
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA; (A.N.); (I.K.); (M.A.); (A.B.)
| | - Arvind Bagde
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA; (A.N.); (I.K.); (M.A.); (A.B.)
| | - Yan Li
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL 32310, USA;
| | - Mandip Singh
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA; (A.N.); (I.K.); (M.A.); (A.B.)
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Rotte A. Development of Cell and Gene Therapies for Clinical Use in the US and EU: Summary of Regulatory Guidelines. Curr Gene Ther 2024; 25:10-21. [PMID: 38676481 DOI: 10.2174/0115665232306205240419091414] [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: 02/26/2024] [Revised: 03/24/2024] [Accepted: 04/03/2024] [Indexed: 04/29/2024]
Abstract
Recent decades have seen advancements in the management and treatment of difficultto- treat diseases such as cancer. A special class of therapeutics called cell and gene therapy has been introduced in the past 10 years. Cell and gene therapy products have strengthened the treatment options for life-threatening diseases with unmet clinical needs and also provided the possibility of a potential cure for the disease in some of the patients. Cell and gene therapy products are gaining recognition, and the interest in clinical development of cell and gene therapy products is increasing. Moreover, as the class of cell and gene therapy products is relatively new, there is a limited regulatory experience in the development, and the developers of the cell and gene therapy products can often be puzzled with an array of questions on regulations. The current review intends to provide a basic understanding of regulatory guidelines from the FDA and EMA that are applicable to cell and gene therapy products. Essentials such as which office is responsible for the evaluation of applications, which regulatory class/pathway is appropriate for development, and what are the quality, nonclinical and clinical studies that are needed to support the application are discussed in the article. In addition, a summary of regulatory designations and the post-approval requirements, such as Risk Evaluation and Mitigation Strategies (REMS) and long-term follow- up, is included in the article. Developers (referred to as 'sponsors' in this article) of cell and gene therapies can use the respective guidance documents and other specific review articles cited in this review for detailed information on the topics.
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Affiliation(s)
- Anand Rotte
- Clinical and Regulatory Affairs, Arcellx Inc, Redwood City, California, CA, USA
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Dong W, Xu L, Chang C, Jiang T, Chen CP, Zhang G. A novel self-assembled nucleobase-nanofiber platform of CDN to activate the STING pathway for synergistic cancer immunotherapy. Colloids Surf B Biointerfaces 2023; 232:113597. [PMID: 37862947 DOI: 10.1016/j.colsurfb.2023.113597] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 10/07/2023] [Accepted: 10/14/2023] [Indexed: 10/22/2023]
Abstract
2', 3'-cGAMP (CDN) as cGAS-STING pathway agonist is extensively used in tumor treatment. However, due to its negatively charged nature (containing two phosphate groups) and high hydrophilicity, CDN faces challenges in crossing cell membranes, resulting in reduced efficiency of its use. Additionally, CDN is susceptible to inactivation through phosphodiesterase hydrolysis. Therefore, the development of a new drug delivery system for CDN is necessary to prevent hydrolysis and enhance targeted accumulation in tumors, as well as improve cellular uptake for STING activation. In this study, we have developed peptide-polymer nanofibers (PEG-Q11) that incorporate thymine (T) and arginine (R) residues to facilitate complexation with CDN through the principles of Watson-Crick base pairing with thymine and favorable electrostatic interactions and bidentate hydrogen bonding with arginine side chains. The entrapment efficiency (EE) of PEG-Q11T3R4@CDN was found to be 51% higher than that of PEG-Q11@CDN. Due to its favorable biocompatibility, PEG-Q11T3R4@CDN was employed for immunotherapy in mouse CT26 tumors. In local tumor treatment, the administration of PEG-Q11T3R4@CDN at a low dose and through a single injection exhibited inhibitory effects. Furthermore, the local injection of PEG-Q11T3R4@CDN resulted in systemic therapeutic responses, effectively suppressing tumor metastasis by activating CD8 + T cells to target distant tumors. This research not only underscores the potential of PEG-Q11T3R4@CDN as an efficient therapeutic agent but also highlights its ability to achieve long-lasting systemic therapeutic outcomes following local treatment. Consequently, PEG-Q11T3R4@CDN represents a promising strategy for immunization.
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Affiliation(s)
- Wenpei Dong
- Key Laboratory of Green Chemical Media and Reactions of Ministry of Education, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Henan Engineering Research Centre of Chiral Hydroxyl Pharmaceutical, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, China
| | - Lingyun Xu
- Key Laboratory of Green Chemical Media and Reactions of Ministry of Education, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Henan Engineering Research Centre of Chiral Hydroxyl Pharmaceutical, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, China
| | - Chun Chang
- Key Laboratory of Green Chemical Media and Reactions of Ministry of Education, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Henan Engineering Research Centre of Chiral Hydroxyl Pharmaceutical, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, China
| | - Tao Jiang
- Key Laboratory of Green Chemical Media and Reactions of Ministry of Education, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Henan Engineering Research Centre of Chiral Hydroxyl Pharmaceutical, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, China.
| | - Chang-Po Chen
- Key Laboratory of Green Chemical Media and Reactions of Ministry of Education, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Henan Engineering Research Centre of Chiral Hydroxyl Pharmaceutical, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, China.
| | - Guisheng Zhang
- Key Laboratory of Green Chemical Media and Reactions of Ministry of Education, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Henan Engineering Research Centre of Chiral Hydroxyl Pharmaceutical, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, China.
