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Seyedi S, Harris VK, Kapsetaki SE, Narayanan S, Saha D, Compton Z, Yousefi R, May A, Fakir E, Boddy AM, Gerlinger M, Wu C, Mina L, Huijben S, Gouge DH, Cisneros L, Ellsworth PC, Maley CC. Resistance Management for Cancer: Lessons from Farmers. Cancer Res 2024; 84:3715-3727. [PMID: 39356625 PMCID: PMC11565176 DOI: 10.1158/0008-5472.can-23-3374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 06/29/2024] [Accepted: 09/23/2024] [Indexed: 10/04/2024]
Abstract
One of the main reasons we have not been able to cure cancers is that treatments select for drug-resistant cells. Pest managers face similar challenges with pesticides selecting for pesticide-resistant insects, resulting in similar mechanisms of resistance. Pest managers have developed 10 principles that could be translated to controlling cancers: (i) prevent onset, (ii) monitor continuously, (iii) identify thresholds below which there will be no intervention, (iv) change interventions in response to burden, (v) preferentially select nonchemical control methods, (vi) use target-specific drugs, (vii) use the lowest effective dose, (viii) reduce cross-resistance, (ix) evaluate success based on long-term management, and (x) forecast growth and response. These principles are general to all cancers and cancer drugs and so could be employed broadly to improve oncology. Here, we review the parallel difficulties in controlling drug resistance in pests and cancer cells. We show how the principles of resistance management in pests might be applied to cancer. Integrated pest management inspired the development of adaptive therapy in oncology to increase progression-free survival and quality of life in patients with cancers where cures are unlikely. These pest management principles have the potential to inform clinical trial design.
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Affiliation(s)
- Sareh Seyedi
- Arizona Cancer Evolution Center, Arizona State University, Tempe, Arizona
- Center for Biocomputing, Security and Society, Biodesign Institute, Arizona State University, Tempe, Arizona
- School of Life Sciences, Arizona State University, Tempe, Arizona
| | - Valerie K. Harris
- Arizona Cancer Evolution Center, Arizona State University, Tempe, Arizona
- Center for Biocomputing, Security and Society, Biodesign Institute, Arizona State University, Tempe, Arizona
| | - Stefania E. Kapsetaki
- Arizona Cancer Evolution Center, Arizona State University, Tempe, Arizona
- Center for Biocomputing, Security and Society, Biodesign Institute, Arizona State University, Tempe, Arizona
| | - Shrinath Narayanan
- Center for Biocomputing, Security and Society, Biodesign Institute, Arizona State University, Tempe, Arizona
- Department of Ecology and Evolution, University of Lausanne, Lausanne, Switzerland
| | - Daniel Saha
- Arizona Cancer Evolution Center, Arizona State University, Tempe, Arizona
- Center for Biocomputing, Security and Society, Biodesign Institute, Arizona State University, Tempe, Arizona
- School of Life Sciences, Arizona State University, Tempe, Arizona
| | - Zachary Compton
- Arizona Cancer Evolution Center, Arizona State University, Tempe, Arizona
- Center for Biocomputing, Security and Society, Biodesign Institute, Arizona State University, Tempe, Arizona
- School of Life Sciences, Arizona State University, Tempe, Arizona
- University of Arizona Cancer Center, University of Arizona College of Medicine, Tucson, Arizona
| | - Rezvan Yousefi
- Arizona Cancer Evolution Center, Arizona State University, Tempe, Arizona
- Center for Biocomputing, Security and Society, Biodesign Institute, Arizona State University, Tempe, Arizona
- The Polytechnic School, Ira A. Fulton Schools of Engineering, Arizona State University, Tempe, Arizona
| | - Alexander May
- Research Casting International, Quinte West, Ontario, Canada
| | - Efe Fakir
- Istanbul University Cerrahpasa School of Medicine, Istanbul, Turkey
| | - Amy M. Boddy
- Arizona Cancer Evolution Center, Arizona State University, Tempe, Arizona
- Exotic Species Cancer Research Alliance, North Carolina State University, Raleigh, North Carolina
- Department of Anthropology, University of California Santa Barbara, Santa Barbara, California
| | - Marco Gerlinger
- Translational Oncogenomics Laboratory, Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom
- Gastrointestinal Cancer Unit, The Royal Marsden Hospital, London, United Kingdom
| | - Christina Wu
- Division of Hematology and Medical Oncology, Department of Medicine, Mayo Clinic, Phoenix, Arizona
| | | | - Silvie Huijben
- School of Life Sciences, Arizona State University, Tempe, Arizona
- Center for Evolution and Medicine, Arizona State University, Tempe, Arizona
| | - Dawn H. Gouge
- Department of Entomology, University of Arizona, Tucson, Arizona
| | - Luis Cisneros
- Arizona Cancer Evolution Center, Arizona State University, Tempe, Arizona
- Center for Biocomputing, Security and Society, Biodesign Institute, Arizona State University, Tempe, Arizona
- School of Life Sciences, Arizona State University, Tempe, Arizona
| | | | - Carlo C. Maley
- Arizona Cancer Evolution Center, Arizona State University, Tempe, Arizona
- Center for Biocomputing, Security and Society, Biodesign Institute, Arizona State University, Tempe, Arizona
- School of Life Sciences, Arizona State University, Tempe, Arizona
- Center for Evolution and Medicine, Arizona State University, Tempe, Arizona
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Liu Y, Liang J, Zhang Y, Guo Q. Drug resistance and tumor immune microenvironment: An overview of current understandings (Review). Int J Oncol 2024; 65:96. [PMID: 39219258 PMCID: PMC11387120 DOI: 10.3892/ijo.2024.5684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 08/08/2024] [Indexed: 09/04/2024] Open
Abstract
The use of antitumor drugs represents a reliable strategy for cancer therapy. Unfortunately, drug resistance has become increasingly common and contributes to tumor metastasis and local recurrence. The tumor immune microenvironment (TME) consists of immune cells, cytokines and immunomodulators, and collectively they influence the response to treatment. Epigenetic changes including DNA methylation and histone modification, as well as increased drug exportation have been reported to contribute to the development of drug resistance in cancers. In the past few years, the majority of studies on tumors have only focused on the development and progression of a tumor from a mechanistic standpoint; few studies have examined whether the changes in the TME can also affect tumor growth and drug resistance. Recently, emerging evidence have raised more concerns regarding the role of TME in the development of drug resistance. In the present review, it was discussed how the suppressive TME adapts to drug resistance characterized by the cooperation of immune cells, cytokines, immunomodulators, stromal cells and extracellular matrix. Furthermore, it was reviewed how these immunological or metabolic changes alter immuno‑surveillance and thus facilitate tumor drug resistance. In addition, potential targets present in the TME for developing novel therapeutic strategies to improve individualized therapy for cancer treatment were revealed.
