|
1
|
Perez-Medina M, Benito-Lopez JJ, Aguilar-Cazares D, Lopez-Gonzalez JS. A Comprehensive Review of Long Non-Coding RNAs in the Cancer-Immunity Cycle: Mechanisms and Therapeutic Implications. Int J Mol Sci 2025; 26:4821. [PMID: 40429961 PMCID: PMC12111859 DOI: 10.3390/ijms26104821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Revised: 05/10/2025] [Accepted: 05/16/2025] [Indexed: 05/29/2025] Open
Abstract
Long non-coding RNAs (lncRNAs) have emerged as pivotal regulators of the dynamic interplay between cancer progression and immune responses. This review explored their influence on key processes of the cancer-immunity cycle, such as immune cell differentiation, antigen presentation, and tumor immunogenicity. By modulating tumor escape from the immune response, therapeutic resistance, and tumor-stroma interactions, lncRNAs actively shape the tumor microenvironment. Due to their growing knowledge in the area of immune suppression, directly intervening in the induction of regulatory T cells (Tregs), M2 macrophages, and regulating immune checkpoint pathways such as PD-L1, CTLA-4, and others, lncRNAs can be considered promising therapeutic targets. Advances in single-cell technologies and immunotherapy have significantly expanded our understanding of lncRNA-driven regulatory networks, paving the way for novel precision medicine approaches. Ultimately, we discussed how targeting lncRNAs could enhance cancer immunotherapy, offering new avenues for biomarker discovery and therapeutic intervention.
Collapse
Affiliation(s)
- Mario Perez-Medina
- Laboratorio de Investigacion en Cancer Pulmonar, Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City 14080, Mexico; (M.P.-M.); (J.J.B.-L.); (D.A.-C.)
- Asociación Para Evitar la Ceguera en México, I. A. P., Mexico City 04030, Mexico
| | - Jesus J. Benito-Lopez
- Laboratorio de Investigacion en Cancer Pulmonar, Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City 14080, Mexico; (M.P.-M.); (J.J.B.-L.); (D.A.-C.)
| | - Dolores Aguilar-Cazares
- Laboratorio de Investigacion en Cancer Pulmonar, Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City 14080, Mexico; (M.P.-M.); (J.J.B.-L.); (D.A.-C.)
| | - Jose S. Lopez-Gonzalez
- Laboratorio de Investigacion en Cancer Pulmonar, Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City 14080, Mexico; (M.P.-M.); (J.J.B.-L.); (D.A.-C.)
| |
Collapse
|
|
2
|
Kumar P, Choudhary A, Kinger S, Jagtap YA, Prajapati VK, Chitkara D, Chinnathambi S, Verma RK, Mishra A. Autophagy as a potential therapeutic target in regulating improper cellular proliferation. Front Pharmacol 2025; 16:1579183. [PMID: 40444035 PMCID: PMC12119615 DOI: 10.3389/fphar.2025.1579183] [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: 02/18/2025] [Accepted: 04/24/2025] [Indexed: 06/02/2025] Open
Abstract
Autophagy is a degradative process that makes rapid turnover of old and impaired proteins and organelles possible. It is highly instigated by stress signals, like starvation, and contributes to the cell's homeostasis. Autophagy performs a crucial function in keeping cell genomic integrity stable. Impaired autophagic flux is implicated in neurodegenerative diseases, abnormal ageing, and cancerous diseases. In diseases like cancer, autophagy performs a dualistic function; it can have both a tumor-suppressive and supportive role. Autophagy in the initial phases of tumorigenesis maintains the integrity of the genome and, if it fails, leads to cell death, thus having a tumor-suppressive role. Meanwhile, autophagy also imparts the function of the pro-survival mechanism in the latter stages of tumorigenesis and supports the cancerous cells in surviving conditions like hypoxia and increased oxidative stress. Autophagy also helps cancerous cells develop drug resistance in some cases. Thus, modulation of the autophagic mechanism is a possible therapeutic strategy in cancer therapy as its inhibition can sensitise cancer cells to anti-cancerous drugs. The promotion of autophagy, in some cases, can also safeguard cells from toxic protein aggregation and enhanced oxidative stress. Excessive autophagy can result in autophagic cell death. Autophagy also regulates several cellular processes and cell death pathways, like apoptosis. Therefore, an in-depth knowledge of the autophagy process and its regulating molecules is critically important. Pharmaceutical small molecules or cellular target modulation can help modulate the cellular autophagy process in the context of specific disease conditions.
Collapse
Affiliation(s)
- Prashant Kumar
- Department of Biosciences and Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur, Rajasthan, India
| | - Akash Choudhary
- Department of Biosciences and Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur, Rajasthan, India
| | - Sumit Kinger
- Department of Biosciences and Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur, Rajasthan, India
| | - Yuvraj Anandrao Jagtap
- Department of Biosciences and Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur, Rajasthan, India
| | | | - Deepak Chitkara
- Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani, Rajasthan, India
| | - Subashchandrabose Chinnathambi
- Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Institute of National Importance, Bangalore, Karnataka, India
| | | | - Amit Mishra
- Department of Biosciences and Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur, Rajasthan, India
| |
Collapse
|
|
3
|
Huang WQ, You W, Zhu YQ, Gao F, Wu ZZ, Chen G, Xiao J, Shao Q, Wang LH, Nie X, Zhang Z, Hong CY, You YZ. Autophagosomes coated in situ with nanodots act as personalized cancer vaccines. NATURE NANOTECHNOLOGY 2025; 20:451-462. [PMID: 39753731 DOI: 10.1038/s41565-024-01826-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 10/14/2024] [Indexed: 03/20/2025]
Abstract
Autophagosome cancer vaccines can promote cross-presentation of multiple tumour antigens and induce cross-reactive T cell responses. However, so far, there is no effective method for obtaining a highly immunogenic autophagosomal cancer vaccine because autophagosomes, once formed, quickly fuse with lysosomes and cannot easily escape from cells. Here we report a functional Ti2NX nanodot that caps the autophagosome membrane lipid phosphatidylinositol-4-phosphate, blocking the fusion of autophagosomes with lysosomes and producing stable nanodot-coated autophagosomes in tumours. The formed nanodot-coated autophagosomes can escape from cancer cells to lymph nodes, where they activate tumour-specific T cells. We show that our approach reduces tumour burden and provide long-term immune surveillance protection for cured mice. This work provides a method for the direct formation of personalized autophagosome-based cancer vaccines in vivo, offering a promising strategy for tumour treatment.
Collapse
Affiliation(s)
- Wei-Qiang Huang
- Department of Urology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Hefei National Research Centre for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, China
- Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, China
| | - Wei You
- Hefei National Research Centre for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, China
- Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, China
| | - Ya-Qi Zhu
- Department of Urology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Hefei National Research Centre for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, China
| | - Fan Gao
- Hefei National Research Centre for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, China
- Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, China
| | - Zhi-Zhi Wu
- Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, China
| | - Guang Chen
- Hefei National Research Centre for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, China.
- Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, China.
| | - Jun Xiao
- Department of Urology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
| | - Qi Shao
- Hefei National Research Centre for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, China
- Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, China
| | - Long-Hai Wang
- Hefei National Research Centre for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, China.
- Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, China.
| | - Xuan Nie
- Hefei National Research Centre for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, China
- Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, China
| | - Ze Zhang
- Hefei National Research Centre for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, China
- Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, China
| | - Chun-Yan Hong
- Hefei National Research Centre for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, China.
- Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, China.
| | - Ye-Zi You
- Department of Urology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
- Hefei National Research Centre for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, China.
- Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, China.
| |
Collapse
|
|
4
|
Gestal-Mato U, Herhaus L. Autophagy-dependent regulation of MHC-I molecule presentation. J Cell Biochem 2024; 125:e30416. [PMID: 37126231 DOI: 10.1002/jcb.30416] [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: 01/19/2023] [Revised: 04/03/2023] [Accepted: 04/18/2023] [Indexed: 05/02/2023]
Abstract
The major histocompatibility complex (MHC) class I molecules present peptide antigens to MHC class I-restricted CD8+ T lymphocytes to elicit an effective immune response. The conventional antigen-processing pathway for MHC-I presentation depends on proteasome-mediated peptide generation and peptide loading in the endoplasmic reticulum by members of the peptide loading complex. Recent discoveries in this field highlight the role of alternative MHC-I peptide loading and presentation pathways, one of them being autophagy. Autophagy is a cell-intrinsic degradative pathway that ensures cellular homoeostasis and plays critical roles in cellular immunity. In this review article, we discuss the role of autophagy in MHC class I-restricted antigen presentation, elucidating new findings on the crosstalk of autophagy and ER-mediated MHC-I peptide presentation, dendritic cell-mediated cross-presentation and also mechanisms governing immune evasion. A detailed molecular understanding of the key drivers of autophagy-mediated MHC-I modulation holds promising targets to devise effective measures to improve T cell immunotherapies.
Collapse
Affiliation(s)
- Uxia Gestal-Mato
- Goethe University School of Medicine, Institute of Biochemistry II, Frankfurt am Main, Germany
| | - Lina Herhaus
- Goethe University School of Medicine, Institute of Biochemistry II, Frankfurt am Main, Germany
| |
Collapse
|
|
5
|
Hashemi M, Mohandesi Khosroshahi E, Tanha M, Khoushab S, Bizhanpour A, Azizi F, Mohammadzadeh M, Matinahmadi A, Khazaei Koohpar Z, Asadi S, Taheri H, Khorrami R, Ramezani Farani M, Rashidi M, Rezaei M, Fattah E, Taheriazam A, Entezari M. Targeting autophagy can synergize the efficacy of immune checkpoint inhibitors against therapeutic resistance: New promising strategy to reinvigorate cancer therapy. Heliyon 2024; 10:e37376. [PMID: 39309904 PMCID: PMC11415696 DOI: 10.1016/j.heliyon.2024.e37376] [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: 04/06/2024] [Revised: 06/29/2024] [Accepted: 09/02/2024] [Indexed: 09/25/2024] Open
Abstract
Immune checkpoints are a set of inhibitory and stimulatory molecules/mechanisms that affect the activity of immune cells to maintain the existing balance between pro- and anti-inflammatory signaling pathways and avoid the progression of autoimmune disorders. Tumor cells can employ these checkpoints to evade immune system. The discovery and development of immune checkpoint inhibitors (ICIs) was thereby a milestone in the area of immuno-oncology. ICIs stimulate anti-tumor immune responses primarily by disrupting co-inhibitory signaling mechanisms and accelerate immune-mediated killing of tumor cells. Despite the beneficial effects of ICIs, they sometimes encounter some degrees of therapeutic resistance, and thereby do not effectively act against tumors. Among multiple combination therapies have been introduced to date, targeting autophagy, as a cellular degradative process to remove expired organelles and subcellular constituents, has represented with potential capacities to overcome ICI-related therapy resistance. It has experimentally been illuminated that autophagy induction blocks the immune checkpoint molecules when administered in conjugation with ICIs, suggesting that autophagy activation may restrict therapeutic challenges that ICIs have encountered with. However, the autophagy flux can also provoke the immune escape of tumors, which must be considered. Since the conventional FDA-approved ICIs have designed and developed to target programmed cell death receptor/ligand 1 (PD-1/PD-L1) as well as cytotoxic T lymphocyte-associated molecule 4 (CTLA-4) immune checkpoint molecules, we aim to review the effects of autophagy targeting in combination with anti-PD-1/PD-L1- and anti-CTLA-4-based ICIs on cancer therapeutic resistance and tumor immune evasion.
Collapse
Affiliation(s)
- Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elaheh Mohandesi Khosroshahi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mahsa Tanha
- Department of Biological Sciences, University of Alabama, Tuscaloosa, AL, United States
| | - Saloomeh Khoushab
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Anahita Bizhanpour
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Farnaz Azizi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mahsa Mohammadzadeh
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Arash Matinahmadi
- Department of Cellular and Molecular Biology, Nicolaus Copernicus University, Torun, Poland
| | - Zeinab Khazaei Koohpar
- Department of Cell and Molecular Biology, Faculty of Biological Sciences, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran
| | - Saba Asadi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Hengameh Taheri
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Ramin Khorrami
- Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Marzieh Ramezani Farani
- Department of Biological Sciences and Bioengineering, Nano Bio High-Tech Materials Research Center, Inha University, 100 Inha-ro, Michuhol-gu, Incheon, 22212, Republic of Korea
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
- The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mahdi Rezaei
- Health Research Center, Chamran Hospital, Tehran, Iran
| | - Eisa Fattah
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| |
Collapse
|
|
6
|
Wang Y, Qiao SL, Wang J, Yu MZ, Wang NN, Mamuti M, An HW, Lin YX, Wang H. Engineered CpG-Loaded Nanorobots Drive Autophagy-Mediated Immunity for TLR9-Positive Cancer Therapy. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2306248. [PMID: 37897408 DOI: 10.1002/adma.202306248] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 10/21/2023] [Indexed: 10/30/2023]
Abstract
Smart nanorobots have emerged as novel drug delivery platforms in nanomedicine, potentially improving anti-cancer efficacy and reducing side effects. In this study, an intelligent tumor microenvironment-responsive nanorobot is developed that effectively delivers CpG payloads to Toll-like receptor 9 (TLR9)-positive tumors to induce autophagy-mediated cell death for immunotherapy. The nanorobots are fabricated by co-self-assembly of two amphiphilic triblock polymer peptides: one containing the matrix metallopeptidase 2 (MMP2)-cleaved GPLGVRGS motif to control the mechanical opening of the nanorobots and provide targeting capability for TLR-9-positive tumors and the other consisting of an arginine-rich GRRRDRGRS sequence that can condense nuclear acid payloads through electrostatic interactions. Using multiple tumor-bearing mouse models, it is investigated whether the intravenous injection of CpG-loaded nanorobots could effectively deliver CpG payloads to TLR-9-positive tumors and elicit anti-tumor immunity through TLR9 signaling and autophagy. Therefore, besides being a commonly used adjuvant for tumor vaccination, CpG-loaded nanorobots can effectively reprogram the tumor immunosuppressive microenvironment and suppress tumor growth and recurrence. This nanorobot-based CpG immunotherapy can be considered a feasible approach to induce anti-tumor immunity, showing great therapeutic potential for the future treatment of TLR9-positive cancers.