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Luo P, Chen G, Shi Z, Yang J, Wang X, Pan J, Zhu L. Comprehensive multi-omics analysis of tryptophan metabolism-related gene expression signature to predict prognosis in gastric cancer. Front Pharmacol 2023; 14:1267186. [PMID: 37908977 PMCID: PMC10613981 DOI: 10.3389/fphar.2023.1267186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 09/18/2023] [Indexed: 11/02/2023] Open
Abstract
Introduction: The 5-year survival of gastric cancer (GC) patients with advanced stage remains poor. Some evidence has indicated that tryptophan metabolism may induce cancer progression through immunosuppressive responses and promote the malignancy of cancer cells. The role of tryptophan and its metabolism should be explored for an in-depth understanding of molecular mechanisms during GC development. Material and methods: We utilized the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) dataset to screen tryptophan metabolism-associated genes via single sample gene set enrichment analysis (ssGSEA) and correlation analysis. Consensus clustering analysis was employed to construct different molecular subtypes. Most common differentially expressed genes (DEGs) were determined from the molecular subtypes. Univariate cox analysis as well as lasso were performed to establish a tryptophan metabolism-associated gene signature. Gene Set Enrichment Analysis (GSEA) was utilized to evaluate signaling pathways. ESTIMATE, ssGSEA, and TIDE were used for the evaluation of the gastric tumor microenvironment. Results: Two tryptophan metabolism-associated gene molecular subtypes were constructed. Compared to the C2 subtype, the C1 subtype showed better prognosis with increased CD4 positive memory T cells as well as activated dendritic cells (DCs) infiltration and suppressed M2-phenotype macrophages inside the tumor microenvironment. The immune checkpoint was downregulated in the C1 subtype. A total of eight key genes, EFNA3, GPX3, RGS2, CXCR4, SGCE, ADH4, CST2, and GPC3, were screened for the establishment of a prognostic risk model. Conclusion: This study concluded that the tryptophan metabolism-associated genes can be applied in GC prognostic prediction. The risk model established in the current study was highly accurate in GC survival prediction.
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Affiliation(s)
| | | | | | | | | | | | - Linghua Zhu
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Yasodha K, Lizha Mary L, Surajit P, Satish R. Exosomes from metastatic colon cancer cells drive the proliferation and migration of primary colon cancer through increased expression of cancer stem cell markers CD133 and DCLK1. Tissue Cell 2023; 84:102163. [PMID: 37487255 DOI: 10.1016/j.tice.2023.102163] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 07/03/2023] [Accepted: 07/11/2023] [Indexed: 07/26/2023]
Abstract
The exchange of biological material between the neighbouring cells is essential for homeostasis. In pathological conditions, such as cancer, the major challenge in cancer treatment is the abnormal expression of crucial proteins and miRNA exchanged between the cancer cells through extracellular vesicles called exosomes. Clinically, it has been noticed that the primary tumour and the distal metastases are interconnected and co-dependent. The exosomes are key factors responsible for preparing the pre-metastatic niche and communicating between the tumour and the distal metastatic site. Cancer stem cells (CSCs) are a subpopulation of cancer cells with self-renewal characteristics and are shown to be responsible for metastasis. This study aims to understand the effect of metastatic cell line-derived exosomes and their regulation of CSC marker expressions on primary colon cancer cell lines. We have identified that treatment of primary colon cancer cell lines with metastatic colon cancer cell-derived exosomes has significantly increased the proliferation, colony formation, cell migration, and invasion. In addition, there was a significant increase in the number and size of spheroids following the exosomes treatment. We found that this metastatic phenotype is due to the increased expression of CD133 and DCLK1 in primary colon cancer cells.
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Affiliation(s)
- K Yasodha
- Department of Genetic Engineering, School of Bio-Engineering, SRM Institute of Science and Technology, kattankulathur, Chengalpattu, Tamil Nadu 603203, India
| | - L Lizha Mary
- Department of Genetic Engineering, School of Bio-Engineering, SRM Institute of Science and Technology, kattankulathur, Chengalpattu, Tamil Nadu 603203, India
| | - Pathak Surajit
- Department of Allied Health Sciences. Chettinad Academy of Science and Technology, Kelambakkam, Kanchipuram, Tamil Nadu 603103, India
| | - R Satish
- Department of Genetic Engineering, School of Bio-Engineering, SRM Institute of Science and Technology, kattankulathur, Chengalpattu, Tamil Nadu 603203, India.
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Charles C, Bardet A, Ibrahimi N, Aromatario O, Cambon L, Imbert A, Pons M, Raynard B, Sauveplane D, Pouchepadass C, Baudinet C, Lambotte O, Marabelle A, Dauchy S. Delivering adapted physical activity by videoconference to patients with fatigue under immune checkpoint inhibitors: Lessons learned from the PACTIMe-FEAS feasibility study. J Telemed Telecare 2023; 29:716-724. [PMID: 34137641 DOI: 10.1177/1357633x211021743] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Fatigue is one of the most frequent symptoms in anti-cancer immune therapy. Physical activity has been proven effective in reducing fatigue, but unmet needs remain regarding the provision and access to adapted programmes, which efficiently addresses the main barriers to PA. METHODS The PACTIMe-FEAS study primarily aimed at primarily to evaluate the feasibility and the acceptability of a videoconference-based 6-month programme promoting physical activity, and secondarily to assess its potential post-immediate and short-term effectiveness in reducing fatigue in cancer patients under immune therapy. Numeric self-reported questionnaires (Visual Analogue Scale-fatigue, Multidimensional Fatigue Inventory, International Physical Activity Questionnaire, Échelle de Motivation envers l'Activité Physique en contexte de Santé, Medical Outcomes Study 36-Item Short Form Health Survey, Hospital Anxiety and Depression Scale and Insomnia Severity Index) were completed by participants through an online secure platform at three time points: just before (T1), and after (T2) the programme, and 3 months later (T3). RESULTS Sixteen participants (50% male, 50% female, mean age 54 years, 69% melanoma, 31% overweight), with moderate-to-severe fatigue, entered the internet-delivered intervention; 14 completed it, with an average completion rate of physical activity supervised sessions of 75%. Satisfaction was high, confirming a demand for group format, personalised approach, professional guidance and home-based device, to support the practice of regular physical activity. A decrease in fatigue was observed at the end of the programme. DISCUSSION The recruitment process did prove to be challenging, with a relatively small eligible population, and will need to be reconsidered to envision a larger scale trial. But here and now, this feasibility study provides the first promising foundations to develop further research on the effectiveness of an original remote programme.