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Affiliation(s)
- Yan Liu
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Jun Liang
- Department of Radiology, Qingdao Haici Hospital, Qingdao, Shandong 266000, P.R. China
| | - Yanping Zhang
- Department of Radiology, Qingdao Haici Hospital, Qingdao, Shandong 266000, P.R. China
| | - Qie Guo
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
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Dhanyamraju PK. Drug resistance mechanisms in cancers: Execution of pro-survival strategies. J Biomed Res 2024; 38:95-121. [PMID: 38413011 PMCID: PMC11001593 DOI: 10.7555/jbr.37.20230248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 11/21/2023] [Accepted: 12/07/2023] [Indexed: 02/29/2024] Open
Abstract
One of the quintessential challenges in cancer treatment is drug resistance. Several mechanisms of drug resistance have been described to date, and new modes of drug resistance continue to be discovered. The phenomenon of cancer drug resistance is now widespread, with approximately 90% of cancer-related deaths associated with drug resistance. Despite significant advances in the drug discovery process, the emergence of innate and acquired mechanisms of drug resistance has impeded the progress in cancer therapy. Therefore, understanding the mechanisms of drug resistance and the various pathways involved is integral to treatment modalities. In the present review, I discuss the different mechanisms of drug resistance in cancer cells, including DNA damage repair, epithelial to mesenchymal transition, inhibition of cell death, alteration of drug targets, inactivation of drugs, deregulation of cellular energetics, immune evasion, tumor-promoting inflammation, genome instability, and other contributing epigenetic factors. Furthermore, I highlight available treatment options and conclude with future directions.
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Affiliation(s)
- Pavan Kumar Dhanyamraju
- Fels Cancer Institute of Personalized Medicine, Lewis-Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
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4
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Fang ZX, Chen WJ, Wu Z, Hou YY, Lan YZ, Wu HT, Liu J. Inflammatory response in gastrointestinal cancers: Overview of six transmembrane epithelial antigens of the prostate in pathophysiology and clinical implications. World J Clin Oncol 2024; 15:9-22. [PMID: 38292664 PMCID: PMC10823946 DOI: 10.5306/wjco.v15.i1.9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 11/24/2023] [Accepted: 12/19/2023] [Indexed: 01/23/2024] Open
Abstract
Chronic inflammation is known to increase the risk of gastrointestinal cancers (GICs), the common solid tumors worldwide. Precancerous lesions, such as chronic atrophic inflammation and ulcers, are related to inflammatory responses in vivo and likely to occur in hyperplasia and tumorigenesis. Unfortunately, due to the lack of effective therapeutic targets, the prognosis of patients with GICs is still unsatisfactory. Interestingly, it is found that six transmembrane epithelial antigens of the prostate (STEAPs), a group of metal reductases, are significantly associated with the progression of malignancies, playing a crucial role in systemic metabolic homeostasis and inflammatory responses. The structure and functions of STEAPs suggest that they are closely related to intracellular oxidative stress, responding to inflammatory reactions. Under the imbalance status of abnormal oxidative stress, STEAP members are involved in cell transformation and the development of GICs by inhibiting or activating inflammatory process. This review focuses on STEAPs in GICs along with exploring their potential molecular regulatory mechanisms, with an aim to provide a theoretical basis for diagnosis and treatment strategies for patients suffering from these types of cancers.
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Affiliation(s)
- Ze-Xuan Fang
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Wen-Jia Chen
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Zheng Wu
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yan-Yu Hou
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yang-Zheng Lan
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Hua-Tao Wu
- Department of General Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jing Liu
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
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Yang Z, He F. An immune cell infiltration landscape classification to predict prognosis and immunotherapy effect in oral squamous cell carcinoma. Comput Methods Biomech Biomed Engin 2024; 27:191-203. [PMID: 36794748 DOI: 10.1080/10255842.2023.2179364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 02/07/2023] [Indexed: 02/17/2023]
Abstract
Tumor immune cell infiltration (ICI) is associated with the prognosis of oral squamous cell carcinoma (OSCC) patients and the effect of immunotherapy. The combat algorithm was used to merge the data from three databases and the Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm to quantify the amount of infiltrated immune cells. Unsupervised consistent cluster analysis was used to determine ICI subtypes, and differentially expressed genes (DEGs) were determined according to these subtypes. The DEGs were then clustered again to obtain the ICI gene subtypes. The principal component analysis (PCA) and the Boruta algorithm were used to construct the ICI scores. Three different ICI clusters and gene clusters with a prognosis of significant difference were found and the ICI score was constructed. Patients with higher ICI scores have a better prognosis following internal and external verification. Besides, the proportion of patients with effective immunotherapy was higher than those with low scores in two external datasets with immunotherapy. This study shows that the ICI score is an effective prognostic biomarker and a predictor of immunotherapy.