Collapse
Affiliation(s)
- Yi Wang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Beijing, 100190, P. R. China
- School of Nanoscience and Technology, University of Chinese Academy of Sciences (UCAS), Beijing, 100149, P. R. China
- Institute of Bioengineering and Institute of Materials Science & Engineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, 1015, Switzerland
| | - Sheng-Lin Qiao
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Beijing, 100190, P. R. China
- Lab of Functional and Biomedical Nanomaterials, College of Materials Science and Engineering, Qingdao University of Science and Technology (QUST), Qingdao, 266042, P. R. China
| | - Jie Wang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Beijing, 100190, P. R. China
- School of Nanoscience and Technology, University of Chinese Academy of Sciences (UCAS), Beijing, 100149, P. R. China
| | - Meng-Zhen Yu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Beijing, 100190, P. R. China
- School of Nanoscience and Technology, University of Chinese Academy of Sciences (UCAS), Beijing, 100149, P. R. China
| | - Nan-Nan Wang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Beijing, 100190, P. R. China
- School of Nanoscience and Technology, University of Chinese Academy of Sciences (UCAS), Beijing, 100149, P. R. China
| | - Muhetaerjiang Mamuti
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Beijing, 100190, P. R. China
| | - Hong-Wei An
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Beijing, 100190, P. R. China
| | - Yao-Xin Lin
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Beijing, 100190, P. R. China
- School of Nanoscience and Technology, University of Chinese Academy of Sciences (UCAS), Beijing, 100149, P. R. China
| | - Hao Wang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Beijing, 100190, P. R. China
- School of Nanoscience and Technology, University of Chinese Academy of Sciences (UCAS), Beijing, 100149, P. R. China
| |
Collapse
|
|
7
|
Hua X, Liu X, Zhu Q, Liu Y, Zhou S, Huang P, Li Q, Liu S. Three-Dimensional Microfluidic Chip for Efficient Capture of Secretory Autophagosomes and Sensitive Detection of Their Surface Proteins. Anal Chem 2022; 94:8489-8496. [DOI: 10.1021/acs.analchem.2c01419] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Xin Hua
- Jiangsu Engineering Laboratory of Smart Carbon-Rich Materials and Device, Jiangsu Provincial Key Laboratory of Critical Care Medicine, Key Laboratory of Environmental Medicine Engineering, Ministry of Education, State Key Laboratory of Bioelectronics, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China
| | - Xi Liu
- Jiangsu Engineering Laboratory of Smart Carbon-Rich Materials and Device, Jiangsu Provincial Key Laboratory of Critical Care Medicine, Key Laboratory of Environmental Medicine Engineering, Ministry of Education, State Key Laboratory of Bioelectronics, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China
| | - Qian Zhu
- Jiangsu Engineering Laboratory of Smart Carbon-Rich Materials and Device, Jiangsu Provincial Key Laboratory of Critical Care Medicine, Key Laboratory of Environmental Medicine Engineering, Ministry of Education, State Key Laboratory of Bioelectronics, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China
| | - Yu Liu
- College of Chemistry and Materials Science, Sichuan Normal University, Chengdu 610068, Sichuan, China
| | - Sisi Zhou
- Jiangsu Engineering Laboratory of Smart Carbon-Rich Materials and Device, Jiangsu Provincial Key Laboratory of Critical Care Medicine, Key Laboratory of Environmental Medicine Engineering, Ministry of Education, State Key Laboratory of Bioelectronics, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China
| | - Puzhen Huang
- Jiangsu Engineering Laboratory of Smart Carbon-Rich Materials and Device, Jiangsu Provincial Key Laboratory of Critical Care Medicine, Key Laboratory of Environmental Medicine Engineering, Ministry of Education, State Key Laboratory of Bioelectronics, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China
| | - Quan Li
- College of Chemistry and Materials Science, Sichuan Normal University, Chengdu 610068, Sichuan, China
| | - Songqin Liu
- Jiangsu Engineering Laboratory of Smart Carbon-Rich Materials and Device, Jiangsu Provincial Key Laboratory of Critical Care Medicine, Key Laboratory of Environmental Medicine Engineering, Ministry of Education, State Key Laboratory of Bioelectronics, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China
| |
Collapse
|
|
8
|
The Dual Role of Autophagy in Crizotinib-Treated ALK + ALCL: From the Lymphoma Cells Drug Resistance to Their Demise. Cells 2021; 10:cells10102517. [PMID: 34685497 PMCID: PMC8533885 DOI: 10.3390/cells10102517] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 09/14/2021] [Accepted: 09/18/2021] [Indexed: 02/06/2023] Open
Abstract
Autophagy has been described as harboring a dual role in cancer development and therapy. Depending on the context, it can exert either pro-survival or pro-death functions. Here, we review what is known about autophagy in crizotinib-treated ALK+ ALCL. We first present our main findings on the role and regulation of autophagy in these cells. Then, we provide literature-driven hypotheses that could explain mechanistically the pro-survival properties of autophagy in crizotinib-treated bulk and stem-like ALK+ ALCL cells. Finally, we discuss how the potentiation of autophagy, which occurs with combined therapies (ALK and BCL2 or ALK and RAF1 co-inhibition), could convert it from a survival mechanism to a pro-death process.
Collapse
|
|
9
|
Association between circulating CD39+CD8+ T cells pre-chemoradiotherapy and prognosis in patients with nasopharyngeal carcinoma. Chin Med J (Engl) 2021; 134:2066-2072. [PMID: 34435978 PMCID: PMC8439997 DOI: 10.1097/cm9.0000000000001745] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Background The mortality rate among patients with nasopharyngeal carcinoma (NPC) has improved significantly with the advent of chemoradiotherapy strategies. However, distant metastasis remains problematic. Tumor-specific reactivity in cancer patients has been detected exclusively in CD39+ T cells, particularly in CD39+CD103+ T cells. Circulating cancer-specific T cells are important for protecting against metastasis. This study aimed to evaluate the predictive value of circulating CD39+CD8+ T cells for metastasis in patients with NPC. Methods We performed a cross-sectional, longitudinal study of 55 patients with newly diagnosed NPC of stage III–IVa. All patients were initially treated with standard combined chemoradiotherapy. Blood samples were obtained from 24 patients before and at 1 month and 6 months after treatment. T cell expression of CD39 and CD103, together with the markers of T cell exhaustion programmed death-1 (PD-1)/T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) and markers of cell differentiation CD27/CC-chemokine receptor 7/CD45RA, was examined by flow cytometry. The Wilcoxon rank-sum test analysis was used to analyze the differences between two groups. Kaplan-Meier analysis was used for analysis of progression-free survival (PFS). Results The expression of circulating CD39+CD8+ and CD39+CD103+ CD8+ T cells was significantly higher in patients without distant metastasis (CD39+CD8+: 6.52% [1.24%, 12.58%] vs. 2.41% [0.58%, 5.31%], Z=−2.073, P=0.038 and CD39+CD103+CD8+: 0.72% [0.26%, 2.05%] vs. 0.26% [0.12%, 0.64%], Z=−2.313, P = 0.021). Most CD39+ T cells did not express PD-1 or Tim-3. Patients with high expression of CD39+CD103+CD8+ T cells had better PFS than patients with low expression (log rank value = 4.854, P = 0.028). CD39+CD8+ T cells were significantly elevated at 1-month post-treatment (10.02% [0.98%, 17.42%] vs. 5.91% [0.61%, 10.23%], Z = −2.943, P = 0.003). The percentage of advanced differentiated CD8+ T cells also increased at 1-month post-treatment compared with pre-treatment (33.10% [21.60%, 43.05%] vs. 21.00% [11.65%, 43.00%], Z = −2.155, P = 0.031). There was a significant correlation between elevated CD39+CD8+ T cells and increased effector memory T cells (intermediate stage: r = 0.469, P = 0.031; advanced stage: r = 0.508, P = 0.019). Conclusions CD39+CD8+ circulating T cells have preserved effector function, contributing to an improved prognosis and a reduced risk of metastasis among NPC patients. These cells may thus be a useful predictive marker for a better prognosis in patients with NPC.
Collapse
|
|
10
|
Mandhair HK, Novak U, Radpour R. Epigenetic regulation of autophagy: A key modification in cancer cells and cancer stem cells. World J Stem Cells 2021; 13:542-567. [PMID: 34249227 PMCID: PMC8246247 DOI: 10.4252/wjsc.v13.i6.542] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 05/02/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023] Open
Abstract
Aberrant epigenetic alterations play a decisive role in cancer initiation and propagation via the regulation of key tumor suppressor genes and oncogenes or by modulation of essential signaling pathways. Autophagy is a highly regulated mechanism required for the recycling and degradation of surplus and damaged cytoplasmic constituents in a lysosome dependent manner. In cancer, autophagy has a divergent role. For instance, autophagy elicits tumor promoting functions by facilitating metabolic adaption and plasticity in cancer stem cells (CSCs) and cancer cells. Moreover, autophagy exerts pro-survival mechanisms to these cancerous cells by influencing survival, dormancy, immunosurveillance, invasion, metastasis, and resistance to anti-cancer therapies. In addition, recent studies have demonstrated that various tumor suppressor genes and oncogenes involved in autophagy, are tightly regulated via different epigenetic modifications, such as DNA methylation, histone modifications and non-coding RNAs. The impact of epigenetic regulation of autophagy in cancer cells and CSCs is not well-understood. Therefore, uncovering the complex mechanism of epigenetic regulation of autophagy provides an opportunity to improve and discover novel cancer therapeutics. Subsequently, this would aid in improving clinical outcome for cancer patients. In this review, we provide a comprehensive overview of the existing knowledge available on epigenetic regulation of autophagy and its importance in the maintenance and homeostasis of CSCs and cancer cells.
Collapse
Affiliation(s)
- Harpreet K Mandhair
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Urban Novak
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Ramin Radpour
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| |
Collapse
|
|
11
|
Daussy CF, Pied N, Wodrich H. Understanding Post Entry Sorting of Adenovirus Capsids; A Chance to Change Vaccine Vector Properties. Viruses 2021; 13:1221. [PMID: 34202573 PMCID: PMC8310329 DOI: 10.3390/v13071221] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/15/2021] [Accepted: 06/17/2021] [Indexed: 12/25/2022] Open
Abstract
Adenovirus vector-based genetic vaccines have emerged as a powerful strategy against the SARS-CoV-2 health crisis. This success is not unexpected because adenoviruses combine many desirable features of a genetic vaccine. They are highly immunogenic and have a low and well characterized pathogenic profile paired with technological approachability. Ongoing efforts to improve adenovirus-vaccine vectors include the use of rare serotypes and non-human adenoviruses. In this review, we focus on the viral capsid and how the choice of genotypes influences the uptake and subsequent subcellular sorting. We describe how understanding capsid properties, such as stability during the entry process, can change the fate of the entering particles and how this translates into differences in immunity outcomes. We discuss in detail how mutating the membrane lytic capsid protein VI affects species C viruses' post-entry sorting and briefly discuss if such approaches could have a wider implication in vaccine and/or vector development.
Collapse
Affiliation(s)
| | | | - Harald Wodrich
- Microbiologie Fondamentale et Pathogénicité, MFP CNRS UMR 5234, University of Bordeaux, 146 rue Leo Saignat, CEDEX, 33076 Bordeaux, France; (C.F.D.); (N.P.)
| |
Collapse
|
|
12
|
Münz C. Non-canonical functions of autophagy proteins in immunity and infection. Mol Aspects Med 2021; 82:100987. [PMID: 34147281 DOI: 10.1016/j.mam.2021.100987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 04/20/2021] [Accepted: 06/08/2021] [Indexed: 10/21/2022]
Abstract
The molecular machinery of macroautophagy, a catabolic pathway for cytoplasmic constituent degradation in lysosomes, remodels membranes by lipid phosphorylation and conjugation of LC3 and GABARAP proteins. In recent year it has become clear that these membrane modifications also regulate endo- and exocytosis. Here I will discuss recent evidence of how such non-canonical functions of the macroautophagy machinery with its autophagy related gene (atg) products influences infectious viral particle secretion, inflammation, and MHC restricted antigen presentation. Especially LC3-Associated Phagocytosis and ATG supported exocytosis will be high-lighted during immunity and infection.
Collapse
Affiliation(s)
- Christian Münz
- Viral Immunobiology, Institute of Experimental Immunology, University of Zurich, Switzerland.
| |
Collapse
|
|
13
|
MERTK-Mediated LC3-Associated Phagocytosis (LAP) of Apoptotic Substrates in Blood-Separated Tissues: Retina, Testis, Ovarian Follicles. Cells 2021; 10:cells10061443. [PMID: 34207717 PMCID: PMC8229618 DOI: 10.3390/cells10061443] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 06/05/2021] [Accepted: 06/07/2021] [Indexed: 01/22/2023] Open
Abstract
Timely and efficient elimination of apoptotic substrates, continuously produced during one’s lifespan, is a vital need for all tissues of the body. This task is achieved by cells endowed with phagocytic activity. In blood-separated tissues such as the retina, the testis and the ovaries, the resident cells of epithelial origin as retinal pigmented epithelial cells (RPE), testis Sertoli cells and ovarian granulosa cells (GC) provide phagocytic cleaning of apoptotic cells and cell membranes. Disruption of this process leads to functional ablation as blindness in the retina and compromised fertility in males and females. To ensure the efficient elimination of apoptotic substrates, RPE, Sertoli cells and GC combine various mechanisms allowing maintenance of tissue homeostasis and avoiding acute inflammation, tissue disorganization and functional ablation. In tight cooperation with other phagocytosis receptors, MERTK—a member of the TAM family of receptor tyrosine kinases (RTK)—plays a pivotal role in apoptotic substrate cleaning from the retina, the testis and the ovaries through unconventional autophagy-assisted phagocytosis process LAP (LC3-associated phagocytosis). In this review, we focus on the interplay between TAM RTKs, autophagy-related proteins, LAP, and Toll-like receptors (TLR), as well as the regulatory mechanisms allowing these components to sustain tissue homeostasis and prevent functional ablation of the retina, the testis and the ovaries.