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Affiliation(s)
- Cécile Charles
- Gustave Roussy, Université Paris-Saclay, France
- Bordeaux Population Health Research Center (BPH- INSERM U1219), Methods for Intervention Research in Population Health (MéRISP), Bordeaux University, France
| | | | | | - Olivier Aromatario
- Bordeaux Population Health Research Center (BPH- INSERM U1219), Methods for Intervention Research in Population Health (MéRISP), Bordeaux University, France
| | - Linda Cambon
- Bordeaux Population Health Research Center (BPH- INSERM U1219), Methods for Intervention Research in Population Health (MéRISP), Bordeaux University, France
| | | | - Magali Pons
- Gustave Roussy, Université Paris-Saclay, France
| | | | | | | | - Cédric Baudinet
- Mooven SAS, Research and Development Unit, Montpellier University, France
| | - Olivier Lambotte
- Clinical Immunology Department, AP-HP, Université Paris-Saclay, Hôpital Bicêtre, France
- Center for Immunology of Viral, Auto-immune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Université Paris-Saclay, INSERM, CEA, France
| | - Aurélien Marabelle
- Drug Development Department, Gustave Roussy, Université Paris-Saclay, France
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Ma J, Yan S, Zhao Y, Yan H, Zhang Q, Li X. Blockade of PD-1 and LAG-3 expression on CD8+ T cells promotes the tumoricidal effects of CD8+ T cells. Front Immunol 2023; 14:1265255. [PMID: 37841254 PMCID: PMC10568325 DOI: 10.3389/fimmu.2023.1265255] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Accepted: 09/13/2023] [Indexed: 10/17/2023] Open
Abstract
Background The diffuse large B-cell lymphoma (DLBCL) has the highest incidence of all lymphomas worldwide. To investigate the functions of lymphocyte activation gene 3 (LAG-3) and programmed cell death 1 (PD-1) in tissues and peripheral blood of patients with DLBCL, the expression of LAG-3 and PD-1 genes in DLBCL-TCGA were analyzed. Methods LAG-3 and PD-1 mRNA levels in DLBCL were analyzed using data from The Cancer Genome Atlas (TCGA) database. Utilize the Genotype-Tissue Expression (GTEx) database for assessing the variance in the expression of LAG-3, PD-1, and other associated factors between the tissues of DLBCL patients and healthy individuals. Immunohistochemistry was applied to detect the expression of LAG-3 and PD-1 levels in 137 cases of DLBCL tissues and 20 cases of reactive lymphoid hyperplasia. The prognostic value of LAG-3 and PD-1 were assessed using the Kaplan-Meier curve. The Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE) and ssGSEA algorithm were used to explore the immune microenvironment of DLBCL. Additionally, the expression and co-expression of LAG-3 and PD-1 were detected on CD4 and CD8 T cells in peripheral blood samples from 100 cases of DLBCL tissues and 30 cases of healthy individuals using flow cytometry. Results According to TCGA database, LAG-3 and PD-1 gene expression levels were significantly up-regulated in DLBCL tissues. LAG-3 and PD-1 levels were also strongly positively correlated with those of most infiltrating immune cells. Overall survival of patients with high LAG-3 and PD-1 co-expression was significantly shorter than that of patients with low co-expression. In DLBCL patients, LAG-3 and PD-1 were highly expressed in peripheral blood CD8+ T cells. In addition, LAG-3 was highly expressed in CD4+ T cells, while the expression of PD-1 in CD4+ T cells of DLBCL patients showed no significant difference compared to healthy individuals. Additionally, CD8+ T cells and SU-DHL6/OCI-LY3 from patients with DLBCL were co-cultured in vitro; after addition of LAG-3 and/or PD-1 inhibitors alone, an increased perforin and granzyme B secretion levels by CD8+ T cells were detected, as well as an increase in the overall proportion of tumor cells undergoing apoptosis. Conclusion High LAG-3 and PD-1 levels significantly inhibit CD8+ T cell function, resulting in weakened ability to kill tumor cells. Combined LAG-3 and PD-1 blockade can restore CD8+ T cell function and provides a potential avenue for development of personalized cellular immunotherapy for DLBCL.
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Affiliation(s)
- Jiajia Ma
- Department of Pathology, Xinjiang Medical University Affiliated Tumor Hospital, Urumqi, Xinjiang, China
| | - Shufang Yan
- Department of Critical Care, Medicine of Karamay Central Hospital, Karamay, Xinjiang, China
| | - Ying Zhao
- Department of General Practice, Third People’s Hospital of Xinjiang Uygur Autonomous Region, Urumuqi, Xinjiang, China
| | - Huifang Yan
- Department of Pathology, Xinjiang Medical University Affiliated Tumor Hospital, Urumqi, Xinjiang, China
| | - Qian Zhang
- Department of Pathology, Xinjiang Medical University Affiliated Tumor Hospital, Urumqi, Xinjiang, China
| | - Xinxia Li
- Department of Pathology, Xinjiang Medical University Affiliated Tumor Hospital, Urumqi, Xinjiang, China
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Pei Y, Han S, Li C, Lei J, Wen F. Data-based modeling of breast cancer and optimal therapy. J Theor Biol 2023; 573:111593. [PMID: 37544589 DOI: 10.1016/j.jtbi.2023.111593] [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: 04/02/2023] [Revised: 07/19/2023] [Accepted: 08/02/2023] [Indexed: 08/08/2023]
Abstract
Excessive accumulation of β-catenin proteins is a vital driver in the development of breast cancer. Many clinical assessments incorporating immunotherapy with targeted mRNA of β-catenin are costly endeavor. This paper develops novel mathematical models for different treatments by invoking available clinical data to calibrate models, along with the selection and evaluation of therapy strategies in a faster manner with lower cost. Firstly, in order to explore the interactions between cancer cells and the immune system within the tumor microenvironment, we construct different types of breast cancer treatment models based on RNA interference technique and immune checkpoint inhibitors, which have been proved to be an effective combined therapy in pre-clinical trials associated with the inhibition of β-catenin proteins to enhance intrinsic anti-tumor immune response. Secondly, various techniques including MCMC are adopted to estimate multiple parameters and thus simulations in agreement with experimental results sustain the validity of our models. Furthermore, the gradient descent method and particle swarm algorithm are designed to optimize therapy schemes to inhibit the growth of tumor and lower the treatment cost. Considering the mechanisms of drug resistance in vivo, simulations exhibit that therapies are ineffective resulting in cancer relapse in the prolonged time. For this reason, parametric sensitivity analysis sheds light on the choice of new treatments which indicate that, in addition to inhibiting β-catenin proteins and improving self-immunity, the injection of dendritic cells promoting immunity may provide a novel vision for the future of cancer treatment. Overall, our study provides witness of principle from a mathematical perspective to guide clinical trials and the selection of treatment regimens.