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Affiliation(s)
- Zhiqiang Yang
- Department of Stomatology, Meishan People's Hospital, Meishan, China
| | - Fan He
- Department of Stomatology, Meishan People's Hospital, Meishan, China
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Shao J, Jin Y, Jin C. A new approach to overcoming resistance to immunotherapy: nanotechnology. Front Oncol 2023; 13:1210245. [PMID: 37637050 PMCID: PMC10457008 DOI: 10.3389/fonc.2023.1210245] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 07/27/2023] [Indexed: 08/29/2023] Open
Abstract
Immunotherapy for immune response has ushered in a new era of cancer treatment. In recent years, new immunotherapeutic agents have been introduced into clinical trials and even approved for marketing. However, the widespread use of immunotherapeutic agents faces an unavoidable challenge: immunotherapy does not work at all for some patients, or has good efficacy in the initial phase, but immunotherapy resistance develops within a short period of time, and immunotherapy can also cause serious adverse effects such as autoimmune inflammation and non-specific inflammation. How to enable patients to overcome drug resistance, reduce the toxic side effects of drugs, enhance patient compliance and improve patient survival has become a problem that clinicians have to face. The advent of nanotechnology provides an encouraging platform for immunotherapy. It can not only improve the bioavailability and stability of drugs and reduce toxic side effects, but also reduce resistance to immunotherapy. Here, we discuss these research advances and discuss potential challenges and future directions.
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Affiliation(s)
- Jiangbo Shao
- Department of Ultrasound, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
| | - Ying Jin
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Chunxiang Jin
- Department of Ultrasound, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
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Jalalizadeh M, Yadollahvandmiandoab R, Reis LO. Immune Checkpoint Glycoproteins Have Polymorphism: Are Monoclonal Antibodies Too Specific? Curr Oncol 2023; 30:1267-1274. [PMID: 36661747 PMCID: PMC9857673 DOI: 10.3390/curroncol30010098] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 01/11/2023] [Accepted: 01/13/2023] [Indexed: 01/19/2023] Open
Abstract
Since the 2018 Nobel prize in medicine was granted to the discovery of immune escape by cancer cells, billions of dollars have been spent on a new form of cancer immunotherapy called immune checkpoint inhibition (ICI). In this treatment modality, monoclonal antibodies (mAbs) are used to block cell-surface glycoproteins responsible for cancer immune escape. However, only a subset of patients benefit from this treatment. In this commentary, we focus on the polymorphism in the target molecules of these mAbs, namely PD-1, PD-L1 and CTLA4; we explain that using a single mAb from one clone is unlikely to succeed in treating all humans because humans have a genotype and phenotype polymorphism in these molecules. Monoclonal antibodies are highly specific and are capable of recognizing only one epitope ("monospecific"), which makes them ideal for use in laboratory animals because these animals are generationally inbred and genetically identical (isogenic). In humans, however, the encoding genes for PD-1, PD-L1 and CTLA4 have variations (alleles), and the final protein products have phenotype polymorphism. This means that small differences exist in these proteins among individual humans, rendering one mAb too specific to cover all patients. Our suggestion for the next step in advancing this oncotherapy is to focus on methods to tailor the mAb treatment individually for each patient or replace a single clone of mAb with less specific alternatives, e.g., a "cocktail of mAbs", oligoclonal antibodies or recombinant polyclonal antibodies. Fortunately, there are ongoing clinical trials on oligoclonal antibodies at the moment.
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Affiliation(s)
- Mehrsa Jalalizadeh
- UroScience, School of Medical Sciences, University of Campinas, UNICAMP, Campinas 13083-970, SP, Brazil
| | - Reza Yadollahvandmiandoab
- UroScience, School of Medical Sciences, University of Campinas, UNICAMP, Campinas 13083-970, SP, Brazil
| | - Leonardo Oliveira Reis
- UroScience, School of Medical Sciences, University of Campinas, UNICAMP, Campinas 13083-970, SP, Brazil
- Center for Life Sciences, Pontifical Catholic University of Campinas, PUC-Campinas, Campinas 13034-685, SP, Brazil
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8
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Hanna A, Balko JM. Breast cancer resistance mechanisms: challenges to immunotherapy. Breast Cancer Res Treat 2021; 190:5-17. [PMID: 34322780 PMCID: PMC8560575 DOI: 10.1007/s10549-021-06337-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 07/18/2021] [Indexed: 12/26/2022]
Abstract
PURPOSE The clinical implementation of immunotherapy has profoundly transformed cancer treatment. Targeting the immune system to mount anti-tumor responses can elicit a systemically durable response. Employing immune checkpoint blockade (ICB) has suppressed tumor growth and vastly improved patient overall and progression-free survival in several cancer types, most notably melanoma and non-small cell lung carcinoma. Despite widescale clinical success, ICB response is heterogeneously efficacious across tumor types. Many cancers, including breast cancer, are frequently refractory to ICB. In this review, we will discuss the challenges facing immunotherapy success and address the underlying mechanisms responsible for primary and acquired breast cancer resistance to immunotherapy. FINDINGS Even in initially ICB-responsive tumors, many acquire resistance due to tumor-specific alterations, loss of tumor-specific antigens, and extrinsic mechanisms that reshape the immune landscape within the tumor microenvironment (TME). The tumor immune interaction circumvents the benefits of immunotherapy; tumors rewire the tumor-suppressive functions of activated immune cells within their stroma to propagate tumor growth and progression. CONCLUSIONS The breast cancer immune TME is complex and the mechanisms driving resistance to ICB are multifaceted. Continued study in both preclinical models and clinical trials should help elucidate these mechanisms so they can be targeted to benefit more breast cancer patients.