Collapse
|
|
14
|
Jiang T, Chen X, Ren X, Yang JM, Cheng Y. Emerging role of autophagy in anti-tumor immunity: Implications for the modulation of immunotherapy resistance. Drug Resist Updat 2021; 56:100752. [PMID: 33765484 DOI: 10.1016/j.drup.2021.100752] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 01/29/2021] [Accepted: 02/02/2021] [Indexed: 02/07/2023]
Abstract
Immunotherapies such as CAR-T cell transfer and antibody-targeted therapy have produced promising clinical outcomes in patients with advanced and metastatic cancer that are resistant to conventional therapies. However, with increasing use of cancer immunotherapy in clinical treatment, multiple therapy-resistance mechanisms have gradually emerged. The tumor microenvironment (TME), an integral component of cancer, can significantly influence the therapeutic response. Thus, it is worth exploring the potential of TME in modulating therapy resistance, in the hope to devise novel strategies to reinforcing anti-cancer treatments such as immunotherapy. As a crucial recycling process in the complex TME, the role of autophagy in tumor immunity has been increasingly appreciated. Firstly, autophagy in tumor cells can affect their immune response through modulating MHC-I-antigen complexes, thus modulating immunogenic tumor cell death, changing functions of immune cells via secretory autophagy, reducing the NK- and CTL-mediated cell lysis and degradation of immune checkpoint proteins. Secondly, autophagy is critical for the differentiation, maturation and survival of immune cells in the TME and can significantly affect the immune function of these cells, thereby regulating the anti-tumor immune response. Thirdly, alteration of autophagic activity in stromal cells, especially in fibroblasts, can reconstruct the three-dimensional stromal environment and metabolic reprogramming in the TME. A number of studies have demonstrated that optimal induction or inhibition of autophagy may lead to effective therapeutic regimens when combined with immunotherapy. This review discusses the important roles of autophagy in tumor cells, immune cells and stromal cells in the context of tumor immunity, and the potential of combining the autophagy-based therapy with immunotherapy as novel therapeutic approaches against cancer.
Collapse
Affiliation(s)
- Ting Jiang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Xisha Chen
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Xingcong Ren
- Department of Toxicology and Cancer Biology, Department of Pharmacology, and Markey Cancer Center, University of Kentucky, Lexington, KY, 40536, USA
| | - Jin-Ming Yang
- Department of Toxicology and Cancer Biology, Department of Pharmacology, and Markey Cancer Center, University of Kentucky, Lexington, KY, 40536, USA.
| | - Yan Cheng
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
| |
Collapse
|
|
15
|
Medler TR, Blair TC, Crittenden MR, Gough MJ. Defining Immunogenic and Radioimmunogenic Tumors. Front Oncol 2021; 11:667075. [PMID: 33816320 PMCID: PMC8017281 DOI: 10.3389/fonc.2021.667075] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 03/02/2021] [Indexed: 12/21/2022] Open
Abstract
In the cancer literature tumors are inconsistently labeled as ‘immunogenic’, and experimental results are occasionally dismissed since they are only tested in known ‘responsive’ tumor models. The definition of immunogenicity has moved from its classical definition based on the rejection of secondary tumors to a more nebulous definition based on immune infiltrates and response to immunotherapy interventions. This review discusses the basis behind tumor immunogenicity and the variation between tumor models, then moves to discuss how these principles apply to the response to radiation therapy. In this way we can identify radioimmunogenic tumor models that are particularly responsive to immunotherapy only when combined with radiation, and identify the interventions that can convert unresponsive tumors so that they can also respond to these treatments.
Collapse
Affiliation(s)
- Terry R Medler
- Earle A. Chiles Research Institute, Providence Cancer Institute, Providence Portland Medical Center, Portland, OR, United States
| | - Tiffany C Blair
- Earle A. Chiles Research Institute, Providence Cancer Institute, Providence Portland Medical Center, Portland, OR, United States.,Molecular Microbiology and Immunology, OHSU, Portland, OR, United States
| | - Marka R Crittenden
- Earle A. Chiles Research Institute, Providence Cancer Institute, Providence Portland Medical Center, Portland, OR, United States.,Molecular Microbiology and Immunology, OHSU, Portland, OR, United States.,The Oregon Clinic, Portland, OR, United States
| | - Michael J Gough
- Earle A. Chiles Research Institute, Providence Cancer Institute, Providence Portland Medical Center, Portland, OR, United States.,Molecular Microbiology and Immunology, OHSU, Portland, OR, United States
| |
Collapse
|
|
16
|
Münz C. The Macroautophagy Machinery in MHC Restricted Antigen Presentation. Front Immunol 2021; 12:628429. [PMID: 33717153 PMCID: PMC7947692 DOI: 10.3389/fimmu.2021.628429] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 01/18/2021] [Indexed: 11/18/2022] Open
Abstract
Autophagy-related (ATG) gene products regulate macroautophagy, LC3-associated phagocytosis (LAP) and LC3-dependent extracellular vesicle loading and secretion (LDELS). These processes also influence antigen processing for presentation on major histocompatibility complex (MHC) molecules to T cells. Here, I summarize how these different pathways use the macroautophagy machinery, contribute to MHC class I and II restricted antigen presentation and influence autoimmunity, tumor immunology and immune control of infectious diseases. Targeting these different pathways should allow the regulation of intracellular and extracellular antigen presentation to T cells to modulate protective and pathological immune responses.
Collapse
Affiliation(s)
- Christian Münz
- Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland
| |
Collapse
|
|
17
|
Fu C, Tian G, Duan J, Liu K, Zhang C, Yan W, Wang Y. Therapeutic Antitumor Efficacy of Cancer Stem Cell-Derived DRibble Vaccine on Colorectal Carcinoma. Int J Med Sci 2021; 18:3249-3260. [PMID: 34400894 PMCID: PMC8364449 DOI: 10.7150/ijms.61510] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 07/12/2021] [Indexed: 12/13/2022] Open
Abstract
Dendritic cell (DC)-based immunotherapy has been a promising strategy for colon cancer therapy, but the efficacy of dendritic cell vaccines is in part limited by immunogenicity of loaded antigens. In this study, we aimed to identify a putative tumor antigen that can generate or enhance anti-tumor immune responses against colon cancer. CD44+ colon cancer stem cells (CCSCs) were isolated from mouse colorectal carcinoma CT-26 cell cultures and induced to form defective ribosomal products-containing autophagosome-rich blebs (DRibbles) by treatment with rapamycin, bortezomib, and ammonium chloride. DRibbles were characterized by western blot and transmission electron microscopy. DCs generated from the mice bone marrow monocytes were cocultured with DRibbles, then surface markers of DCs were analyzed by flow cytometry. Meanwhile, the efficacy of DRibble-DCs was examined in vivo. Our results showed that CCSC-derived DRibbles upregulated CD80, CD86, major histocompatibility complex (MHC)-I, and MHC-II on DCs and induced proliferation of mouse splenic lymphocytes and CD8+ T cells. In a model of colorectal carcinoma using BALB/c mice with robust tumor growth and mortality, DC vaccine pulsed with CCSC-derived DRibbles suppressed tumor growth and extended survival. A lactate dehydrogenase test indicated a strong cytolytic activity of cytotoxic T-cells derived from mice vaccinated with CCSC-derived DRibbles against CT-26 cells. Furthermore, flow cytometry analyses showed that the percentages of IFN-γ-producing CD8+ T-cells were increased in SD-DC group compare with the other groups. These findings provide a rationale for novel immunotherapeutic anti-tumor approaches based on DRibbles derived from colon cancer stem cells.
Collapse
Affiliation(s)
- Changhao Fu
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, China.,Stanford University Medical School, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA
| | - Geer Tian
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, China
| | - Jinyue Duan
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, China
| | - Kun Liu
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, China
| | - Chen Zhang
- Institute of Oceanography, Minjiang University, Fuzhou, Fujian 350108, China
| | - Weiqun Yan
- Medical Institute of Regeneration Sciences, Jilin University, Changchun, Jilin 130021, China
| | - Yi Wang
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, China
| |
Collapse
|
|
18
|
Li W, Peng A, Wu H, Quan Y, Li Y, Lu L, Cui M. Anti-Cancer Nanomedicines: A Revolution of Tumor Immunotherapy. Front Immunol 2020; 11:601497. [PMID: 33408716 PMCID: PMC7779686 DOI: 10.3389/fimmu.2020.601497] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 11/20/2020] [Indexed: 12/17/2022] Open
Abstract
Immunotherapies have been accelerating the development of anti-cancer clinical treatment, but its low objective responses and severe off-target immune-related adverse events (irAEs) limit the range of application. Strategies to remove these obstacles primarily focus on the combination of different therapies and the exploitation of new immunotherapeutic agents. Nanomedicine potentiates the effects of activating immune cells selectively and reversing tumor induced immune deficiency microenvironment through multiple mechanisms. In the last decade, a variety of nano-enabled tumor immunotherapies was under clinical investigation. As time goes by, the advantages of nanomedicine are increasingly prominent. With the continuous development of nanotechnology, nanomedicine will offer more distinctive perspectives in imaging diagnosis and treatment of tumors. In this Review, we wish to provide an overview of tumor immunotherapy and the mechanisms of nanomaterials that aim to enhance the efficacy of tumor immunotherapy under development or in clinic treatment.
Collapse
Affiliation(s)
- Wei Li
- Department of General Surgery, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Jinan University, Zhuhai, China
| | - Anghui Peng
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Jinan University, Zhuhai, China
| | - Huajun Wu
- Department of General Surgery, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Jinan University, Zhuhai, China
| | - Yingyao Quan
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Jinan University, Zhuhai, China.,Faculty of Health Sciences, University of Macau, Macau, China
| | - Yong Li
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Jinan University, Zhuhai, China
| | - Ligong Lu
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Jinan University, Zhuhai, China
| | - Min Cui
- Department of General Surgery, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Jinan University, Zhuhai, China
| |
Collapse
|
|
19
|
Huang F, Zhao J, Wei Y, Wen Z, Zhang Y, Wang X, Shen Y, Wang LX, Pan N. Anti-Tumor Efficacy of an Adjuvant Built-In Nanovaccine Based on Ubiquitinated Proteins from Tumor Cells. Int J Nanomedicine 2020; 15:1021-1035. [PMID: 32103954 PMCID: PMC7025662 DOI: 10.2147/ijn.s237578] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 01/26/2020] [Indexed: 12/11/2022] Open
Abstract
Background and Aim We have previously identified ubiquitinated proteins (UPs) from tumor cell lysates as a promising vaccine for cancer immunotherapy in different mouse tumor models. In this study, we aimed at developing a highly efficient therapeutic adjuvant built-in nanovaccine (α-Al2O3-UPs) by a simple method, in which UPs from tumor cells could be efficiently and conveniently enriched by α-Al2O3 nanoparticles covalently coupled with Vx3 proteins (α-Al2O3-CONH-Vx3). Methods The α-Al2O3 nanoparticles were modified with 4-hydroxybenzoic acid followed by coupling with ubiquitin-binding protein Vx3. It was then used to enrich UPs from 4T1 cell lysate. The stability and the efficiency for the UPs enrichment of α-Al2O3-CONH-Vx3 were examined. The ability of α-Al2O3-UPs to activate DCs was examined in vitro subsequently. The splenocytes from the vaccinated mice were re-stimulated with inactivated tumor cells, and the IFN-γ secretion was detected by ELISA and flow cytometry. Moreover, the therapeutic efficacy of α-Al2O3-UPs, alone and in combination with chemotherapy, was examined in 4T1 tumor-bearing mice. Results Our results showed that α-Al2O3-UPs were successfully synthesized and abundant UPs from tumor cell lysate were enriched by the new method. In vitro study showed that compared to the physical mixture of α-Al2O3 nanoparticles and UPs (α-Al2O3+UPs), α-Al2O3-UPs stimulation resulted in higher upregulations of CD80, CD86, MHC class I, and MHC class II on DCs, indicating the higher ability of DC activation. Moreover, α-Al2O3-UPs elicited a more effective immune response in mice, demonstrated by higher IFN-γ secretion than α-Al2O3+UPs. Furthermore, α-Al2O3-UPs also exhibited a more potent effect on tumor growth inhibition and survival prolongation in 4T1 tumor-bearing mice. Notably, when in combination with low dose chemotherapy, the anti-tumor effect was further enhanced, rather than using α-Al2O3-UPs alone. Conclusion This study presents an adjuvant built-in nanovaccine generated by a new simple method that can be potentially applied to cancer immunotherapy and lays the experimental foundation for future clinical application.