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Affiliation(s)
- Yongzhen Pei
- School of Mathematical Sciences, Tiangong University, Tianjin 300387, China.
| | - Siqi Han
- School of Mathematical Sciences, Tiangong University, Tianjin 300387, China.
| | - Changguo Li
- Department of Basic Science, Army Military Transportation University, Tianjin 300161, China.
| | - Jinzhi Lei
- School of Mathematical Sciences, Tiangong University, Tianjin 300387, China.
| | - Fengxi Wen
- School of Mathematical Sciences, Tiangong University, Tianjin 300387, China.
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Lee KW, Yam JWP, Mao X. Dendritic Cell Vaccines: A Shift from Conventional Approach to New Generations. Cells 2023; 12:2147. [PMID: 37681880 PMCID: PMC10486560 DOI: 10.3390/cells12172147] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/21/2023] [Accepted: 08/23/2023] [Indexed: 09/09/2023] Open
Abstract
In the emerging era of cancer immunotherapy, immune checkpoint blockades (ICBs) and adoptive cell transfer therapies (ACTs) have gained significant attention. However, their therapeutic efficacies are limited due to the presence of cold type tumors, immunosuppressive tumor microenvironment, and immune-related side effects. On the other hand, dendritic cell (DC)-based vaccines have been suggested as a new cancer immunotherapy regimen that can address the limitations encountered by ICBs and ACTs. Despite the success of the first generation of DC-based vaccines, represented by the first FDA-approved DC-based therapeutic cancer vaccine Provenge, several challenges remain unsolved. Therefore, new DC vaccine strategies have been actively investigated. This review addresses the limitations of the currently most adopted classical DC vaccine and evaluates new generations of DC vaccines in detail, including biomaterial-based, immunogenic cell death-inducing, mRNA-pulsed, DC small extracellular vesicle (sEV)-based, and tumor sEV-based DC vaccines. These innovative DC vaccines are envisioned to provide a significant breakthrough in cancer immunotherapy landscape and are expected to be supported by further preclinical and clinical studies.
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Affiliation(s)
- Kyu-Won Lee
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; (K.-W.L.); (J.W.P.Y.)
| | - Judy Wai Ping Yam
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; (K.-W.L.); (J.W.P.Y.)
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Xiaowen Mao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao
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Liu Y, Chen X, Luo W, Zhao Y, Nashan B, Huang L, Yuan X. Identification and validation of Birc5 as a novel activated cell cycle program biomarker associated with infiltration of immunosuppressive myeloid-derived suppressor cells in hepatocellular carcinoma. Cancer Med 2023; 12:16370-16385. [PMID: 37326143 PMCID: PMC10469657 DOI: 10.1002/cam4.6271] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 06/05/2023] [Accepted: 06/07/2023] [Indexed: 06/17/2023] Open
Abstract
BACKGROUND Preclinical studies and clinical trials have demonstrated that tumor-intrinsic activation of the cell cycle program impedes anticancer immunotherapy. Identification of cell cycle-related biomarkers may provide novel therapeutic targets to augment the efficacy of immunotherapy in hepatocellular carcinoma (HCC). METHOD AND RESULTS Based on the genes related to cell cycle program, two clusters (Cluster 1 and Cluster 2) were detected in HCC patients via non-negative matrix factorization algorithm. Multivariable-adjusted Cox regression analysis indicated that the cell cycle gene-based classification was a significant prognostic factor for predicting the clinical outcome of HCC patients. Cluster 1 showed shorter overall survival time and progression-free interval time was associated with activated cell cycle program, higher infiltration of myeloid-derived suppressor cells (MDSCs) and less sensitivity to immunotherapy. A three-gene prognostic model, including BIRC5, C8G, and SPP1, was constructed to characterize the cell cycle-based classification of HCC, which had strong robustness and a stable predictive performance. Notably, Birc5 was positively correlated with CD11b expression (a MDSC marker) in HCC tissue. Concordant high expression of Birc5 and intratumor infiltration level of MDSCs were correlated with worse prognosis of HCC patients. In vitro, hepatocellular Birc5 overexpression promoted immunosuppressive CD11b+ CD33+ HLA-DR- MDSC expansion from human peripheral blood mononuclear cells. Genetically modified animal model of liver cancer revealed that Birc5 depletion upregulated the genes related to lymphocyte-mediated immunity, natural killer cell-mediated immunity, interferon-gamma production, T-cell activation, and T-cell-mediated cytotoxicity. These results suggest an immunosuppressive function of Birc5 in HCC. CONCLUSION Birc5 was a potential biomarker and inducer of intratumor infiltration of MDSCs, which led to T cell exclusion or dysfunction in tumor immune microenvironment, consequently resulting in reduced response to ICIs in HCC.