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Affiliation(s)
- Ann Hanna
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Justin M Balko
- Department of Medicine, Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, TN, USA.
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Bashash D, Zandi Z, Kashani B, Pourbagheri-Sigaroodi A, Salari S, Ghaffari SH. Resistance to immunotherapy in human malignancies: Mechanisms, research progresses, challenges, and opportunities. J Cell Physiol 2021; 237:346-372. [PMID: 34498289 DOI: 10.1002/jcp.30575] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 08/19/2021] [Accepted: 08/24/2021] [Indexed: 12/31/2022]
Abstract
Despite remarkable advances in different types of cancer therapies, an effective therapeutic strategy is still a major and significant challenge. One of the most promising approaches in this regard is immunotherapy, which takes advantage of the patients' immune system; however, the many mechanisms that cancerous cells harbor to extend their survival make it impossible to gain perfect eradication of tumors. The response rate to cancer immunotherapies, especially checkpoint inhibitors and adoptive T cell therapy, substantially differs in various cancer types with the highest rates in advanced melanoma and non-small cell lung cancer. Indeed, the lack of response in many tumors indicates primary resistance that can originate from either tumor cells (intrinsic) or tumor microenvironment (extrinsic). On the other hand, some tumors show an initial response to immunotherapy followed by relapse in few months (acquired resistance). Understanding the underlying molecular mechanisms of immunotherapy resistance makes it possible to develop effective strategies to overcome this hurdle and boost therapy outcomes. In this review, we take a look at immunotherapy strategies and go through a number of primary and acquired resistance mechanisms. Also, we present various ongoing methods to overcoming resistance and introduce some promising fields to improve the outcome of immunotherapy in patients affected with cancer.
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Affiliation(s)
- Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Zandi
- Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Bahareh Kashani
- Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sina Salari
- Department of Medical Oncology, Hematology and Bone Marrow Transplantation, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed H Ghaffari
- Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Combinatorial therapy in tumor microenvironment: Where do we stand? Biochim Biophys Acta Rev Cancer 2021; 1876:188585. [PMID: 34224836 DOI: 10.1016/j.bbcan.2021.188585] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 05/28/2021] [Accepted: 06/23/2021] [Indexed: 01/09/2023]
Abstract
The tumor microenvironment plays a pivotal role in tumor initiation and progression by creating a dynamic interaction with cancer cells. The tumor microenvironment consists of various cellular components, including endothelial cells, fibroblasts, pericytes, adipocytes, immune cells, cancer stem cells and vasculature, which provide a sustained environment for cancer cell proliferation. Currently, targeting tumor microenvironment is increasingly being explored as a novel approach to improve cancer therapeutics, as it influences the growth and expansion of malignant cells in various ways. Despite continuous advancements in targeted therapies for cancer treatment, drug resistance, toxicity and immune escape mechanisms are the basis of treatment failure and cancer escape. Targeting tumor microenvironment efficiently with approved drugs and combination therapy is the solution to this enduring challenge that involves combining more than one treatment modality such as chemotherapy, surgery, radiotherapy, immunotherapy and nanotherapy that can effectively and synergistically target the critical pathways associated with disease pathogenesis. This review shed light on the composition of the tumor microenvironment, interaction of different components within tumor microenvironment with tumor cells and associated hallmarks, the current status of combinatorial therapies being developed, and various growing advancements. Furthermore, computational tools can also be used to monitor the significance and outcome of therapies being developed. We addressed the perceived barriers and regulatory hurdles in developing a combinatorial regimen and evaluated the present status of these therapies in the clinic. The accumulating depth of knowledge about the tumor microenvironment in cancer may facilitate further development of effective treatment modalities. This review presents the tumor microenvironment as a sweeping landscape for developing novel cancer therapies.
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11
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Lee J, Kim J, Sin JI. B16 melanomas evade antitumor immunity by the loss of epitope presentation and the acquisition of tumor resistance to granzyme B. Cell Immunol 2021; 367:104394. [PMID: 34198057 DOI: 10.1016/j.cellimm.2021.104394] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 05/20/2021] [Accepted: 06/05/2021] [Indexed: 12/25/2022]
Abstract
Melanomas exhibit the highest rate of heterogeneity among cancer cell types. In this study, we tested the two types of B16 melanoma cells (B16-S0-1 and B16-S1-1) showing resistance to antitumor immunity. These cells expressed Trp2 protein. Contrary to B16 and B16-S0-1 cells, B16-S1-1 cells failed to stimulate IFN-γ responses in Trp2-specific CD8+ T cells, suggesting that B16-S1-1 cells may have lost the ability to present antigen to Ag-specific CTLs in the context of MHC class I molecules. However, B16-S0-1 cells exhibited active Stat3 and decreased Bcl-2 expression, which were found to be not associated with immune escape. B16-S0-1 cells were more resistant to granzyme B-mediated caspase activation and apoptosis than B16 cells. Thus, these data show that B16 cells escape antitumor immune responses through the loss of epitope presentation to CTLs and the acquisition of tumor cell resistance to granzyme B-mediated caspase activation.
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Affiliation(s)
- Jaeyeon Lee
- Department of Microbiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do 200-701, South Korea; Interdisciplinary Graduate Program in BIT Medical Convergence, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do 200-701, South Korea
| | - Jiyoon Kim
- Department of Microbiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do 200-701, South Korea
| | - Jeong-Im Sin
- Department of Microbiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do 200-701, South Korea; Interdisciplinary Graduate Program in BIT Medical Convergence, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do 200-701, South Korea.