Collapse
Affiliation(s)
- Fang Huang
- Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu Province 210009, People's Republic of China
| | - Jinjin Zhao
- Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu Province 210009, People's Republic of China
| | - Yiting Wei
- Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu Province 210009, People's Republic of China
| | - Zhifa Wen
- Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu Province 210009, People's Republic of China
| | - Yue Zhang
- Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu Province 210009, People's Republic of China
| | - Xuru Wang
- Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu Province 210009, People's Republic of China
| | - Yanfei Shen
- Department of Bioengineering, Medical School of Southeast University, Nanjing, Jiangsu Province 210009, People's Republic of China
| | - Li-Xin Wang
- Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu Province 210009, People's Republic of China
| | - Ning Pan
- Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu Province 210009, People's Republic of China
| |
Collapse
|
|
20
|
Patel JM, Cui Z, Wen ZF, Dinh CT, Hu HM. Peritumoral administration of DRibbles-pulsed antigen-presenting cells enhances the antitumor efficacy of anti-GITR and anti-PD-1 antibodies via an antigen presenting independent mechanism. J Immunother Cancer 2019; 7:311. [PMID: 31747946 PMCID: PMC6865022 DOI: 10.1186/s40425-019-0786-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 10/22/2019] [Indexed: 01/08/2023] Open
Abstract
Background TNF receptor family agonists and checkpoint blockade combination therapies lead to minimal tumor clearance of poorly immunogenic tumors. Therefore, a need to enhance the efficacy of this combination therapy arises. Antigen-presenting cells (APCs) present antigen to T cells and steer the immune response through chemokine and cytokine secretion. DRibbles (DR) are tumor-derived autophagosomes containing tumor antigens and innate inflammatory adjuvants. Methods Using preclinical murine lung and pancreatic cancer models, we assessed the triple combination therapy of GITR agonist and PD-1 blocking antibodies with peritumoral injections of DRibbles-pulsed-bone marrow cells (BMCs), which consisted mainly of APCs, or CD103+ cross-presenting dendritic cells (DCs). Immune responses were assessed by flow cytometry. FTY720 was used to prevent T-cell egress from lymph nodes to assess lymph node involvement, and MHC-mismatched-BMCs were used to assess the necessity of antigen presentation by the peritumorally-injected DR-APCs. Results Tritherapy increased survival and cures in tumor-bearing mice compared to combined antibody therapy or peritumoral DR-BMCs alone. Peritumorally-injected BMCs remained within the tumor for at least 14 days and tritherapy efficacy was dependent on both CD4+ and CD8+ T cells. Although the overall percent of tumor-infiltrating T cells remained similar, tritherapy increased the ratio of effector CD4+ T cells-to-regulatory T cells, CD4+ T-cell cytokine production and proliferation, and CD8+ T-cell cytolytic activity in the tumor. Despite tritherapy-induced T-cell activation and cytolytic activity in lymph nodes, this T-cell activation was not required for tumor regression and enhanced survival. Replacement of DR-BMCs with DR-pulsed-DCs in the tritherapy led to similar antitumor effects, whereas replacement with DRibbles was less effective but delayed tumor growth. Interestingly, peritumoral administration of DR-pulsed MHC-mismatched-APCs in the tritherapy led to similar antitumor effects as MHC-matched-APCs, indicating that the observed enhanced antitumor effect was mediated independently of antigen presentation by the administered APCs. Conclusions Overall, these results demonstrate that peritumoral DR-pulsed-BMC/DC administration synergizes with GITR agonist and PD-1 blockade to locally modulate and sustain tumor effector T-cell responses independently of T cell priming and perhaps through innate inflammatory modulations mediated by the DRibbles adjuvant. We offer a unique approach to modify the tumor microenvironment to benefit T-cell-targeted immunotherapies.
Collapse
Affiliation(s)
- Jaina M Patel
- Laboratory of Cancer Immunobiology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center, 4805 NE Glisan Street, Portland, OR, 97213, USA
| | - Zhihua Cui
- Laboratory of Cancer Immunobiology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center, 4805 NE Glisan Street, Portland, OR, 97213, USA
| | - Zhi-Fa Wen
- Laboratory of Cancer Immunobiology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center, 4805 NE Glisan Street, Portland, OR, 97213, USA.,Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu Province, People's Republic of China
| | - Catherine T Dinh
- Laboratory of Cancer Immunobiology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center, 4805 NE Glisan Street, Portland, OR, 97213, USA
| | - Hong-Ming Hu
- Laboratory of Cancer Immunobiology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center, 4805 NE Glisan Street, Portland, OR, 97213, USA.
| |
Collapse
|
|
21
|
Fan J, Wu Y, Jiang M, Wang L, Yin D, Zhang Y, Ye W, Yi Y. IFN-DC Loaded with Autophagosomes containing Virus Antigen is Highly Efficient in Inducing Virus-Specific Human T Cells. Int J Med Sci 2019; 16:741-750. [PMID: 31217742 PMCID: PMC6566749 DOI: 10.7150/ijms.31830] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Accepted: 03/27/2019] [Indexed: 12/23/2022] Open
Abstract
Autophagy plays a critical role in the regulation of innate and adaptive immune responses to pathogens and tumors. A previous study utilized proteasome and lysosome inhibitors to form autophagosomes (DRibbles) and the effect of dendritic cells (DCs) loaded with DRibbles in activating antigen-specific T cells has been demonstrated in a mouse experiment and human IL-4-DC. In this study, CMV-DRibbles derived from MDA cell lines expressing cytomegalovirus (CMV) pp65 protein were loaded onto human IFN-DC and IL-4-DC derived from monocytes, respectively. We observed that CMV-DRibbles resulted in the up-regulation of HLA-DR, CD11c, and CD83, but not co-stimulatory molecules CD 80 and CD86 on IFN-DC. Meanwhile, the expression of HLA-DR, CD80, CD83, and CD86, except for CD11c on IL-4-DC loaded with CMV-DRibbles were up-regulated. Moreover, CMV-DRibbles had no ability to stimulate these two moDCs to secrete cytokines IL-6, IL-1β and IL-10. Then, we optimized the conditions for antigen up-take by DCs and found that mature moDCs had a superior ability to up-take CMV-DRibbles compared with immature DCs in a dose-dependent manner. Furthermore, the efficiency of CMV-DRibbles up-take by IFN-DC was superior compared to IL-4-DC. Finally, we observed that mIFN-DC was significantly more efficient at stimulating autologous CMV-specific CD4+ T cells (0.39 vs. 0.28 %, p<0.05) and CD8+ T cells (0.36 vs. 0.12%, p<0.05) to secrete IFN-γ compared with mIL-4-DC. Therefore, DRibbles containing specific viral antigens were efficient activators of human antigen-specific T cells. Our results demonstrated that IFN-DC loaded with CMV-DRibbles revealed a superior ability to induce CMV-specific T cells.
Collapse
Affiliation(s)
- Jing Fan
- Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine. Zhong Fu Road, Gulou District, Nanjing, Jiangsu, PR China 210003
| | - Yinwei Wu
- Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine. Zhong Fu Road, Gulou District, Nanjing, Jiangsu, PR China 210003
| | - Mingchun Jiang
- Out-patient department, Nanjing Army Command College, Nanjing, 210045, China
| | - Lili Wang
- Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine. Zhong Fu Road, Gulou District, Nanjing, Jiangsu, PR China 210003
| | - Dandan Yin
- Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine. Zhong Fu Road, Gulou District, Nanjing, Jiangsu, PR China 210003
| | - Yajuan Zhang
- Department of Hepatobiliary Surgery, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine. Zhong Fu Road, Gulou District, Nanjing, Jiangsu, PR China 210003
| | - Wei Ye
- Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine. Zhong Fu Road, Gulou District, Nanjing, Jiangsu, PR China 210003
- Out-patient department, Nanjing Army Command College, Nanjing, 210045, China
| | - Yongxiang Yi
- Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine. Zhong Fu Road, Gulou District, Nanjing, Jiangsu, PR China 210003
- Liver Disease, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine. Zhong Fu Road, Gulou District, Nanjing, Jiangsu, PR China 210003
| |
Collapse
|
|
22
|
Münz C. Autophagy proteins influence endocytosis for MHC restricted antigen presentation. Semin Cancer Biol 2019; 66:110-115. [PMID: 30928540 DOI: 10.1016/j.semcancer.2019.03.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 03/19/2019] [Accepted: 03/25/2019] [Indexed: 12/25/2022]
Abstract
T cells of the adaptive immune system monitor protein degradation products via their presentation on major histocompatibility complex (MHC) molecules to recognize infected cells. Both macroautophagy and endocytosis target intra- and extracellular constituents, respectively, for lysosomal degradation. This results in antigen processing for MHC presentation and influences the trafficking of MHC molecules. This review will discuss recent evidence that the molecular machinery of macroautophagy regulates also endocytosis at the level of phagosome maturation and cell membrane internalization. These non-canonical functions of this machinery affect both MHC class I and II restricted antigen presentation to CD8+ and CD4+ T cells, respectively, and should be harnessed to improve immune responses against infectious diseases and cancer.
Collapse
Affiliation(s)
- Christian Münz
- Viral Immunobiology, Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
| |
Collapse
|
|
23
|
Medler T, Patel JM, Alice A, Baird JR, Hu HM, Gough MJ. Activating the Nucleic Acid-Sensing Machinery for Anticancer Immunity. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2018; 344:173-214. [PMID: 30798988 PMCID: PMC6754183 DOI: 10.1016/bs.ircmb.2018.08.006] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Nucleic acid sensing pathways have likely evolved as part of a broad pathogen sensing strategy intended to discriminate infectious agents and initiate appropriate innate and adaptive controls. However, in the absence of infectious agents, nucleic acid sensing pathways have been shown to play positive and negative roles in regulating tumorigenesis, tumor progression and metastatic spread. Understanding the normal biology behind these pathways and how they are regulated in malignant cells and in the tumor immune environment can help us devise strategies to exploit nucleic acid sensing to manipulate anti-cancer immunity.
Collapse
Affiliation(s)
- Terry Medler
- Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland, OR, United States
| | - Jaina M Patel
- Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland, OR, United States
| | - Alejandro Alice
- Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland, OR, United States
| | - Jason R Baird
- Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland, OR, United States
| | - Hong-Ming Hu
- Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland, OR, United States
| | - Michael J Gough
- Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland, OR, United States.
| |
Collapse
|
|
24
|
van de Ven R, Hilton TL, Hu HM, Dubay CJ, Haley D, Paustian C, Puri S, Urba WJ, Curti BD, Aung S, Fox BA. Autophagosome-based strategy to monitor apparent tumor-specific CD8 T cells in patients with prostate cancer. Oncoimmunology 2018; 7:e1466766. [PMID: 30524883 PMCID: PMC6279418 DOI: 10.1080/2162402x.2018.1466766] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Revised: 03/23/2018] [Accepted: 04/13/2018] [Indexed: 01/05/2023] Open
Abstract
The immune system plays an essential role in eradicating cancer in concert with various treatment modalities. In the absence of autologous tumor material, no standardized method exists to assess T cell responses against the many antigens that may serve as cancer rejection antigens. Thus, development of methods to screen for therapy-induced anti-tumor responses is a high priority that could help tailor therapy. Here we tested whether a tumor-derived antigen source called DRibbles®, which contain a pool of defective ribosomal products (DRiPs), long-lived and short-lived proteins (SLiPs) and danger-associated molecular patterns (DAMPs), can be used to identify tumor-associated antigen (TAA)-specific responses in patients before or after immunotherapy treatment. Protein content, gene expression and non-synonymous - single nucleotide variants (ns-SNVs) present in UbiLT3 DRibbles were compared with prostate adenocarcinomas and the prostate GVAX vaccine cell lines (PC3/LNCaP). UbiLT3 DRibbles were found to share proteins, as well as match tumor sequences for ns-SNVs with prostate adenocarcinomas and with the cell lines PC3 and LNCaP. UbiLT3 DRibbles were used to monitor anti-tumor responses in patients vaccinated with allogeneic prostate GVAX. UbiLT3-DRibble-reactive CD8+ T-cell responses were detected in post-vaccine PBMC of 6/12 patients (range 0.85-22% of CD8+ cells) after 1 week in vitro stimulation (p = 0.007 vs. pre-vaccine). In conclusion, a cancer-derived autophagosome-enriched preparation, packaging over 100 proteins over-expressed in prostate cancer into microvesicles containing DAMPs, could be used to identify CD8+ T cells in peripheral blood from patients after prostate GVAX vaccination and may represent a general method to monitor anti-cancer T cell responses following immunotherapy.
Collapse
Affiliation(s)
- Rieneke van de Ven
- Laboratory of Molecular and Tumor Immunology
- Department of Medical Oncology, VU University medical center, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | | | - Hong-Ming Hu
- Laboratory of Cancer Immunobiology
- UbiVac LLC, Portland, OR
| | | | | | | | - Sachin Puri
- Laboratory of Molecular and Tumor Immunology
| | - Walter J. Urba
- Robert W. Franz Cancer Research Center at the Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR
| | - Brendan D. Curti
- Robert W. Franz Cancer Research Center at the Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR
| | | | - Bernard A. Fox
- Laboratory of Molecular and Tumor Immunology
- UbiVac LLC, Portland, OR
- Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR
| |
Collapse
|
|
25
|
Zhang W, Wu S, Guo K, Hu Z, Peng J, Li J. Correlation and clinical significance of LC3, CD68+ microglia, CD4+ T lymphocytes, and CD8+ T lymphocytes in gliomas. Clin Neurol Neurosurg 2018; 168:167-174. [DOI: 10.1016/j.clineuro.2018.02.044] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 02/28/2018] [Indexed: 12/31/2022]
|
|
26
|
Gao R, Ma J, Wen Z, Yang P, Zhao J, Xue M, Chen Y, Aldarouish M, Hu HM, Zhu XJ, Pan N, Wang LX. Tumor cell-released autophagosomes (TRAP) enhance apoptosis and immunosuppressive functions of neutrophils. Oncoimmunology 2018; 7:e1438108. [PMID: 29872581 DOI: 10.1080/2162402x.2018.1438108] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 01/28/2018] [Accepted: 02/02/2018] [Indexed: 01/22/2023] Open
Abstract
Our previous studies have confirmed that tumor cell-released autophagosomes (TRAP) could induce the differentiation of B cells into IL-10+ regulatory B cells (Bregs) with suppressive activities on T lymphocytes. However, the mechanism of TRAP-mediated immune suppression is still largely unclear. Herein, we sought to assess the immunomodulatory effect of TRAPs on human neutrophils, a major immune cell type that infiltrates human tumor tissues. We found that TRAPs enriched from malignant effusions or ascites of cancer patients and tumor cell lines were rapidly and effectively phagocytized by neutrophils through macropinocytosis and promoted neutrophil apoptosis via reactive oxygen species (ROS) generation and caspase-3 activation. Moreover, the apoptotic neutrophils that have phagocytized TRAPs inhibited the proliferation and activation of CD4+ T and CD8+ T cells in a cell contact- and ROS-dependent manner. These findings define a novel TRAP-mediated mechanism in neutrophils that potentially suppresses the anti-tumor T cell immunity and highlight TRAPs as an important target for future tumor immunotherapy.