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Affiliation(s)
- Yun Liu
- Department of Radiation Oncology, Anhui Provincial Cancer HospitalThe First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of ChinaHefeiChina
| | - Xi Chen
- Department of Gastrointestinal Oncology Surgery, Anhui Provincial Cancer HospitalThe First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of ChinaHefeiChina
| | - Wenwu Luo
- Department of PathologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiChina
| | - Yufei Zhao
- Department of Radiation Oncology, Anhui Provincial Cancer HospitalThe First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of ChinaHefeiChina
| | - Björn Nashan
- Organ Transplant Center, Department of Hepatobiliary and Transplantation Surgery, The First Affiliated Hospital of USTCDivision of Life Sciences and Medicine, University of Science and Technology of ChinaHefeiChina
| | - Lei Huang
- Department of OncologyRuijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
- Medical Center on Aging of Ruijin Hospital, MCARJH, Shanghai Jiaotong University School of MedicineShanghaiChina
| | - Xiaodong Yuan
- Organ Transplant Center, Department of Hepatobiliary and Transplantation Surgery, The First Affiliated Hospital of USTCDivision of Life Sciences and Medicine, University of Science and Technology of ChinaHefeiChina
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Zheng Z, Wieder T, Mauerer B, Schäfer L, Kesselring R, Braumüller H. T Cells in Colorectal Cancer: Unravelling the Function of Different T Cell Subsets in the Tumor Microenvironment. Int J Mol Sci 2023; 24:11673. [PMID: 37511431 PMCID: PMC10380781 DOI: 10.3390/ijms241411673] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/17/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
Therapeutic options for metastatic colorectal cancer (mCRC) are very limited, and the prognosis using combination therapy with a chemotherapeutic drug and a targeted agent, e.g., epidermal growth factor receptor or tyrosine kinase, remains poor. Therefore, mCRC is associated with a poor median overall survival (mOS) of only 25-30 months. Current immunotherapies with checkpoint inhibitor blockade (ICB) have led to a substantial change in the treatment of several cancers, such as melanoma and non-small cell lung cancer. In CRC, ICB has only limited effects, except in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) tumors, which comprise about 15% of sporadic CRC patients and about 4% of patients with metastatic CRC. The vast majority of sporadic CRCs are microsatellite-stable (MSS) tumors with low levels of infiltrating immune cells, in which immunotherapy has no clinical benefit so far. Immunotherapy with checkpoint inhibitors requires the presence of infiltrating T cells into the tumor microenvironment (TME). This makes T cells the most important effector cells in the TME, as evidenced by the establishment of the immunoscore-a method to estimate the prognosis of CRC patients. The microenvironment of a tumor contains several types of T cells that are anti-tumorigenic, such as CD8+ T cells or pro-tumorigenic, such as regulatory T cells (Tregs) or T helper 17 (Th17) cells. However, even CD8+ T cells show marked heterogeneity, e.g., they can become exhausted, enter a state of hyporesponsiveness or become dysfunctional and express high levels of checkpoint molecules, the targets for ICB. To kill cancer cells, CD8+ T cells need the recognition of the MHC class I, which is often downregulated on colorectal cancer cells. In this case, a population of unconventional T cells with a γδ T cell receptor can overcome the limitations of the conventional CD8+ T cells with an αβT cell receptor. γδ T cells recognize antigens in an MHC-independent manner, thus acting as a bridge between innate and adaptive immunity. Here, we discuss the effects of different T cell subsets in colorectal cancer with a special emphasis on γδ T cells and the possibility of using them in CAR-T cell therapy. We explain T cell exclusion in microsatellite-stable colorectal cancer and the possibilities to overcome this exclusion to enable immunotherapy even in these "cold" tumors.
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Affiliation(s)
- Ziwen Zheng
- Department of General and Visceral Surgery, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Thomas Wieder
- Department of Vegetative and Clinical Physiology, Institute of Physiology, Eberhard Karls University Tübingen, 72074 Tübingen, Germany
| | - Bernhard Mauerer
- Department of General and Visceral Surgery, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- German Cancer Consortium (DKTK) Partner Site Freiburg, 79106 Freiburg, Germany
- German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Luisa Schäfer
- Department of General and Visceral Surgery, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Rebecca Kesselring
- Department of General and Visceral Surgery, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- German Cancer Consortium (DKTK) Partner Site Freiburg, 79106 Freiburg, Germany
- German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Heidi Braumüller
- Department of General and Visceral Surgery, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
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Cheng F, Su T, Zhou S, Liu X, Yang S, Lin S, Guo W, Zhu G. Single-dose injectable nanovaccine-in-hydrogel for robust immunotherapy of large tumors with abscopal effect. SCIENCE ADVANCES 2023; 9:eade6257. [PMID: 37450588 PMCID: PMC10348685 DOI: 10.1126/sciadv.ade6257] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 06/09/2023] [Indexed: 07/18/2023]
Abstract
Current cancer immunotherapy [e.g., immune checkpoint blockade (ICB)] only benefits small subsets of patients, largely due to immunosuppressive tumor microenvironment (TME). In situ tumor vaccination can reduce TME immunosuppression and thereby improve cancer immunotherapy. Here, we present single-dose injectable (nanovaccines + ICBs)-in-hydrogel (NvIH) for robust immunotherapy of large tumors with abscopal effect. NvIH is thermo-responsive hydrogel co-encapsulated with ICB antibodies and novel polymeric nanoparticles loaded with three immunostimulatory agonists for Toll-like receptors 7/8/9 (TLR7/8/9) and stimulator of interferon genes (STING). Upon in situ tumor vaccination, NvIH undergoes rapid sol-to-gel transformation, prolongs tumor retention, sustains the release of immunotherapeutics, and reduces acute systemic inflammation. In multiple poorly immunogenic tumor models, single-dose NvIH reduces multitier TME immunosuppression, elicits potent TME and systemic innate and adaptive antitumor immunity with memory, and regresses both local (vaccinated) and distant large tumors with abscopal effect, including distant orthotopic glioblastoma. Overall, NvIH holds great potential for tumor immunotherapy.