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12
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Dar HA, Ismail S, Waheed Y, Ahmad S, Jamil Z, Aziz H, Hetta HF, Muhammad K. Designing a multi-epitope vaccine against Mycobacteroides abscessus by pangenome-reverse vaccinology. Sci Rep 2021; 11:11197. [PMID: 34045649 PMCID: PMC8159972 DOI: 10.1038/s41598-021-90868-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 05/19/2021] [Indexed: 02/07/2023] Open
Abstract
Mycobacteroides abscessus (Previously Mycobacterium abscessus) is an emerging microorganism of the newly defined genera Mycobacteroides that causes mainly skin and tissue diseases in humans. The recent availability of total 34 fully sequenced genomes of different strains belonging to this species has provided an opportunity to utilize this genomics data to gain novel insights and guide the development of specific antimicrobial therapies. In the present study, we collected collectively 34 complete genome sequences of M. abscessus from the NCBI GenBank database. Pangenome analysis was conducted on these genomes to understand the genetic diversity and to obtain proteins associated with its core genome. These core proteins were then subjected to various subtractive filters to identify potential antigenic targets that were subjected to multi-epitope vaccine design. Our analysis projected the open pangenome of M. abscessus containing 3443 core genes. After applying various stepwise filtration steps on the core proteins, a total of four potential antigenic targets were identified. Utilizing their constituent CD4 and CD8 T-cell epitopes, a multi-epitope based subunit vaccine was computationally designed. Sequence-based analysis as well as structural characterization revealed the immunological effectiveness of this designed vaccine. Further molecular docking, molecular dynamics simulation and binding free energy estimation with Toll-like receptor 2 indicated strong structural associations of the vaccine with the immune receptor. The promising results are encouraging and need to be validated by additional wet laboratory studies for confirmation.
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Affiliation(s)
- Hamza Arshad Dar
- Foundation University Medical College, Foundation University Islamabad, DHA-I, Islamabad, 44000, Pakistan
| | - Saba Ismail
- Foundation University Medical College, Foundation University Islamabad, DHA-I, Islamabad, 44000, Pakistan
| | - Yasir Waheed
- Foundation University Medical College, Foundation University Islamabad, DHA-I, Islamabad, 44000, Pakistan.
| | - Sajjad Ahmad
- Foundation University Medical College, Foundation University Islamabad, DHA-I, Islamabad, 44000, Pakistan
| | - Zubia Jamil
- Foundation University Medical College, Foundation University Islamabad, DHA-I, Islamabad, 44000, Pakistan
| | - Hafsa Aziz
- Nuclear Medicine, Oncology, and Radiotherapy Institute, Islamabad, 44000, Pakistan
| | - Helal F Hetta
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, 71515, Egypt
| | - Khalid Muhammad
- Department of Biology, College of Science, United Arab Emirates University, 15551, Al Ain, United Arab Emirates.
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Chen Y, Liu X, Guo Y, Wang J, Zhang D, Mei Y, Shi J, Tan W, Zheng JH. Genetically engineered oncolytic bacteria as drug delivery systems for targeted cancer theranostics. Acta Biomater 2021; 124:72-87. [PMID: 33561563 DOI: 10.1016/j.actbio.2021.02.006] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 01/28/2021] [Accepted: 02/02/2021] [Indexed: 12/16/2022]
Abstract
Drug delivery systems based on genetically engineered oncolytic bacteria have properties that cannot be achieved by traditional therapeutic interventions. Thus, they have attracted considerable attention in cancer therapies. Attenuated bacteria can specifically target and actively penetrate tumor tissues and play an important role in cancer suppression as the "factories" of diverse anticancer drugs. Over the past decades, several bacterial strains including Salmonella and Clostridium have been shown to effectively retard tumor growth and metastasis, and thus improve survival in preclinical models or clinical cases. In this review, we summarize the unique properties of oncolytic bacteria and their anticancer mechanisms and highlight the particular advantages compared with traditional strategies. With the current research progress, we demonstrate the potential value of oncolytic bacteria-based drug delivery systems for clinical applications. In addition, we discuss novel strategies of cancer therapies integrating oncolytic bacteria, which will provide hope to further improve and standardize the current regimens in the near future.
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14
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Martinet L, Le Guellec S, Filleron T, Lamant L, Meyer N, Rochaix P, Garrido I, Girard JP. High endothelial venules (HEVs) in human melanoma lesions: Major gateways for tumor-infiltrating lymphocytes. Oncoimmunology 2021; 1:829-839. [PMID: 23162750 PMCID: PMC3489738 DOI: 10.4161/onci.20492] [Citation(s) in RCA: 157] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
The presence of tumor-infiltrating lymphocytes (TILs) is a strong prognostic parameter for local dissemination and overall survival in melanoma. Lymphocyte migration from blood into peripheral tissues is mainly regulated by vascular endothelium. However, the blood vessels and mechanisms governing the recruitment of TILs in melanoma tumors remain poorly understood. Here, we show that high endothelial venules (HEVs), specialized blood vessels for lymphocyte extravasation into lymphoid tissues, are frequently found in melanoma tumors and are associated with high levels of lymphocyte infiltration. The analysis of 225 primary melanomas revealed that lymphocytes specifically infiltrated HEV-rich areas of melanoma tumors and that the density of MECA-79+ HEVs was variable among patients and strongly correlated with CD3+, CD8+ and CD20+ TIL densities. Inflammatory (CCL5, CXCL9, CXCL10 and CXCL11) and lymphoid (CCL21, CCL19 and CXCL13) chemokines as well as TH1 and naïve T-cell genes were overexpressed in melanoma samples with high densities of tumor HEVs. Mature dendritic cells (mDCs) were frequently found around tumor HEVs and densities of HEVs and DC-LAMP+ mDCs within tumor stroma were strongly correlated. DCs which maintain HEVs in lymph nodes, may thus also contribute to the regulation of HEVs in melanomas. Finally, we found significantly higher densities of tumor HEVs in melanomas with tumor regression, low Clark level of invasion and thin Breslow thickness (all p < 0.001). The strong association between tumor HEVs, TILs, mDCs and clinical parameters of melanoma, supports a critical role for HEVs in limiting malignant melanoma development through both naïve and effector T-lymphocyte recruitment and activation.