Collapse
Affiliation(s)
- Rong Gao
- Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu Province, China
| | - Jie Ma
- Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu Province, China
| | - Zhifa Wen
- Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu Province, China
| | - Peiying Yang
- Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu Province, China
| | - Jinjin Zhao
- Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu Province, China
| | - Meng Xue
- Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu Province, China
| | - Yongqiang Chen
- Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu Province, China
| | - Mohanad Aldarouish
- Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu Province, China
| | - Hong-Ming Hu
- Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu Province, China.,Laboratory of Cancer Immunobiology, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA
| | - Xue-Jun Zhu
- Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu Province, China.,Division of Hematology, Department of Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, Jiangsu Province, China
| | - Ning Pan
- Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu Province, China
| | - Li-Xin Wang
- Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu Province, China
| |
Collapse
|
|
27
|
Frentzel J, Sorrentino D, Giuriato S. Targeting Autophagy in ALK-Associated Cancers. Cancers (Basel) 2017; 9:E161. [PMID: 29186933 PMCID: PMC5742809 DOI: 10.3390/cancers9120161] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 11/17/2017] [Accepted: 11/23/2017] [Indexed: 12/15/2022] Open
Abstract
Autophagy is an evolutionarily conserved catabolic process, which is used by the cells for cytoplasmic quality control. This process is induced following different kinds of stresses e.g., metabolic, environmental, or therapeutic, and acts, in this framework, as a cell survival mechanism. However, under certain circumstances, autophagy has been associated with cell death. This duality has been extensively reported in solid and hematological cancers, and has been observed during both tumor development and cancer therapy. As autophagy plays a critical role at the crossroads between cell survival and cell death, its involvement and therapeutic modulation (either activation or inhibition) are currently intensively studied in cancer biology, to improve treatments and patient outcomes. Over the last few years, studies have demonstrated the occurrence of autophagy in different Anaplastic Lymphoma Kinase (ALK)-associated cancers, notably ALK-positive anaplastic large cell lymphoma (ALCL), non-small cell lung carcinoma (NSCLC), Neuroblastoma (NB), and Rhabdomyosarcoma (RMS). In this review, we will first briefly describe the autophagic process and how it can lead to opposite outcomes in anti-cancer therapies, and we will then focus on what is currently known regarding autophagy in ALK-associated cancers.
Collapse
Affiliation(s)
- Julie Frentzel
- Merck Serono S.A., Route de Fenil 25, Z.I. B, 1804 Corsier-sur-Vevey, Switzerland.
| | - Domenico Sorrentino
- Inserm, UMR1037, CNRS, ERL5294, Université Toulouse III-Paul Sabatier, CRCT, F-31000 Toulouse, France.
| | - Sylvie Giuriato
- Inserm, UMR1037, CNRS, ERL5294, Université Toulouse III-Paul Sabatier, CRCT, F-31000 Toulouse, France.
- European Research Initiative on ALK-related malignancies (ERIA).
- TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138.
| |
Collapse
|
|
28
|
Morales J, Barrera-Avalos C, Castro C, Castillo S, Barrientos C, Robles-Planells C, López X, Torres E, Montoya M, Cortez-San Martín M, Riquelme D, Escobar A, Fernández R, Imarai M, Sauma D, Rojo LE, Leiva-Salcedo E, Acuña-Castillo C. Dead Tumor Cells Expressing Infectious Salmon Anemia Virus Fusogenic Protein Favor Antigen Cross-Priming In Vitro. Front Immunol 2017; 8:1170. [PMID: 29062313 PMCID: PMC5640808 DOI: 10.3389/fimmu.2017.01170] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Accepted: 09/04/2017] [Indexed: 12/17/2022] Open
Abstract
Antigen cross-presentation is a crucial step in the assembly of an antitumor immune response leading to activation of naïve CD8 T cells. This process has been extensively used in clinical trials, in which dendritic cells generated in vitro are loaded with tumor antigens and then autotransplanted to the patients. Recently, the use of autologous transplant of dendritic cells fused with dying tumor cells has demonstrated good results in clinical studies. In this work, we generated a similar process in vivo by treating mice with dead tumor cells [cell bodies (CBs)] expressing the fusogenic protein of the infectious salmon anemia virus (ISAV). ISAV fusion protein retains its fusogenic capability when is expressed on mammalian cells in vitro and the CBs expressing it facilitates DCs maturation, antigen transfer by antigen-presenting cells, and increase cross-presentation by DCs in vitro. Additionally, we observed in the melanoma model that CBs with or without ISAV fusion protein reduce tumor growth in prophylactic treatment; however, only ISAV expressing CBs showed an increase CD4 and CD8 cells in spleen. Overall, our results suggest that CBs could be used as a complement with other type of strategies to amplify antitumor immune response.
Collapse
Affiliation(s)
- Jonathan Morales
- Centro de Biotecnología Acuícola, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, USACH, Santiago, Chile
| | - Carlos Barrera-Avalos
- Centro de Biotecnología Acuícola, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, USACH, Santiago, Chile
| | - Carlos Castro
- Centro de Biotecnología Acuícola, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, USACH, Santiago, Chile
| | - Stephanie Castillo
- Centro de Biotecnología Acuícola, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, USACH, Santiago, Chile
| | - Claudio Barrientos
- Centro de Biotecnología Acuícola, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, USACH, Santiago, Chile
| | - Claudia Robles-Planells
- Centro de Biotecnología Acuícola, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, USACH, Santiago, Chile
| | - Ximena López
- Centro de Biotecnología Acuícola, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, USACH, Santiago, Chile
| | - Ernesto Torres
- Centro de Biotecnología Acuícola, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, USACH, Santiago, Chile
| | - Margarita Montoya
- Centro de Biotecnología Acuícola, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, USACH, Santiago, Chile
| | - Marcelo Cortez-San Martín
- Centro de Biotecnología Acuícola, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, USACH, Santiago, Chile
| | - Denise Riquelme
- Centro de Biotecnología Acuícola, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, USACH, Santiago, Chile
| | - Alejandro Escobar
- Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología, Universidad de Chile, Santiago, Chile
| | | | - Mónica Imarai
- Centro de Biotecnología Acuícola, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, USACH, Santiago, Chile
| | - Daniela Sauma
- Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago, Chile
| | - Leonel E Rojo
- Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, USACH, Santiago, Chile
| | - Elias Leiva-Salcedo
- Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, USACH, Santiago, Chile
| | - Claudio Acuña-Castillo
- Centro de Biotecnología Acuícola, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, USACH, Santiago, Chile
| |
Collapse
|
|
29
|
Münz C. Autophagy Proteins in Phagocyte Endocytosis and Exocytosis. Front Immunol 2017; 8:1183. [PMID: 29018446 PMCID: PMC5614925 DOI: 10.3389/fimmu.2017.01183] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 09/07/2017] [Indexed: 02/04/2023] Open
Abstract
Autophagy was initially described as a catabolic pathway that recycles nutrients of cytoplasmic constituents after lysosomal degradation during starvation. Since the immune system monitors products of lysosomal degradation via major histocompatibility complex (MHC) class II restricted antigen presentation, autophagy was found to process intracellular antigens for display on MHC class II molecules. In recent years, however, it has become apparent that the molecular machinery of autophagy serves phagocytes in many more membrane trafficking pathways, thereby regulating immunity to infectious disease agents. In this minireview, we will summarize the recent evidence that autophagy proteins regulate phagocyte endocytosis and exocytosis for myeloid cell activation, pathogen replication, and MHC class I and II restricted antigen presentation. Selective stimulation and inhibition of the respective functional modules of the autophagy machinery might constitute valid therapeutic options in the discussed disease settings.
Collapse
Affiliation(s)
- Christian Münz
- Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland
| |
Collapse
|
|
30
|
Chen S, Sun C, Gu H, Wang H, Li S, Ma Y, Wang J. Salubrinal protects against Clostridium difficile toxin B-induced CT26 cell death. Acta Biochim Biophys Sin (Shanghai) 2017; 49:228-237. [PMID: 28119311 DOI: 10.1093/abbs/gmw139] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Indexed: 12/18/2022] Open
Abstract
Clostridium difficile (C. difficile) is considered to be the major cause of the antibiotic-associated diarrhea and pseudomembranous colitis in animals and humans. The prevalence of C. difficile infections (CDI) has been increasing since 2000. Two exotoxins of C. difficile, Toxin A (TcdA) and Toxin B (TcdB), are the main virulence factors of CDI, which can induce glucosylation of Rho GTPases in host cytosol, leading to cell morphological changes, cell apoptosis, and cell death. The mechanism of TcdB-induced cell death has been investigated for decades, but it is still not completely understood. It has been reported that TcdB induces endoplasmic reticulum stress via PERK-eIF2α signaling pathway in CT26 cell line (BALB/C mouse colon tumor cells). In this study, we found that salubrinal, a selective inhibitor of eIF2α dephosphorylation, efficiently protects CT26 cell line against TcdB-induced cell death and tried to explore the mechanism underlying in this protective effect. Our results demonstrated that salubrinal protects CT26 cells from TcdB-mediated cytotoxic and cytopathic effect, inhibits apoptosis and death of the toxin-exposed cells via caspase-9-dependent pathway, eIF2α signaling pathway, and autophagy. These findings will be helpful for the development of CDI therapies.
Collapse
Affiliation(s)
- Shuyi Chen
- School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China
| | - Chunli Sun
- School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China
| | - Huawei Gu
- School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China
| | - Haiying Wang
- School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China
| | - Shan Li
- School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China
| | - Yi Ma
- School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China
| | - Jufang Wang
- School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China
| |
Collapse
|
|
31
|
Abstract
The discovery of the molecular machinery of autophagy, namely Atg proteins, was awarded with the Nobel prize in physiology and medicine to Yoshinori Ohsumi in 2016. While this machinery was originally identified by its ability to allow cells to survive starvation via lysosomal degradation to recycle cellular components, it has recently become apparent that it also is used by cells to secrete cytoplasmic constituents. Furthermore, viruses have learned to use this Atg supported exocytosis to exit cells, acquire envelopes in the cytosol and select lipids into their surrounding membranes that might allow for increased robustness of their virions and altered infection behavior. Along these lines, picornaviruses exit infected cells in packages wrapped into autophagic membranes, herpesviruses recruit autophagic membranes into their envelopes and para- as well as orthomyxoviruses redirect autophagic membranes to the cell membrane, which increases the robustness of their envelope that they acquire at this site. These recent findings open a new exciting field on the regulation of degradation vs. release of autophagic membranes and will be discussed in this minireview.
Collapse
Affiliation(s)
- Christian Münz
- Viral Immunobiology, Institute of Experimental Immunology, University of Zurich Zurich, Switzerland
| |
Collapse
|
|
32
|
Münz C. The Macroautophagy Machinery in Endo- and Exocytosis. J Mol Biol 2016; 429:473-485. [PMID: 27932293 DOI: 10.1016/j.jmb.2016.11.028] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 11/28/2016] [Accepted: 11/29/2016] [Indexed: 12/30/2022]
Abstract
Macroautophagy and the autophagy-related gene (Atg) machinery execute during their canonical function cytoplasmic constituent degradation in lysosomes. This canonical function contributes to pathogen restriction and intracellular antigen presentation on major histocompatibility complex (MHC) class II molecules to CD4+ T cells. However, in the recent years, it has become clear that the Atg machinery is also used for other membrane transport functions, including endocytosis and exocytosis. This review describes these non-canonical functions in the context of antigen presentation on MHC class I and II molecules to CD8+ and CD4+ T cells, respectively, and during viral replication. Future studies will need to address how the Atg machinery is modified for these non-canonical functions, gets recruited to the respective sites of membrane modification, and recruits alternative Atg interactors to execute endo- and exocytosis instead of macroautophagy.
Collapse
Affiliation(s)
- Christian Münz
- Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, CH-8057, Switzerland.
| |
Collapse
|
|
33
|
Viry E, Noman MZ, Arakelian T, Lequeux A, Chouaib S, Berchem G, Moussay E, Paggetti J, Janji B. Hijacker of the Antitumor Immune Response: Autophagy Is Showing Its Worst Facet. Front Oncol 2016; 6:246. [PMID: 27917371 PMCID: PMC5114287 DOI: 10.3389/fonc.2016.00246] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Accepted: 11/04/2016] [Indexed: 12/19/2022] Open
Abstract
Macroautophagy (hereafter referred to as autophagy) is a housekeeping process constitutively executed at basal level in all cells to promote cellular homeostasis by regulating organelle and protein turnover. However, autophagy deregulation caused by several stress factors, such as hypoxia, is prevalent in many cancers. It is now well established that autophagy can act as tumor suppressor or tumor promoter depending on tumor type, stage, and genetic context. In developed tumors, autophagy promotes the survival of cancer cells and therefore operates as a cell resistance mechanism. Emerging evidence point to the prominent role of autophagy in disabling the antitumor immune response by multiple overlapping mechanisms leading to tumor escape from immune cell attack mediated by both natural killer cells and cytotoxic T-lymphocytes. Such a role has inspired significant interest in applying anti-autophagy therapies as an entirely new approach to overcome tumor escape from immune surveillance, which constitutes so far a major challenge in developing more effective cancer immunotherapies. In this review, we will summarize recent reports describing how tumor cells, by activating autophagy, manage to hijack the immune system. In particular, we will focus on the emerging role of hypoxia-induced autophagy in shaping the antitumor immune response and in allowing tumor cells to outmaneuver an effective immune response and escape immunosurveillance. In keeping with this, we strongly believe that autophagy represents an attractive future therapeutic target to develop innovative and effective cancer immunotherapeutic approaches.
Collapse
Affiliation(s)
- Elodie Viry
- Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health , Luxembourg City , Luxembourg
| | - Muhammad Zaeem Noman
- Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health, Luxembourg City, Luxembourg; INSERM U1186, Gustave Roussy Cancer Center, Villejuif, France
| | - Tsolère Arakelian
- Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health , Luxembourg City , Luxembourg
| | - Audrey Lequeux
- Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health , Luxembourg City , Luxembourg
| | - Salem Chouaib
- INSERM U1186, Gustave Roussy Cancer Center , Villejuif , France
| | - Guy Berchem
- Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health, Luxembourg City, Luxembourg; Department of Hemato-Oncology, Centre Hospitalier du Luxembourg, Luxembourg City, Luxembourg
| | - Etienne Moussay
- Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health , Luxembourg City , Luxembourg
| | - Jérôme Paggetti
- Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health , Luxembourg City , Luxembourg
| | - Bassam Janji
- Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health , Luxembourg City , Luxembourg
| |
Collapse
|
|
34
|
Li J, Xing Y, Zhou Z, Yao W, Cao R, Li T, Xu M, Wu J. Microbial HSP70 peptide epitope 407–426 as adjuvant in tumor-derived autophagosome vaccine therapy of mouse lung cancer. Tumour Biol 2016; 37:15097-15105. [DOI: 10.1007/s13277-016-5309-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Accepted: 09/05/2016] [Indexed: 11/25/2022] Open
|
|
35
|
Münz C. Autophagy Beyond Intracellular MHC Class II Antigen Presentation. Trends Immunol 2016; 37:755-763. [PMID: 27667710 DOI: 10.1016/j.it.2016.08.017] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Revised: 08/31/2016] [Accepted: 08/31/2016] [Indexed: 01/09/2023]
Abstract
Autophagy is a group of cellular pathways that deliver cytoplasmic constituents for lysosomal degradation. The peptides generated from these pathways can be presented by MHC II molecules, making autophagy an important source of antigens for CD4+ T cells. In addition, modules of the molecular machinery of autophagy were found in recent years to also influence extracellular antigen processing for MHC Class I and Class II presentation, as well as regulation of MHC Class I surface expression. These studies paint a more complicated picture of how regulation of individual autophagy proteins influences adaptive immunity. The respective pathways, especially in regard to their net outcome for CD4+ helper and CD8+ cytotoxic T cell responses in vivo, will be discussed in this review.