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Affiliation(s)
- Furong Cheng
- Translational Medicine Center, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China
- Department of Pharmaceutics and Center for Pharmaceutical Engineering and Sciences, Institute for Structural Biology and Drug Discovery, School of Pharmacy, The Developmental Therapeutics Program, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Ting Su
- Department of Pharmaceutics and Center for Pharmaceutical Engineering and Sciences, Institute for Structural Biology and Drug Discovery, School of Pharmacy, The Developmental Therapeutics Program, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
- Center for Translational Medicine, Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Shurong Zhou
- Department of Pharmaceutics and Center for Pharmaceutical Engineering and Sciences, Institute for Structural Biology and Drug Discovery, School of Pharmacy, The Developmental Therapeutics Program, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
- Department of Pharmaceutical Sciences, College of Pharmacy, Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | - Xiang Liu
- Department of Pharmaceutics and Center for Pharmaceutical Engineering and Sciences, Institute for Structural Biology and Drug Discovery, School of Pharmacy, The Developmental Therapeutics Program, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
- Department of Pharmaceutical Sciences, College of Pharmacy, Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | - Suling Yang
- Department of Pharmaceutical Sciences, College of Pharmacy, Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | - Shuibin Lin
- Center for Translational Medicine, Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Weisheng Guo
- Translational Medicine Center, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China
| | - Guizhi Zhu
- Department of Pharmaceutical Sciences, College of Pharmacy, Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA
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Agostara AG, Roazzi L, Villa F, Romano' R, Piscazzi D, Martinelli F, Ciarlo G, Oresti S, Travaglini F, Marando A, Sartore-Bianchi A, Giannetta L, Cerea G, Siena S, Pizzutilo EG, Signorelli D. What to do after immune-checkpoint inhibitors failure in advanced non-small cell lung cancer: an expert opinion and review. Expert Rev Respir Med 2023; 17:787-803. [PMID: 37817448 DOI: 10.1080/17476348.2023.2268509] [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: 07/23/2023] [Accepted: 10/05/2023] [Indexed: 10/12/2023]
Abstract
INTRODUCTION Immune-checkpoint inhibitors (IO) have significantly improved outcomes of patients with non-oncogene-addicted non-small cell lung cancer (NSCLC), becoming the first-line agents for advanced disease. However, resistance remains a significant clinical challenge, limiting their effectiveness. AREAS COVERED Hereby, we addressed standard and innovative therapeutic approaches for NSCLC patients experiencing progression after IO treatment, discussing the emerging resistance mechanisms and the ongoing efforts to overcome them. In order to provide a complete overview of the matter, we performed a comprehensive literature search across prominent databases, including PubMed, EMBASE (Excerpta Medica dataBASE), and the Cochrane Library, and a research of the main ongoing studies on clinicaltrials.gov. EXPERT OPINION The dynamics of progression to IO, especially in terms of time to treatment failure and burden of progressive disease, should guide the best subsequent management, together with patient clinical conditions. Long-responders to IO might benefit from continuation of IO beyond-progression, in combination with other treatments. Patients who experience early progression should be treated with salvage CT in case of preserved clinical conditions. Finally, patients who respond to IO for a considerable timeframe and who later present oligo-progression could be treated with a multimodal approach in order to maximize the benefit of immunotherapy.
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Affiliation(s)
- Alberto Giuseppe Agostara
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Laura Roazzi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Federica Villa
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Rebecca Romano'
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Daniele Piscazzi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Francesca Martinelli
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Gabriele Ciarlo
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Sara Oresti
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | | | - Alessandro Marando
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Andrea Sartore-Bianchi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Laura Giannetta
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Giulio Cerea
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Salvatore Siena
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Elio Gregory Pizzutilo
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Diego Signorelli
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
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Ben-Akiva E, Karlsson J, Hemmati S, Yu H, Tzeng SY, Pardoll DM, Green JJ. Biodegradable lipophilic polymeric mRNA nanoparticles for ligand-free targeting of splenic dendritic cells for cancer vaccination. Proc Natl Acad Sci U S A 2023; 120:e2301606120. [PMID: 37339211 PMCID: PMC10293809 DOI: 10.1073/pnas.2301606120] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Accepted: 05/22/2023] [Indexed: 06/22/2023] Open
Abstract
Nanoparticle (NP)-based mRNA cancer vaccines hold great promise to realize personalized cancer treatments. To advance this technology requires delivery formulations for efficient intracellular delivery to antigen-presenting cells. We developed a class of bioreducible lipophilic poly(beta-amino ester) nanocarriers with quadpolymer architecture. The platform is agnostic to the mRNA sequence, with one-step self-assembly allowing for delivery of multiple antigen-encoding mRNAs as well as codelivery of nucleic acid-based adjuvants. We examined structure-function relationships for NP-mediated mRNA delivery to dendritic cells (DCs) and identified that a lipid subunit of the polymer structure was critical. Following intravenous administration, the engineered NP design facilitated targeted delivery to the spleen and preferential transfection of DCs without the need for surface functionalization with targeting ligands. Treatment with engineered NPs codelivering antigen-encoding mRNA and toll-like receptor agonist adjuvants led to robust antigen-specific CD8+ T cell responses, resulting in efficient antitumor therapy in in vivo models of murine melanoma and colon adenocarcinoma.
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Affiliation(s)
- Elana Ben-Akiva
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD21231
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD21231
- Institute for NanoBioTechnology, Johns Hopkins University School of Medicine, Baltimore, MD21231
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD21287
| | - Johan Karlsson
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD21231
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD21231
- Institute for NanoBioTechnology, Johns Hopkins University School of Medicine, Baltimore, MD21231
- Department of Chemistry–Ångström Laboratory, Uppsala University, UppsalaSE-75121, Sweden
| | - Shayan Hemmati
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD21231
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD21231
- Institute for NanoBioTechnology, Johns Hopkins University School of Medicine, Baltimore, MD21231
| | - Hongzhe Yu
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD21231
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD21231
- Institute for NanoBioTechnology, Johns Hopkins University School of Medicine, Baltimore, MD21231
| | - Stephany Y. Tzeng
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD21231
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD21231
- Institute for NanoBioTechnology, Johns Hopkins University School of Medicine, Baltimore, MD21231
| | - Drew M. Pardoll
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD21287
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD21231
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD21231
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD21231
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD21231
| | - Jordan J. Green
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD21231
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD21231
- Institute for NanoBioTechnology, Johns Hopkins University School of Medicine, Baltimore, MD21231
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD21287
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD21231
- Department of Materials Science & Engineering, Johns Hopkins University, Baltimore, MD21231
- Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD21231
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD21231
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD21231
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Tang Y, Cao J, Peng R, Mao X, Su B, Tang H, Tu D, Zhou J, Jiang G, Jin S, Wang Q, Zhang C, Liu R, Zhang C, Bai D. Screening and Verification of Key Ubiquitination Genes Related to Immune Infiltration in Stage III/IV Hepatocellular Carcinoma. J Hepatocell Carcinoma 2023; 10:765-781. [PMID: 37250505 PMCID: PMC10216869 DOI: 10.2147/jhc.s407536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 05/08/2023] [Indexed: 05/31/2023] Open
Abstract
Introduction Immune checkpoint therapy (ICIs) effectively improves the prognosis of advanced (stage III/IV) hepatocellular carcinoma (HCC) patients. However, its objective response rate (ORR) is below 20%, significantly limiting ICI use in advanced HCC patients. The level of tumour immune infiltration influences ICI response rate. Recent studies have found ubiquitinase to be an important factor that regulates tumour immune infiltration. Therefore, the aim of this study is to explore the key ubiquitination genes that regulate immune infiltration in advanced HCC and further validate them. Methods A biotechnological process was performed as a means of classifying 90 advanced HCC patients into three immune subtypes and identifying associations with immune infiltration in the co-expressed modules. Ubiquitination-related genes were then screened with WGCNA. Gene enrichment analysis was performed for the target module and 30 hub genes were screened out by protein-protein interaction network (PPI). ssGSEA, single-gene sequencing and the MCP counter were used for exploring immune infiltration. TIDE score was applied for predicting drug efficacy and GSEA was used for exploring potential pathways. Finally, GRB2 expression in HCC tissue was validated by in vitro experiments. Results GRB2 expression was found to have a significant correlation with the pathological stage and prognosis of HCC patients and a positive correlation with immune infiltration and tumour mutation burden (TMB). In addition, significant correlations with the efficacy of ICIs, sorafenib and transarterial chemoembolization (TACE) were identified. GRB2 was found to be most significantly associated with the JAK-STAT signalling pathway and cytosolic DNA sensing pathway. Finally, it was found that GRB2 expression is closely related to the prognosis, tumour size and TMN stage. Conclusion A significant association was observed between the ubiquitinated gene GRB2 and the prognosis and immune infiltration of advanced HCC patients and it may potentially be used for predicting therapy efficacy in advanced HCC patients in the future.