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Affiliation(s)
- Ludovic Martinet
- CNRS; IPBS (Institut de Pharmacologie et de Biologie Structurale); Toulouse, France ; Université de Toulouse; Toulouse, France ; Institut Claudius Regaud; Toulouse, France
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15
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High Endothelial Venule with Concomitant High CD8+ Tumor-Infiltrating Lymphocytes Is Associated with a Favorable Prognosis in Resected Gastric Cancer. J Clin Med 2020; 9:jcm9082628. [PMID: 32823631 PMCID: PMC7464373 DOI: 10.3390/jcm9082628] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 08/12/2020] [Accepted: 08/12/2020] [Indexed: 12/24/2022] Open
Abstract
CD8+ tumor-infiltrating lymphocytes (TILs) play a major role in antitumor immunity. High endothelial venules (HEVs) are related to diverse immune cells in solid tumors. We analyzed CD8+ and Foxp3+ TILs in combination with HEVs to determine their prognostic role in advanced gastric cancer (AGC). We enrolled 157 patients with AGC in this study. The densities of CD8+ TILs and Foxp3+ TILs were calculated using immunohistochemical staining. HEVs were evaluated by MECA-79 expression. HEVs were identified in 60 (38.2%) cases and was significantly associated with an increased number of CD8+ TILs (p = 0.027) but not of Foxp3+ TILs (p = 0.455) and CD20+ TILs (p = 0.163). A high CD8+/HEV+ level was significantly associated with nodal metastasis (p = 0.048). In survival analysis, patients with high CD8+/HEV+ levels demonstrated the longest overall survival (OS) (p = 0.015). Furthermore, a high CD8+/HEV+ level was an independent prognostic factor in AGC (p = 0.011; hazard ratio (HR) = 0.435; 95% confidence interval (CI) = 0.245–0.837). HEVs were found to play an important role in antitumor immunity associated with CD8+ TILs in AGC. This analysis of HEVs and CD8+ TILs helps stratify patients with AGC and sheds light on tumor immunity.
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16
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Bai R, Chen N, Li L, Du N, Bai L, Lv Z, Tian H, Cui J. Mechanisms of Cancer Resistance to Immunotherapy. Front Oncol 2020; 10:1290. [PMID: 32850400 PMCID: PMC7425302 DOI: 10.3389/fonc.2020.01290] [Citation(s) in RCA: 206] [Impact Index Per Article: 41.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 06/22/2020] [Indexed: 12/16/2022] Open
Abstract
Over the last decade, based on the extensive development of preclinical animal studies and clinical trials, the efficacy, and mechanisms of immunotherapy have been fully explored. Significant and lasting clinical responses with immunotherapy provide a new breakthrough treatment for a variety of refractory cancer histologies, which gradually change the treatment pattern of tumors. However, although immune checkpoint inhibitor drugs are promising for achieving longer-term efficacy, their benefits in the overall population are still very low, such as low frequency of response in some common tumor types such as breast and prostate, and heterogeneity in the degree of response among different tumor lesions in the same patient, making immunotherapy with many limitations and challenges. Most patients do not respond to immunotherapy or inevitably develop resistance to treatment after a period of treatment, manifesting with primary resistance or acquired resistance who initially respond to treatment. The mechanisms of tumor immune resistance are very complex and involve multiple aspects such as genes, metabolism, inflammation, and abnormal neovascularization. Currently, many mechanisms of immunotherapy resistance have been characterized, and more continue to be uncovered. These efforts can improve the quality of medical care for cancer diagnosis and treatment, which improve the quality of life of patients, and finally lead to accurate individualized treatment. This review discusses mechanisms of cancer immunotherapy resistance including tumor-intrinsic factors and tumor-extrinsic factors.
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Affiliation(s)
| | | | | | | | | | | | | | - Jiuwei Cui
- Cancer Center, The First Hospital of Jilin University, Changchun, China
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17
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Hu A, Ding M, Zhu J, Liu JQ, Pan X, Ghoshal K, Bai XF. Intra-Tumoral Delivery of IL-27 Using Adeno-Associated Virus Stimulates Anti-tumor Immunity and Enhances the Efficacy of Immunotherapy. Front Cell Dev Biol 2020; 8:210. [PMID: 32292786 PMCID: PMC7118910 DOI: 10.3389/fcell.2020.00210] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 03/11/2020] [Indexed: 12/22/2022] Open
Abstract
IL-27 is an anti-inflammatory cytokine that has been shown to have potent anti-tumor activity. We recently reported that systemic delivery of IL-27 using recombinant adeno-associated virus (rAAV) induced depletion of Tregs and significantly enhanced the efficacy of cancer immunotherapy in a variety of mouse tumor models. A potential caveat of systemic delivery of IL-27 using rAAV is that there is no practical method to terminate IL-27 production when its biological activity is no longer needed. Therefore, in this work, we tested if directly injecting AAV-IL-27 into tumors could lead to similar anti-tumor effect yet avoiding uncontrolled IL-27 production. We found that high levels of IL-27 was produced in tumors and released to peripheral blood after AAV-IL-27 intra-tumoral injection. AAV-IL-27 local therapy showed potent anti-tumor activity in mice bearing plasmacytoma J558 tumors and modest anti-tumor activity in mice bearing B16.F10 tumors. Intra-tumoral injection of AAV-IL-27 induced infiltration of immune effectors including CD8+ T cells and NK cells into tumors, caused systemic reduction of Tregs and stimulated protective immunity. Mechanistically, we found that IL-27 induced T cell expression of CXCR3 in an IL-27R-dependent manner. Additionally, we found that AAV-IL-27 local therapy had significant synergy with anti-PD-1 or T cell adoptive transfer therapy. Importantly, in mice whose tumors were completely rejected, IL-27 serum levels were significantly reduced or diminished. Thus, intra-tumoral injection of AAV-IL-27 is a feasible approach that can be used alone and in combination with anti-PD-1 antibody or T cell adoptive transfer for the treatment of cancer.