Collapse
Affiliation(s)
- Christian Münz
- Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
| |
Collapse
|
|
36
|
TLR and NLRP3 inflammasome-dependent innate immune responses to tumor-derived autophagosomes (DRibbles). Cell Death Dis 2016; 7:e2322. [PMID: 27490927 PMCID: PMC5108312 DOI: 10.1038/cddis.2016.206] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Revised: 06/02/2016] [Accepted: 06/07/2016] [Indexed: 01/10/2023]
Abstract
Autophagosomes derived from tumor cells, also referred to as defective ribosomal products in blebs (DRibbles), have been previously shown to stimulate potent T-cell responses and mediate tumor regression when used as therapeutic cancer vaccines in multiple preclinical cancer models. In this report, we investigated the underlining mechanisms by which DRibbles induced T-cell activation, particularly how DRibbles activated antigen-presenting cells (APCs). We found that DRibbles could induce a rapid differentiation of monocytes and DC precursor (pre-DC) cells into functional APCs. DRibbles triggered innate receptor signaling via Toll-like Receptors (TLR)-2, TLR4, TLR7, TLR8, and nucleotide-binding oligomerization domain-containing protein 2 (NOD2), but not TLR3, TLR5, or TLR9. DRibbles induced PBMCs to produce pro-inflammatory cytokines, such as IL-6, IL-10, TNF-α, and IL-1β. DRibbles induced IL-1β release from PBMC or THP-1 cells without LPS priming, but required the core machinery of NLRP3 inflammasomes. Active endocytosis was required for inflammasome activation and cross presentation, and blocking endosome acidification or the ER-associated degradation (ERAD) pathway resulted in opposite effects on these two processes. Our data show that DRibbles could induce strong innate immune responses via multiple pattern recognition receptors, and explain why DRibbles could function as excellent antigen carriers to induce adaptive immune responses to both tumor cells and viruses. In contrast to the well-established inhibitory effect of autophagy on the inflammasome activation of APCs, our study demonstrates that isolated autophagosomes (DRibbles) from antigen donor cells activate inflammasomes by providing first and second signals required for IL-1β production by PMBC.
Collapse
|
|
37
|
Yi Y, Han J, Fang Y, Liu D, Wu Z, Wang L, Zhao L, Wei Q. Sorafenib and a novel immune therapy in lung metastasis from hepatocellular carcinoma following hepatectomy: A case report. Mol Clin Oncol 2016; 5:337-341. [PMID: 27446575 DOI: 10.3892/mco.2016.925] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Accepted: 04/08/2016] [Indexed: 11/05/2022] Open
Abstract
Sorafenib is the standard therapeutic strategy for recurrent hepatocellular carcinoma (HCC) following hepatectomy. However, only few patients truly benefit from this therapy. Thus, new strategies combined with sorafenib are urgently required. We herein present the case of a patient with hepatic and extrahepatic HCC recurrence following hepatectomy, who was treated by combined sorafenib, focused ultrasound knife and DRibbles-pulsed dendritic cell (DC) vaccine. Enzyme-Linked ImmunoSpot assay (ELISPOT) and intracellular staining (ICS) analysis were used to detect the secretion of interferon (IFN)-γ by T cells at different timepoints of the vaccine in order to evaluate the patient's specific T-cell response to SMMC-7721-derived DRibbles vaccine. The α-fetoprotein level decreased from 103,295 to 5 ng/ml and the patient displayed improved liver function, an Eastern Cooperative Oncology Group performance status score of 0, remission of liver metastases and disappearance of the lung metastases 8 months post-combination therapy. The computed tomography scan revealed the disappearance of liver metastases 2 years post-combination therapy. The ELISPOT data revealed a low antigen-specific T-cell response 4 weeks after the first vaccine cycle and the response decreased to nearly zero prior to the second cycle. However, high antigen-specific T-cell response was observed 2 weeks after the second vaccine cycle and did not decrease, even after 10 months, which was consistent with the result of the ICS analysis, which demonstrated that most of the secreted IFN-γ was produced by CD4+ T cells, whereas a low CD8+ T-cell response was observed (0.429 vs. 0.0665%, respectively). Our results demonstrated that antigen-specific T-cell response aimed to treat recurrent HCC may be induced through stimulation by the DC-DRibbles vaccine. The success of the treatment supports the combination of sorafenib, focused ultrasound knife and DC-DRibbles vaccine as a therapeutic strategy for patients with HCC recurrence following hepatectomy.
Collapse
Affiliation(s)
- Yongxiang Yi
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Southeast University, Nanjing, Jiangsu 210003, P.R. China
| | - Jianbo Han
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Southeast University, Nanjing, Jiangsu 210003, P.R. China
| | - Yuan Fang
- Department of Pathology, The Second Affiliated Hospital of Southeast University, Nanjing, Jiangsu 210003, P.R. China
| | - Dongxiao Liu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Southeast University, Nanjing, Jiangsu 210003, P.R. China
| | - Zuoyou Wu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Southeast University, Nanjing, Jiangsu 210003, P.R. China
| | - Lili Wang
- Biological Treatment Center, The Second Affiliated Hospital of Southeast University, Nanjing, Jiangsu 210003, P.R. China
| | - Liang Zhao
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Southeast University, Nanjing, Jiangsu 210003, P.R. China
| | - Qiang Wei
- Department of Ultrasonography, The Second Affiliated Hospital of Southeast University, Nanjing, Jiangsu 210003, P.R. China
| |
Collapse
|
|
38
|
Page DB, Hulett TW, Hilton TL, Hu HM, Urba WJ, Fox BA. Glimpse into the future: harnessing autophagy to promote anti-tumor immunity with the DRibbles vaccine. J Immunother Cancer 2016; 4:25. [PMID: 27190627 PMCID: PMC4869314 DOI: 10.1186/s40425-016-0130-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 04/05/2016] [Indexed: 12/01/2022] Open
Abstract
Because the benefits of immune checkpoint blockade may be restricted to tumors with pre-existing immune recognition, novel therapies that facilitate de novo immune activation are needed. DRibbles is a novel multi-valent vaccine that is created by disrupting degradation of intracellular proteins by the ubiquitin proteasome system. The DRibbles vaccine is comprised of autophagosome vesicles that are enriched with defective ribosomal products and short-lived proteins, known tumor-associated antigens, mediators of innate immunity, and surface markers that encourage phagocytosis and cross-presentation by antigen presenting cells. Here we summarize the rationale and preclinical development of DRibbles, translational evidence in support of DRibbles as a therapeutic strategy in humans, as well as recent developments and expected future directions of the DRibbles vaccine in the clinic.
Collapse
Affiliation(s)
- David B Page
- Earle A. Chiles Research Institute / Providence Portland Cancer Center, 4805 N.E. Glisan St., North Tower, Suite 2N87, Portland, OR 97213 USA
| | - Tyler W Hulett
- Earle A. Chiles Research Institute / Providence Portland Cancer Center, 4805 N.E. Glisan St., North Tower, Suite 2N87, Portland, OR 97213 USA.,Oregon Health & Science University, Portland, OR USA
| | | | | | - Walter J Urba
- Earle A. Chiles Research Institute / Providence Portland Cancer Center, 4805 N.E. Glisan St., North Tower, Suite 2N87, Portland, OR 97213 USA
| | - Bernard A Fox
- Earle A. Chiles Research Institute / Providence Portland Cancer Center, 4805 N.E. Glisan St., North Tower, Suite 2N87, Portland, OR 97213 USA.,UbiVac, Inc., Portland, OR USA.,Oregon Health & Science University, Portland, OR USA
| |
Collapse
|
|
39
|
Zhou M, Wen Z, Cheng F, Ma J, Li W, Ren H, Sheng Y, Dong H, Lu L, Hu HM, Wang LX. Tumor-released autophagosomes induce IL-10-producing B cells with suppressive activity on T lymphocytes via TLR2-MyD88-NF-κB signal pathway. Oncoimmunology 2016; 5:e1180485. [PMID: 27622036 DOI: 10.1080/2162402x.2016.1180485] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Revised: 03/26/2016] [Accepted: 04/14/2016] [Indexed: 12/15/2022] Open
Abstract
Recent studies have shown that tumor cells can release autophagosomes, which transport a broad array of biologically active molecules with potential modulatory effects on immune cell functions. In this study, we aimed to investigate the role of tumor cells-released autophagosomes (i.e. TRAP) in regulating B cell differentiation and function. TRAPs from murine tumor cell lines were found to induce splenic B cells to differentiate into IL-10-producing regulatory B cells (Bregs) with a distinct phenotype of CD1d(+) CD5(+), which could potently inhibit CD8(+) and CD4(+) T cell responses in IL-10-depedent manner both in vitro and in vivo. Notably, adoptive transfer of TRAP-induced Bregs abrogated the immune response and antitumor effect induced by OVA-loaded DC vaccinations in E.G7-OVA-bearing mouse model. Mechanistic studies revealed that membrane-bound high-mobility group B1 (HMGB1) on the intact TRAPs was crucial for inducing Breg differentiation via the activation of TLR2-MyD88-NF-κB signal pathway in B cells. Moreover, TRAPs enriched from malignant effusions of cancer patients could induce human B cells to differentiate into IL-10-producing B cells with immunoregulatory functions, the frequency of which were positively correlated with the HMGB1 levels on TRAPs. Together, our findings have demonstrated that TRAPs promote the generation of IL-10(+) Bregs, which may contribute to the suppression of antitumor immunity.
Collapse
Affiliation(s)
- Meng Zhou
- Department of Microbiology and Immunology, Medical School of Southeast University , Nanjing, Jiangsu Province, P.R. China
| | - Zhifa Wen
- Department of Microbiology and Immunology, Medical School of Southeast University , Nanjing, Jiangsu Province, P.R. China
| | - Feng Cheng
- Department of Microbiology and Immunology, Medical School of Southeast University , Nanjing, Jiangsu Province, P.R. China
| | - Jie Ma
- Department of Microbiology and Immunology, Medical School of Southeast University , Nanjing, Jiangsu Province, P.R. China
| | - Weixia Li
- Department of Microbiology and Immunology, Medical School of Southeast University , Nanjing, Jiangsu Province, P.R. China
| | - Hongyan Ren
- Department of Microbiology and Immunology, Medical School of Southeast University , Nanjing, Jiangsu Province, P.R. China
| | - Yemeng Sheng
- Department of Microbiology and Immunology, Medical School of Southeast University , Nanjing, Jiangsu Province, P.R. China
| | - Huixia Dong
- Department of Microbiology and Immunology, Medical School of Southeast University , Nanjing, Jiangsu Province, P.R. China
| | - Liwei Lu
- Department of Pathology and Center of Infection and Immunology, The University of Hong Kong , Hong Kong, Special Administrative Region, P.R. China
| | - Hong-Ming Hu
- Laboratory of Cancer Immunobiology, Earle A. Chiles Research Institute, Providence Portland Medical Center , Portland, OR, USA
| | - Li-Xin Wang
- Department of Microbiology and Immunology, Medical School of Southeast University , Nanjing, Jiangsu Province, P.R. China
| |
Collapse
|
|
40
|
Münz C. Of LAP, CUPS, and DRibbles - Unconventional Use of Autophagy Proteins for MHC Restricted Antigen Presentation. Front Immunol 2015; 6:200. [PMID: 25972871 PMCID: PMC4413810 DOI: 10.3389/fimmu.2015.00200] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Accepted: 04/13/2015] [Indexed: 11/23/2022] Open
Abstract
Macroautophagy delivers cytoplasmic constituents for lysosomal degradation. Because MHC class II molecules are loaded with lysosomal products for CD4+ T-cell stimulation, macroautophagy supports intracellular antigen processing onto MHC class II molecules. The molecular machinery of macroautophagy, however, does not only support this autophagic antigen processing, but seems to also modify extracellular antigen uptake for MHC class II presentation, antigen exocytosis, and packaging for improved cross-presentation onto MHC class I molecules. The different membrane trafficking pathways with LC3-associated phagocytosis, compartment for unconventional protein secretion, and DRibbles as well as the role that autophagic proteins play in them will be discussed in this review.