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Affiliation(s)
- Yuhong Tang
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China
| | - Jun Cao
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China
| | - Rui Peng
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China
| | - Xingkang Mao
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China
| | - Bingbing Su
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China
| | - Hao Tang
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China
| | - Daoyuan Tu
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China
| | - Jie Zhou
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China
| | - Guoqing Jiang
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China
| | - Shengjie Jin
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China
| | - Qian Wang
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China
| | - Chen Zhang
- The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China
| | - Renjie Liu
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China
| | - Chi Zhang
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China
- General Surgery Institute of Yangzhou, Yangzhou University, Yangzhou, People’s Republic of China
| | - Dousheng Bai
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China
- General Surgery Institute of Yangzhou, Yangzhou University, Yangzhou, People’s Republic of China
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Wang T, Wu L, Wang S, Shi X, Liu H, Deng W. Chang Wei Qing Decoction enhances the anti-tumor effect of PD-1 inhibitor therapy by regulating the immune microenvironment and gut microbiota in colorectal cancer. Chin J Nat Med 2023; 21:333-345. [PMID: 37245872 DOI: 10.1016/s1875-5364(23)60451-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Indexed: 05/30/2023]
Abstract
The anti-tumor effect of anti-PD-1 antibody has long been shown to be strongly related to the tumor immune microenvironment (TIME). This study aimed to mechanistically assess whether Chang Wei Qing (CWQ) Decoction can enhance the anti-tumor effect of PD-1 inhibitor therapy. PD-1 inhibitor therapy showed the significant anti-tumor effect in patients with mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) colorectal cancer (CRC), rather than those with mismatch repair-proficient/microsatellite stable (pMMR/MSS) CRC. Hence, immunofluorescence double-label staining was utilized to explore the difference in the TIME between dMMR/MSI-H and pMMR/MSS CRC patients. Flow cytometry was used to analyze T-lymphocytes in tumors from mice. Western blot was used to measure the expression of PD-L1 protein in mouse tumors. The intestinal mucosal barrier of mice was evaluated by hematoxylin-eosin staining and immunohistochemistry. 16S rRNA-gene sequencing was used to examine the structure of the gut microbiota in mice. Subsequently, Spearmanapos;s correlation analysis was used to analyze the relationship between the gut microbiota and tumor-infiltrating T-lymphocytes. The results showed that dMMR/MSI-H CRC patients had more CD8+T cells and higher expression of PD-1 and PD-L1 proteins. In vivo, CWQ enhanced the anti-tumor effect of anti-PD-1 antibody and increased the infiltration of CD8+ and PD-1+CD8+ T cells in tumors. Additionally, the combination of CWQ with anti-PD-1 antibody resulted in lower inflammation in the intestinal mucosa than that induced by anti-PD-1 antibody alone. CWQ and anti-PD-1 antibody co-treatment upregulated PD-L1 protein and reduced the abundance of Bacteroides in the gut microbiota but increased the abundance of Akkermansia,Firmicutes, andActinobacteria. Additionally, the proportion of infiltrated CD8+PD-1+, CD8+, and CD3+ T cells were found to be positively correlated with the abundance of Akkermansia. Accordingly, CWQ may modulate the TIME by modifying the gut microbiota and consequently enhance the anti-tumor effect of PD-1 inhibitor therapy.
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Affiliation(s)
- Ting Wang
- Department of Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China; Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Linguangjin Wu
- Department of Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China; Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Shuyun Wang
- Department of Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China; Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiaolan Shi
- Department of Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China.
| | - Hui Liu
- Department of Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China.
| | - Wanli Deng
- Department of Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China.
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Guo Z, Zhu AT, Fang RH, Zhang L. Recent Developments in Nanoparticle-Based Photo-Immunotherapy for Cancer Treatment. SMALL METHODS 2023; 7:e2300252. [PMID: 36960932 PMCID: PMC10192221 DOI: 10.1002/smtd.202300252] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 03/11/2023] [Indexed: 05/17/2023]
Abstract
Phototherapy is an emerging approach for cancer treatment that is effective at controlling the growth of primary tumors. In the presence of light irradiation, photothermal and photodynamic agents that are delivered to tumor sites can induce local hyperthermia and the production of reactive oxygen species, respectively, that directly eradicate cancer cells. Nanoparticles, characterized by their small size and tunable physiochemical properties, have been widely utilized as carriers for phototherapeutic agents to improve their biocompatibility and tumor-targeted delivery. Nanocarriers can also be used to implement various codelivery strategies for further enhancing phototherapeutic efficiency. More recently, there has been considerable interest in augmenting the immunological effects of nanoparticle-based phototherapies, which can yield durable and systemic antitumor responses. This review provides an overview of recent developments in using nanoparticle technology to achieve photo-immunotherapy.