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Affiliation(s)
- Aiyan Hu
- Institute of Pediatric Translational Medicine, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
- The Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Miao Ding
- Institute of Pediatric Translational Medicine, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jianmin Zhu
- Institute of Pediatric Translational Medicine, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
- The Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Jin-Qing Liu
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
- The Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Xueliang Pan
- Center for Biostatistics, The Ohio State University, Columbus, OH, United States
| | - Kalpana Ghoshal
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
- The Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Xue-Feng Bai
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
- The Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United States
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18
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Khrustalev VV, Khrustaleva TA, Poboinev VV, Yurchenko KV. Mutational pressure and natural selection in epidermal growth factor receptor gene during germline and somatic mutagenesis in cancer cells. Mutat Res 2019; 815:1-9. [PMID: 30974384 DOI: 10.1016/j.mrfmmm.2019.03.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Revised: 01/15/2019] [Accepted: 03/26/2019] [Indexed: 06/09/2023]
Abstract
In this study we investigated nucleotide usage biases along the length of a gene encoding human epidermal growth factor receptor (EGFR) and found out that there had been mutational GC-pressure with stronger asymmetric C-pressure in that gene before the preferable direction of nucleotide mutations changed. Current preferable direction of germline mutations in EGFR gene has been estimated with the help of Ensembl data base of gene variations. Preferable direction of somatic mutations in EGFR gene from cancer cells has been estimated with the help of COSMIC data base. Both germline and somatic mutations in cancer cells have the same GC to AT preferable direction in EGFR gene. These data have been used with the aim to find fragments of EGFR gene that have lower probability of missense C to T and G to A transitions to occur. So, the less mutable parts of extracellular EGFR domain are: C-terminal part of the first beta barrel and the central part of the second beta barrel. The less mutable parts of tyrosine kinase EGFR domain are: ATP-binding site (partially), regulatory alpha helix, and fragments that change their secondary structure during the activation process. These parts of EGFR should be considered as the best targets for new types of therapy development. Such criterion as low mutability is especially important for the selection of targets for anti-tumor therapy, since we have detected positive selection of amino acid replacements during somatic mutagenesis of EGFR gene in cancer cells.
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Affiliation(s)
| | - Tatyana Aleksandrovna Khrustaleva
- Biochemical Group of the Multidisciplinary Diagnostic Laboratory, Institute of Physiology of the National Academy of Sciences of Belarus, Academicheskaya, 28, Minsk, Belarus
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19
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Van Acker HH, Versteven M, Lichtenegger FS, Roex G, Campillo-Davo D, Lion E, Subklewe M, Van Tendeloo VF, Berneman ZN, Anguille S. Dendritic Cell-Based Immunotherapy of Acute Myeloid Leukemia. J Clin Med 2019; 8:E579. [PMID: 31035598 PMCID: PMC6572115 DOI: 10.3390/jcm8050579] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 04/16/2019] [Accepted: 04/24/2019] [Indexed: 12/20/2022] Open
Abstract
Acute myeloid leukemia (AML) is a type of blood cancer characterized by the uncontrolled clonal proliferation of myeloid hematopoietic progenitor cells in the bone marrow. The outcome of AML is poor, with five-year overall survival rates of less than 10% for the predominant group of patients older than 65 years. One of the main reasons for this poor outcome is that the majority of AML patients will relapse, even after they have attained complete remission by chemotherapy. Chemotherapy, supplemented with allogeneic hematopoietic stem cell transplantation in patients at high risk of relapse, is still the cornerstone of current AML treatment. Both therapies are, however, associated with significant morbidity and mortality. These observations illustrate the need for more effective and less toxic treatment options, especially in elderly AML and have fostered the development of novel immune-based strategies to treat AML. One of these strategies involves the use of a special type of immune cells, the dendritic cells (DCs). As central orchestrators of the immune system, DCs are key to the induction of anti-leukemia immunity. In this review, we provide an update of the clinical experience that has been obtained so far with this form of immunotherapy in patients with AML.