Collapse
Affiliation(s)
- Christian Münz
- Viral Immunobiology, Institute of Experimental Immunology, University of Zürich , Zurich , Switzerland
| |
Collapse
|
|
41
|
Ubiquitinated proteins enriched from tumor cells by a ubiquitin binding protein Vx3(A7) as a potent cancer vaccine. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2015; 34:34. [PMID: 25886865 PMCID: PMC4405905 DOI: 10.1186/s13046-015-0156-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Accepted: 04/07/2015] [Indexed: 11/29/2022]
Abstract
Background Our previous studies have demonstrated that autophagosome-enriched vaccine (named DRibbles: DRiPs-containing blebs) induce a potent anti-tumor efficacy in different murine tumor models, in which DRibble-containing ubiquitinated proteins are efficient tumor-specific antigen source for the cross-presentation after being loaded onto dendritic cells. In this study, we sought to detect whether ubiquitinated proteins enriched from tumor cells could be used directly as a novel cancer vaccine. Methods The ubiquitin binding protein Vx3(A7) was used to isolate ubiquitinated proteins from EL4 and B16-F10 tumor cells after blocking their proteasomal degradation pathway. C57BL/6 mice were vaccinated with different doses of Ub-enriched proteins via inguinal lymph nodes or subcutaneous injection and with DRibbles, Ub-depleted proteins and whole cell lysate as comparison groups, respectively. The lymphocytes from the vaccinated mice were re-stimulated with inactivated tumor cells and the levels of IFN-γ in the supernatant were detected by ELISA. Anti-tumor efficacy of Ub-enriched proteins vaccine was evaluated by monitoring tumor growth in established tumor mice models. Graphpad Prism 5.0 was used for all statistical analysis. Results We found that after stimulation with inactivated tumor cells, the lymphocytes from the Ub-enriched proteins-vaccinated mice secreted high level of IFN-γ in dose dependent manner, in which the priming vaccination via inguinal lymph nodes injection induced higher IFN-γ level than that via subcutaneous injection. Moreover, the level of secreted IFN-γ in the Ub-enriched proteins group was markedly higher than that in the whole cell lysate and Ub-depleted proteins. Interestingly, the lymphocytes from mice vaccinated with Ub-enriched proteins, but not Ub-depleted proteins and whole cell lysates, isolated from EL4 or B16-F10 tumor cells also produced an obvious level of IFN-γ when stimulated alternately with inactivated B16-F10 or EL4 tumor cells. Furthermore, Ub-enriched proteins vaccine showed a significant inhibitory effect on in vivo growth of homologous tumor, as well as allogeneic tumor, compared with Ub-depleted proteins and tumor cell lysate. Tumor growth was regressed after three times of vaccination with Ub-enriched proteins in contrast to other groups. Conclusion These results indicated that Ub-enriched proteins isolated from tumor cells may have a potential as a potent vaccine for immunotherapy against cancer.
Collapse
|
|
42
|
Obrist F, Manic G, Kroemer G, Vitale I, Galluzzi L. Trial Watch: Proteasomal inhibitors for anticancer therapy. Mol Cell Oncol 2015; 2:e974463. [PMID: 27308423 PMCID: PMC4904962 DOI: 10.4161/23723556.2014.974463] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2014] [Revised: 09/15/2014] [Accepted: 09/17/2014] [Indexed: 01/12/2023]
Abstract
The so-called "ubiquitin-proteasome system" (UPS) is a multicomponent molecular apparatus that catalyzes the covalent attachment of several copies of the small protein ubiquitin to other proteins that are generally (but not always) destined to proteasomal degradation. This enzymatic cascade is crucial for the maintenance of intracellular protein homeostasis (both in physiological conditions and in the course of adaptive stress responses), and regulates a wide array of signaling pathways. In line with this notion, defects in the UPS have been associated with aging as well as with several pathological conditions including cardiac, neurodegenerative, and neoplastic disorders. As transformed cells often experience a constant state of stress (as a result of the hyperactivation of oncogenic signaling pathways and/or adverse microenvironmental conditions), their survival and proliferation are highly dependent on the integrity of the UPS. This rationale has driven an intense wave of preclinical and clinical investigation culminating in 2003 with the approval of the proteasomal inhibitor bortezomib by the US Food and Drug Administration for use in multiple myeloma patients. Another proteasomal inhibitor, carfilzomib, is now licensed by international regulatory agencies for use in multiple myeloma patients, and the approved indications for bortezomib have been extended to mantle cell lymphoma. This said, the clinical activity of bortezomib and carfilzomib is often limited by off-target effects, innate/acquired resistance, and the absence of validated predictive biomarkers. Moreover, the antineoplastic activity of proteasome inhibitors against solid tumors is poor. In this Trial Watch we discuss the contribution of the UPS to oncogenesis and tumor progression and summarize the design and/or results of recent clinical studies evaluating the therapeutic profile of proteasome inhibitors in cancer patients.
Collapse
Affiliation(s)
- Florine Obrist
- Université Paris-Sud/Paris XI; Le Kremlin-Bicêtre, France
- INSERM, U1138; Paris, France
- Equipe 11 labelisée par la Ligue Nationale contre le Cancer, Center de Recherche des Cordeliers; Paris, France
- Gustave Roussy Cancer Campus; Villejuif, France
| | | | - Guido Kroemer
- INSERM, U1138; Paris, France
- Equipe 11 labelisée par la Ligue Nationale contre le Cancer, Center de Recherche des Cordeliers; Paris, France
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France
- Pôle de Biologie, Hôpital Européen Georges Pompidou; Paris, France
- Metabolomics and Cell Biology Platforms; Gustave Roussy Cancer Campus; Villejuif, France
| | - Ilio Vitale
- Regina Elena National Cancer Institute; Rome, Italy
- Department of Biology, University of Rome “Tor Vergata”
| | - Lorenzo Galluzzi
- INSERM, U1138; Paris, France
- Equipe 11 labelisée par la Ligue Nationale contre le Cancer, Center de Recherche des Cordeliers; Paris, France
- Gustave Roussy Cancer Campus; Villejuif, France
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France
| |
Collapse
|
|
43
|
Galluzzi L, Vacchelli E, Pedro JMBS, Buqué A, Senovilla L, Baracco EE, Bloy N, Castoldi F, Abastado JP, Agostinis P, Apte RN, Aranda F, Ayyoub M, Beckhove P, Blay JY, Bracci L, Caignard A, Castelli C, Cavallo F, Celis E, Cerundolo V, Clayton A, Colombo MP, Coussens L, Dhodapkar MV, Eggermont AM, Fearon DT, Fridman WH, Fučíková J, Gabrilovich DI, Galon J, Garg A, Ghiringhelli F, Giaccone G, Gilboa E, Gnjatic S, Hoos A, Hosmalin A, Jäger D, Kalinski P, Kärre K, Kepp O, Kiessling R, Kirkwood JM, Klein E, Knuth A, Lewis CE, Liblau R, Lotze MT, Lugli E, Mach JP, Mattei F, Mavilio D, Melero I, Melief CJ, Mittendorf EA, Moretta L, Odunsi A, Okada H, Palucka AK, Peter ME, Pienta KJ, Porgador A, Prendergast GC, Rabinovich GA, Restifo NP, Rizvi N, Sautès-Fridman C, Schreiber H, Seliger B, Shiku H, Silva-Santos B, Smyth MJ, Speiser DE, Spisek R, Srivastava PK, Talmadge JE, Tartour E, Van Der Burg SH, Van Den Eynde BJ, Vile R, Wagner H, Weber JS, Whiteside TL, Wolchok JD, Zitvogel L, Zou W, Kroemer G. Classification of current anticancer immunotherapies. Oncotarget 2014; 5:12472-508. [PMID: 25537519 PMCID: PMC4350348 DOI: 10.18632/oncotarget.2998] [Citation(s) in RCA: 339] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2014] [Accepted: 12/15/2014] [Indexed: 11/25/2022] Open
Abstract
During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into "passive" and "active" based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches.
Collapse
Affiliation(s)
- Lorenzo Galluzzi
- Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- INSERM, U1138, Paris, France
- Gustave Roussy Cancer Campus, Villejuif, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
| | - Erika Vacchelli
- Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- INSERM, U1138, Paris, France
- Gustave Roussy Cancer Campus, Villejuif, France
| | - José-Manuel Bravo-San Pedro
- Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- INSERM, U1138, Paris, France
- Gustave Roussy Cancer Campus, Villejuif, France
| | - Aitziber Buqué
- Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- INSERM, U1138, Paris, France
- Gustave Roussy Cancer Campus, Villejuif, France
| | - Laura Senovilla
- Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- INSERM, U1138, Paris, France
- Gustave Roussy Cancer Campus, Villejuif, France
| | - Elisa Elena Baracco
- Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- INSERM, U1138, Paris, France
- Gustave Roussy Cancer Campus, Villejuif, France
- Faculté de Medicine, Université Paris Sud/Paris XI, Le Kremlin-Bicêtre, France
| | - Norma Bloy
- Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- INSERM, U1138, Paris, France
- Gustave Roussy Cancer Campus, Villejuif, France
- Faculté de Medicine, Université Paris Sud/Paris XI, Le Kremlin-Bicêtre, France
| | - Francesca Castoldi
- Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- INSERM, U1138, Paris, France
- Gustave Roussy Cancer Campus, Villejuif, France
- Faculté de Medicine, Université Paris Sud/Paris XI, Le Kremlin-Bicêtre, France
- Sotio a.c., Prague, Czech Republic
| | - Jean-Pierre Abastado
- Pole d'innovation thérapeutique en oncologie, Institut de Recherches Internationales Servier, Suresnes, France
| | - Patrizia Agostinis
- Cell Death Research and Therapy (CDRT) Laboratory, Dept. of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium
| | - Ron N. Apte
- The Shraga Segal Dept. of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Fernando Aranda
- Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- INSERM, U1138, Paris, France
- Gustave Roussy Cancer Campus, Villejuif, France
- Group of Immune receptors of the Innate and Adaptive System, Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Maha Ayyoub
- INSERM, U1102, Saint Herblain, France
- Institut de Cancérologie de l'Ouest, Saint Herblain, France
| | - Philipp Beckhove
- Translational Immunology Division, German Cancer Research Center, Heidelberg, Germany
| | - Jean-Yves Blay
- Equipe 11, Centre Léon Bérard (CLR), Lyon, France
- Centre de Recherche en Cancérologie de Lyon (CRCL), Lyon, France
| | - Laura Bracci
- Dept. of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Anne Caignard
- INSERM, U1160, Paris, France
- Groupe Hospitalier Saint Louis-Lariboisière - F. Vidal, Paris, France
| | - Chiara Castelli
- Unit of Immunotherapy of Human Tumors, Dept. of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy
| | - Federica Cavallo
- Molecular Biotechnology Center, Dept. of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Estaban Celis
- Cancer Immunology, Inflammation and Tolerance Program, Georgia Regents University Cancer Center, Augusta, GA, USA
| | - Vincenzo Cerundolo
- MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
| | - Aled Clayton
- Institute of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff, UK
- Velindre Cancer Centre, Cardiff, UK
| | - Mario P. Colombo
- Unit of Immunotherapy of Human Tumors, Dept. of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy
| | - Lisa Coussens
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Madhav V. Dhodapkar
- Sect. of Hematology and Immunobiology, Yale Cancer Center, Yale University, New Haven, CT, USA
| | | | | | - Wolf H. Fridman
- INSERM, U1138, Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
- Université Pierre et Marie Curie/Paris VI, Paris, France
- Equipe 13, Centre de Recherche des Cordeliers, Paris, France
| | - Jitka Fučíková
- Sotio a.c., Prague, Czech Republic
- Dept. of Immunology, 2nd Faculty of Medicine and University Hospital Motol, Charles University, Prague, Czech Republic
| | - Dmitry I. Gabrilovich
- Dept. of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Jérôme Galon
- INSERM, U1138, Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
- Université Pierre et Marie Curie/Paris VI, Paris, France
- Laboratory of Integrative Cancer Immunology, Centre de Recherche des Cordeliers, Paris, France
| | - Abhishek Garg
- Cell Death Research and Therapy (CDRT) Laboratory, Dept. of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium
| | - François Ghiringhelli
- INSERM, UMR866, Dijon, France
- Centre Georges François Leclerc, Dijon, France
- Université de Bourgogne, Dijon, France
| | - Giuseppe Giaccone
- Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
| | - Eli Gilboa
- Dept. of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Sacha Gnjatic
- Sect. of Hematology/Oncology, Immunology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Axel Hoos
- Glaxo Smith Kline, Cancer Immunotherapy Consortium, Collegeville, PA, USA
| | - Anne Hosmalin
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
- INSERM, U1016, Paris, France
- CNRS, UMR8104, Paris, France
- Hôpital Cochin, AP-HP, Paris, France
| | - Dirk Jäger
- National Center for Tumor Diseases, University Medical Center Heidelberg, Heidelberg, Germany
| | - Pawel Kalinski
- Dept. of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
- University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA, USA
- Dept. of Immunology and Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Klas Kärre
- Dept. of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden
| | - Oliver Kepp
- Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- INSERM, U1138, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France
| | - Rolf Kiessling
- Dept. of Oncology, Karolinska Institute Hospital, Stockholm, Sweden
| | - John M. Kirkwood
- University of Pittsburgh Cancer Institute Laboratory, Pittsburgh, PA, USA
| | - Eva Klein
- Dept. of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden
| | - Alexander Knuth
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Claire E. Lewis
- Academic Unit of Inflammation and Tumour Targeting, Dept. of Oncology, University of Sheffield Medical School, Sheffield, UK
| | - Roland Liblau
- INSERM, UMR1043, Toulouse, France
- CNRS, UMR5282, Toulouse, France
- Laboratoire d'Immunologie, CHU Toulouse, Université Toulouse II, Toulouse, France
| | - Michael T. Lotze
- Dept. of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
- University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA, USA
| | - Enrico Lugli
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Institute, Rozzano, Italy
| | - Jean-Pierre Mach
- Dept. of Biochemistry, University of Lausanne, Epalinges, Switzerland
| | - Fabrizio Mattei
- Dept. of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Domenico Mavilio
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Institute, Rozzano, Italy
- Dept. of Medical Biotechnologies and Translational Medicine, University of Milan, Rozzano, Italy
| | - Ignacio Melero
- Dept. of Immunology, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain
- Dept. of Oncology, Clínica Universidad de Navarra, Pamplona, Spain
| | - Cornelis J. Melief
- ISA Therapeutics, Leiden, The Netherlands
- Dept. of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
| | - Elizabeth A. Mittendorf
- Research Dept. of Surgical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | | | - Adekunke Odunsi
- Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Hideho Okada
- Dept. of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA
| | | | - Marcus E. Peter
- Div. of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
| | - Kenneth J. Pienta
- The James Buchanan Brady Urological Institute, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Angel Porgador
- The Shraga Segal Dept. of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - George C. Prendergast
- Lankenau Institute for Medical Research, Wynnewood, PA, USA
- Dept. of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Philadelphia, PA, USA
- Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Gabriel A. Rabinovich
- Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Buenos Aires, Argentina
| | - Nicholas P. Restifo
- National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Naiyer Rizvi
- Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA
| | - Catherine Sautès-Fridman
- INSERM, U1138, Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
- Université Pierre et Marie Curie/Paris VI, Paris, France
- Equipe 13, Centre de Recherche des Cordeliers, Paris, France
| | - Hans Schreiber
- Dept. of Pathology, The Cancer Research Center, The University of Chicago, Chicago, IL, USA
| | - Barbara Seliger
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Hiroshi Shiku
- Dept. of Immuno-GeneTherapy, Mie University Graduate School of Medicine, Tsu, Japan
| | - Bruno Silva-Santos
- Instituto de Medicina Molecular, Universidade de Lisboa, Lisboa, Portugal
| | - Mark J. Smyth
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
- School of Medicine, University of Queensland, Herston, Queensland, Australia
| | - Daniel E. Speiser
- Dept. of Oncology, University of Lausanne, Lausanne, Switzerland
- Ludwig Cancer Research Center, Lausanne, Switzerland
| | - Radek Spisek
- Sotio a.c., Prague, Czech Republic
- Dept. of Immunology, 2nd Faculty of Medicine and University Hospital Motol, Charles University, Prague, Czech Republic
| | - Pramod K. Srivastava
- Dept. of Immunology, University of Connecticut School of Medicine, Farmington, CT, USA
- Carole and Ray Neag Comprehensive Cancer Center, Farmington, CT, USA
| | - James E. Talmadge
- Laboratory of Transplantation Immunology, Dept. of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Eric Tartour
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
- INSERM, U970, Paris, France
- Paris-Cardiovascular Research Center (PARCC), Paris, France
- Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou (HEGP), AP-HP, Paris, France
| | | | - Benoît J. Van Den Eynde
- Ludwig Institute for Cancer Research, Brussels, Belgium
- de Duve Institute, Brussels, Belgium
- Université Catholique de Louvain, Brussels, Belgium
| | - Richard Vile
- Dept. of Molecular Medicine and Immunology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Hermann Wagner
- Institute of Medical Microbiology, Immunology and Hygiene, Technical University Munich, Munich, Germany
| | - Jeffrey S. Weber
- Donald A. Adam Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, FL, USA
| | - Theresa L. Whiteside
- University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA, USA
- University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Jedd D. Wolchok
- Dept. of Medicine and Ludwig Center, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
| | - Laurence Zitvogel
- Gustave Roussy Cancer Campus, Villejuif, France
- INSERM, U1015, Villejuif, France
- Centre d'Investigation Clinique Biothérapie 507 (CICBT507), Gustave Roussy Cancer Campus, Villejuif, France
| | - Weiping Zou
- University of Michigan, School of Medicine, Ann Arbor, MI, USA
| | - Guido Kroemer
- Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- INSERM, U1138, Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France
- Pôle de Biologie, Hôpital Européen Georges Pompidou (HEGP), AP-HP, Paris, France
| |
Collapse
|
|
44
|
Su S, Zhou H, Xue M, Liu JY, Ding L, Cao M, Zhou ZX, Hu HM, Wang LX. Anti-tumor efficacy of a hepatocellular carcinoma vaccine based on dendritic cells combined with tumor-derived autophagosomes in murine models. Asian Pac J Cancer Prev 2014; 14:3109-16. [PMID: 23803088 DOI: 10.7314/apjcp.2013.14.5.3109] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
The majority of hepatocellular carcinoma (HCC) patients have a poor prognosis with current therapies, and new approaches are urgently needed. We have developed a novel therapeutic cancer vaccine platform based on tumor cell derived autophagosomes (DRibbles) for cancer immunotherapy. We here evaluated the effectiveness of DRibbles-pulsed dendritic cell (DC) immunization to induce anti-tumor immunity in BALB/c mouse HCC and humanized HCC mouse models generated by transplantation of human HCC cells (HepG2) into BALB/c-nu mice. DRibbles were enriched from H22 or BNL cells, BALB/c-derived HCC cell lines, by inducing autophagy and blocking protein degradation. DRibbles-pulsed DC immunization induced a specific T cell response against HCC and resulted in significant inhibition of tumor growth compared to mice treated with DCs alone. Anti- tumor efficacy of the DCs-DRibbles vaccine was also demonstrated in a humanized HCC mouse model. The results indicated that HCC/DRibbles-pulsed DCs immunotherapy might be useful for suppressing the growth of residual tumors after primary therapy of human HCC.