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Affiliation(s)
- Zhongyuan Guo
- Department of NanoEngineering, Chemical Engineering Program, and Moores Cancer Center, University of California San Diego, La Jolla, CA, 92093, USA
| | - Audrey T Zhu
- Department of NanoEngineering, Chemical Engineering Program, and Moores Cancer Center, University of California San Diego, La Jolla, CA, 92093, USA
| | - Ronnie H Fang
- Department of NanoEngineering, Chemical Engineering Program, and Moores Cancer Center, University of California San Diego, La Jolla, CA, 92093, USA
| | - Liangfang Zhang
- Department of NanoEngineering, Chemical Engineering Program, and Moores Cancer Center, University of California San Diego, La Jolla, CA, 92093, USA
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Liu S, Sun Q, Ren X. Novel strategies for cancer immunotherapy: counter-immunoediting therapy. J Hematol Oncol 2023; 16:38. [PMID: 37055849 PMCID: PMC10099030 DOI: 10.1186/s13045-023-01430-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 03/21/2023] [Indexed: 04/15/2023] Open
Abstract
The advent of immunotherapy has made an indelible mark on the field of cancer therapy, especially the application of immune checkpoint inhibitors in clinical practice. Although immunotherapy has proven its efficacy and safety in some tumors, many patients still have innate or acquired resistance to immunotherapy. The emergence of this phenomenon is closely related to the highly heterogeneous immune microenvironment formed by tumor cells after undergoing cancer immunoediting. The process of cancer immunoediting refers to the cooperative interaction between tumor cells and the immune system that involves three phases: elimination, equilibrium, and escape. During these phases, conflicting interactions between the immune system and tumor cells result in the formation of a complex immune microenvironment, which contributes to the acquisition of different levels of immunotherapy resistance in tumor cells. In this review, we summarize the characteristics of different phases of cancer immunoediting and the corresponding therapeutic tools, and we propose normalized therapeutic strategies based on immunophenotyping. The process of cancer immunoediting is retrograded through targeted interventions in different phases of cancer immunoediting, making immunotherapy in the context of precision therapy the most promising therapy to cure cancer.
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Affiliation(s)
- Shaochuan Liu
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, China
- Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
- Key Laboratory of Cancer Immunology and Biotherapy, 300060, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, 300060, Tianjin, China
- Tianjin's Clinical Research Center for Cancer, 300060, Tianjin, China
- Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, China
| | - Qian Sun
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, China.
- Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China.
- Key Laboratory of Cancer Immunology and Biotherapy, 300060, Tianjin, China.
- Key Laboratory of Cancer Prevention and Therapy, 300060, Tianjin, China.
- Tianjin's Clinical Research Center for Cancer, 300060, Tianjin, China.
- Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, China.
| | - Xiubao Ren
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, China.
- Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China.
- Key Laboratory of Cancer Immunology and Biotherapy, 300060, Tianjin, China.
- Key Laboratory of Cancer Prevention and Therapy, 300060, Tianjin, China.
- Tianjin's Clinical Research Center for Cancer, 300060, Tianjin, China.
- Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, China.
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50
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Yang C, Qian Q, Zhao Y, Huang B, Chen R, Gong Q, Ji H, Wang C, Xia L, You Z, Zhang J, Chen X. Fibrinogen-like protein 1 promotes liver-resident memory T-cell exhaustion in hepatocellular carcinoma. Front Immunol 2023; 14:1112672. [PMID: 36993960 PMCID: PMC10040674 DOI: 10.3389/fimmu.2023.1112672] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 03/02/2023] [Indexed: 03/18/2023] Open
Abstract
Background and aimsThe key role of tissue-resident memory T (TRM) cells in the immune regulation of hepatocellular carcinoma (HCC) has been investigated and reported, but the regulatory mechanism of tumor microenvironment on TRM cells is still unclear. Lymphocyte activating gene 3 (LAG-3) is a promising next-generation immune checkpoint that is continuously expressed due to persistent antigen exposure in the tumor microenvironment. Fibrinogen-like protein 1 (FGL1) is a classical ligand of LAG-3 and can promote T cell exhaustion in tumors. Here, we excavated the effect of FGL1-LAG3 regulatory axis on TRM cells in HCC.MethodsThe function and phenotype of intrahepatic CD8+ TRM cells in 35 HCC patients were analyzed using multicolor flow cytometry. Using a tissue microarray of 80 HCC patients, we performed the prognosis analysis. Moreover, we investigated the suppressive effect of FGL1 on CD8+ TRM cells both in in vitro induction model and in vivo orthotopic HCC mouse model.ResultsThere was an increase in LAG3 expression in CD8+ TRM cells in end-stage HCC; moreover, FGL1 levels were negatively correlated with CD103 expression and related to poor outcomes in HCC. Patients with high CD8+ TRM cell proportions have better outcomes, and FGL1-LAG3 binding could lead to the exhaustion of CD8+ TRM cells in tumors, indicating its potential as a target for immune checkpoint therapy of HCC. Increased FGL1 expression in HCC may result in CD8+ TRM cell exhaustion, causing tumor immune escape.ConclusionsWe identified CD8+TRM cells as a potential immunotherapeutic target and reported the effect of FGL1-LAG3 binding on CD8+ TRM cell function in HCC.
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Affiliation(s)
- Changjie Yang
- Department of Liver Surgery, Ren Ji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Qiwei Qian
- Division of Gastroenterology and Hepatology, Ren Ji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yudong Zhao
- Department of Liver Surgery, Ren Ji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Bingyuan Huang
- Division of Gastroenterology and Hepatology, Ren Ji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Ruilin Chen
- Division of Gastroenterology and Hepatology, Ren Ji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Qiyu Gong
- Shanghai Institute of Immunology, Shanghai Jiao Tong University, Shanghai, China
| | - Hao Ji
- Department of Liver Surgery, Ren Ji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Chenchen Wang
- Department of Liver Surgery, Ren Ji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Lei Xia
- Department of Liver Surgery, Ren Ji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Zhengrui You
- Division of Gastroenterology and Hepatology, Ren Ji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Jianjun Zhang
- Department of Liver Surgery, Ren Ji Hospital, Shanghai Jiao Tong University, Shanghai, China
- *Correspondence: Xiaosong Chen, ; Jianjun Zhang,
| | - Xiaosong Chen
- Department of Liver Surgery, Ren Ji Hospital, Shanghai Jiao Tong University, Shanghai, China
- *Correspondence: Xiaosong Chen, ; Jianjun Zhang,
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