Collapse
Affiliation(s)
- Shu Su
- Cancer Research and Biotherapy Center, the Affiliated Nanjing Second Hospital, Medical School of Southeast University, Nanjing, Jiangsu, China
| | | | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Abstract
During the past two decades, several interventions have been shown to increase the healthy lifespan of model organisms as evolutionarily distant from each other as yeast, worms, flies and mammals. These anti-aging maneuvers include (but are not limited to) cycles of caloric restriction, physical exercise as well as the administration of multiple, chemically unrelated agents, such as resveratrol, spermidine and various rapamycin-like compounds collectively known as rapalogs. Most, if not all, lifespan-extending agents promote macroautophagy (hereafter referred to as autophagy), an evolutionarily old mechanism that contributes to the maintenance of intracellular homeostasis and plays a critical role in the adaptive response of cells to stress. In line with this notion, the activation of autophagy appears to mediate significant anti-ageing effects in several organisms, including mice. Here, we focus on rapalogs to discuss the possibility that part of the beneficial activity of lifespan-extending agents stems from their ability to exert immunostimulatory effects. Accumulating evidence indicates indeed that the immune system can recognize and eliminate not only cells that are prone to undergo malignant transformation, but also senescent cells, thus playing a significant role in the control of organismal aging. In addition, it has recently become clear that rapamycin and other rapalogs, which for a long time have been viewed (and used in the clinic) as pure immunosuppressants, can mediate robust immunostimulatory functions, at least in some circumstances.
Collapse
|
|
46
|
Aranda F, Vacchelli E, Obrist F, Eggermont A, Galon J, Sautès-Fridman C, Cremer I, Henrik ter Meulen J, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Toll-like receptor agonists in oncological indications. Oncoimmunology 2014; 3:e29179. [PMID: 25083332 PMCID: PMC4091055 DOI: 10.4161/onci.29179] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Accepted: 05/09/2014] [Indexed: 12/20/2022] Open
Abstract
Toll-like receptors (TLRs) are an evolutionarily conserved group of enzymatically inactive, single membrane-spanning proteins that recognize a wide panel of exogenous and endogenous danger signals. Besides constituting a crucial component of the innate immune response to bacterial and viral pathogens, TLRs appear to play a major role in anticancer immunosurveillance. In line with this notion, several natural and synthetic TLR ligands have been intensively investigated for their ability to boost tumor-targeting immune responses elicited by a variety of immunotherapeutic and chemotherapeutic interventions. Three of these agents are currently approved by the US Food and Drug Administration (FDA) or equivalent regulatory agencies for use in cancer patients: the so-called bacillus Calmette-Guérin, monophosphoryl lipid A, and imiquimod. However, the number of clinical trials testing the therapeutic potential of both FDA-approved and experimental TLR agonists in cancer patients is stably decreasing, suggesting that drug developers and oncologists are refocusing their interest on alternative immunostimulatory agents. Here, we summarize recent findings on the use of TLR agonists in cancer patients and discuss how the clinical evaluation of FDA-approved and experimental TLR ligands has evolved since the publication of our first Trial Watch dealing with this topic.
Collapse
Affiliation(s)
- Fernando Aranda
- Gustave Roussy; Villejuif, France
- INSERM, UMRS1138; Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Paris, France
- Université Paris-Sud/Paris XI; Paris, France
| | - Erika Vacchelli
- Gustave Roussy; Villejuif, France
- INSERM, UMRS1138; Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Paris, France
- Université Paris-Sud/Paris XI; Paris, France
| | - Florine Obrist
- Gustave Roussy; Villejuif, France
- INSERM, UMRS1138; Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Paris, France
- Université Paris-Sud/Paris XI; Paris, France
| | | | - Jérôme Galon
- INSERM, UMRS1138; Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité; Paris, France
- Laboratory of Integrative Cancer Immunology, Centre de Recherche des Cordeliers; Paris, France
| | - Catherine Sautès-Fridman
- INSERM, UMRS1138; Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité; Paris, France
- Université Pierre et Marie Curie/Paris VI; Paris, France
- Equipe 13, Centre de Recherche des Cordeliers; Paris, France
| | - Isabelle Cremer
- INSERM, UMRS1138; Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité; Paris, France
- Université Pierre et Marie Curie/Paris VI; Paris, France
- Equipe 13, Centre de Recherche des Cordeliers; Paris, France
| | | | - Laurence Zitvogel
- Gustave Roussy; Villejuif, France
- INSERM, U1015; CICBT507; Villejuif, France
| | - Guido Kroemer
- INSERM, UMRS1138; Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité; Paris, France
- Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP; Villejuif, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy; Villejuif, France
| | - Lorenzo Galluzzi
- Gustave Roussy; Villejuif, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité; Paris, France
| |
Collapse
|
|
47
|
Ye W, Xing Y, Paustian C, van de Ven R, Moudgil T, Hilton TL, Fox BA, Urba WJ, Zhao W, Hu HM. Cross-presentation of viral antigens in dribbles leads to efficient activation of virus-specific human memory T cells. J Transl Med 2014; 12:100. [PMID: 24735498 PMCID: PMC4021424 DOI: 10.1186/1479-5876-12-100] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2013] [Accepted: 04/03/2014] [Indexed: 12/11/2022] Open
Abstract
Background Autophagy regulates innate and adaptive immune responses to pathogens and tumors. We have reported that autophagosomes derived from tumor cells after proteasome inhibition, DRibbles (Defective ribosomal products in blebs), were excellent sources of antigens for efficient cross priming of tumor-specific CD8+ T cells, which mediated regression of established tumors in mice. But the activity of DRibbles in human has not been reported. Methods DRibbles or cell lysates derived from HEK293T or UbiLT3 cell lines expressing cytomegalovirus (CMV) pp65 protein or transfected with a plasmid encoding dominant HLA-A2 restricted CMV, Epstein-Barr virus (EBV), and Influenza (Flu) epitopes (CEF) were loaded onto human monocytes or PBMCs and the response of human CMV pp65 or CEF antigen-specific CD4+ and CD8+ memory T cells was detected by intracellular staining. The effect of cytokines (GM-CSF, IL-4, IL-12, TNF-α, IFN-α and IFN-γ) TLR agonists (Lipopolysaccharide, Polyinosinic-polycytidylic acid (poly(I:C), M52-CpG, R848, TLR2 ligand) and CD40 ligand on the cross-presentation of antigens contained in DRibbles or cell lysates was explored. Results In this study we showed that purified monocytes, or human PBMCs, loaded with DRibbles isolated from cells expressing CMV or CEF epitopes, could activate CMV- or CEF-specific memory T cells. DRibbles were significantly more efficient at stimulating CD8+ memory T cells compared to cell lysates expressing the same antigenic epitopes. We optimized the conditions for T-cell activation and IFN-γ production following direct loading of DRibbles onto PBMCs. We found that the addition of Poly(I:C), CD40 ligand, and GM-CSF to the PBMCs together with DRibbles significantly increased the level of CD8+ T cell responses. Conclusions DRibbles containing specific viral antigens are an efficient ex vivo activator of human antigen-specific memory T cells specific for those antigens. This function could be enhanced by combining with Poly(I:C), CD40 ligand, and GM-CSF. This study provides proof-of-concept for applying this strategy to activate memory T cells against other antigens, including tumor-specific T cells ex vivo for immunological monitoring and adoptive immunotherapy, and in vivo as vaccines for patients with cancer.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | - Wei Zhao
- Medical School, Southeast University, 87 Dingjiaqiao Street, 210009 Nanjing, Jiangsu, PR China.
| | | |
Collapse
|
|
48
|
Blagosklonny MV. Immunosuppressants in cancer prevention and therapy. Oncoimmunology 2013; 2:e26961. [PMID: 24575379 PMCID: PMC3926869 DOI: 10.4161/onci.26961] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Revised: 10/25/2013] [Accepted: 10/25/2013] [Indexed: 12/13/2022] Open
Abstract
Rapalogs such as rapamycin (sirolimus), everolimus, temserolimus, and deforolimus are indicated for the treatment of some malignancies. Rapamycin is the most effective cancer-preventive agent currently known, at least in mice, dramatically delaying carcinogenesis in both normal and cancer-prone murine strains. In addition, rapamycin and everolimus decrease the risk of cancer in patients receiving these drugs in the context of immunosuppressive regimens. In general, the main concern about the use of immunosuppressants in humans is an increased risk of cancer. Given that rapalogs are useful in cancer prevention and therapy, should they be viewed as immunosuppressants or immunostimulators? Or should we reconsider the role of immunity in cancer altogether? In addition to its anti-viral, anti-inflammatory, anti-angiogenic and anti-proliferative effects, rapamycin operates as a gerosuppressant, meaning that it inhibits the cellular conversion to a senescent state (the so-called geroconversion), a fundamental process involved in aging and age-related pathologies including cancer.
Collapse
|
|
49
|
Nanomaterials and autophagy: new insights in cancer treatment. Cancers (Basel) 2013; 5:296-319. [PMID: 24216709 PMCID: PMC3730308 DOI: 10.3390/cancers5010296] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2013] [Revised: 03/05/2013] [Accepted: 03/19/2013] [Indexed: 12/17/2022] Open
Abstract
Autophagy represents a cell’s response to stress. It is an evolutionarily conserved process with diversified roles. Indeed, it controls intracellular homeostasis by degradation and/or recycling intracellular metabolic material, supplies energy, provides nutrients, eliminates cytotoxic materials and damaged proteins and organelles. Moreover, autophagy is involved in several diseases. Recent evidences support a relationship between several classes of nanomaterials and autophagy perturbation, both induction and blockade, in many biological models. In fact, the autophagic mechanism represents a common cellular response to nanomaterials. On the other hand, the dynamic nature of autophagy in cancer biology is an intriguing approach for cancer therapeutics, since during tumour development and therapy, autophagy has been reported to trigger both an early cell survival and a late cell death. The use of nanomaterials in cancer treatment to deliver chemotherapeutic drugs and target tumours is well known. Recently, autophagy modulation mediated by nanomaterials has become an appealing notion in nanomedicine therapeutics, since it can be exploited as adjuvant in chemotherapy or in the development of cancer vaccines or as a potential anti-cancer agent. Herein, we summarize the effects of nanomaterials on autophagic processes in cancer, also considering the therapeutic outcome of synergism between nanomaterials and autophagy to improve existing cancer therapies.
Collapse
|