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Affiliation(s)
- Heleen H Van Acker
- Laboratory of Experimental Hematology, Vaccine & Infectious Disease Institute, Faculty of Medicine & Health Sciences, University of Antwerp, 2610 Wilrijk, Antwerp, Belgium.
| | - Maarten Versteven
- Laboratory of Experimental Hematology, Vaccine & Infectious Disease Institute, Faculty of Medicine & Health Sciences, University of Antwerp, 2610 Wilrijk, Antwerp, Belgium.
| | - Felix S Lichtenegger
- Department of Medicine III, LMU Munich, University Hospital, 80799 Munich, Germany.
| | - Gils Roex
- Laboratory of Experimental Hematology, Vaccine & Infectious Disease Institute, Faculty of Medicine & Health Sciences, University of Antwerp, 2610 Wilrijk, Antwerp, Belgium.
| | - Diana Campillo-Davo
- Laboratory of Experimental Hematology, Vaccine & Infectious Disease Institute, Faculty of Medicine & Health Sciences, University of Antwerp, 2610 Wilrijk, Antwerp, Belgium.
| | - Eva Lion
- Laboratory of Experimental Hematology, Vaccine & Infectious Disease Institute, Faculty of Medicine & Health Sciences, University of Antwerp, 2610 Wilrijk, Antwerp, Belgium.
| | - Marion Subklewe
- Department of Medicine III, LMU Munich, University Hospital, 80799 Munich, Germany.
| | - Viggo F Van Tendeloo
- Laboratory of Experimental Hematology, Vaccine & Infectious Disease Institute, Faculty of Medicine & Health Sciences, University of Antwerp, 2610 Wilrijk, Antwerp, Belgium.
| | - Zwi N Berneman
- Laboratory of Experimental Hematology, Vaccine & Infectious Disease Institute, Faculty of Medicine & Health Sciences, University of Antwerp, 2610 Wilrijk, Antwerp, Belgium.
- Division of Hematology and Center for Cell Therapy & Regenerative Medicine, Antwerp University Hospital, 2650 Edegem, Antwerp, Belgium.
| | - Sébastien Anguille
- Laboratory of Experimental Hematology, Vaccine & Infectious Disease Institute, Faculty of Medicine & Health Sciences, University of Antwerp, 2610 Wilrijk, Antwerp, Belgium.
- Division of Hematology and Center for Cell Therapy & Regenerative Medicine, Antwerp University Hospital, 2650 Edegem, Antwerp, Belgium.
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20
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Melzer MK, Zeitlinger L, Mall S, Steiger K, Schmid RM, Ebert O, Krackhardt A, Altomonte J. Enhanced Safety and Efficacy of Oncolytic VSV Therapy by Combination with T Cell Receptor Transgenic T Cells as Carriers. MOLECULAR THERAPY-ONCOLYTICS 2018; 12:26-40. [PMID: 30662938 PMCID: PMC6325079 DOI: 10.1016/j.omto.2018.12.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 12/05/2018] [Indexed: 01/21/2023]
Abstract
Vesicular stomatitis virus (VSV) represents an attractive oncolytic virotherapy platform because of its potent tumor cell-killing and immune-stimulating properties; yet the clinical translation of VSV faces numerous challenges, such as inefficient systemic delivery and severe side effects such as neurotoxicity. We hypothesized that we could overcome these limitations and simultaneously enhance the therapy, by combining VSV with adoptively transferred T cell receptor (TCR) transgenic T cells as carrier cells. We show that CD8+ T central memory cells (CD8+ T cm) can be efficiently loaded with VSV, they support intracellular virus production, and they can efficiently transfer VSV to tumor cells without compromising their own viability or antitumor reactivity. Loading VSV onto CD8+ T cm not only improves the safety compared with systemic administration of naked virus, but this approach also allows for an effective delivery of virus to its tumor target, resulting in an effective combination therapy in NSG mice bearing subcutaneous human acute myeloid leukemia (AML) tumors. We conclude that the combination of potent tumor debulking provided by the oncolytic VSV with the added effector functions afforded by the cytotoxic immune carrier cells results in a potent and safer immunotherapeutic, which can be further developed for clinical translation.
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Affiliation(s)
- Michael Karl Melzer
- Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University, 81675 Munich, Germany
| | - Lisa Zeitlinger
- Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University, 81675 Munich, Germany
| | - Sabine Mall
- Klinik und Poliklinik für Innere Medizin III, Klinikum rechts der Isar, Technical University, 81675 Munich, Germany.,German Cancer Consortium of Translational Cancer Research (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Katja Steiger
- Institut für Pathologie, Klinikum rechts der Isar, Technical University, 81675 Munich, Germany
| | - Roland M Schmid
- Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University, 81675 Munich, Germany
| | - Oliver Ebert
- Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University, 81675 Munich, Germany
| | - Angela Krackhardt
- Klinik und Poliklinik für Innere Medizin III, Klinikum rechts der Isar, Technical University, 81675 Munich, Germany.,German Cancer Consortium of Translational Cancer Research (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Jennifer Altomonte
- Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University, 81675 Munich, Germany
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21
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Sun L, Moore E, Berman R, Clavijo PE, Saleh A, Chen Z, Van Waes C, Davies J, Friedman J, Allen CT. WEE1 kinase inhibition reverses G2/M cell cycle checkpoint activation to sensitize cancer cells to immunotherapy. Oncoimmunology 2018; 7:e1488359. [PMID: 30288354 DOI: 10.1080/2162402x.2018.1488359] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Indexed: 01/29/2023] Open
Abstract
Intrinsic resistance to cytotoxic T-lymphocyte (CTL) killing limits responses to immune activating anti-cancer therapies. Here, we established that activation of the G2/M cell cycle checkpoint results in tumor cell cycle pause and protection from granzyme B-induced cell death. This was reversed with WEE1 kinase inhibition, leading to enhanced CTL killing of antigen-positive tumor cells. Similarly, but at a later time point, cell cycle pause following TNFα exposure was reversed with WEE1 kinase inhibition, leading to CTL transmembrane TNFα-dependent induction of apoptosis and necroptosis in bystander antigen-negative tumor cells. Results were reproducible in models of oral cavity carcinoma, melanoma and colon adenocarcinoma harboring variable Tp53 genomic alterations. WEE1 kinase inhibition sensitized tumors to PD-1 mAb immune checkpoint blockade in vivo, resulting in CD8+-dependent rejection of established tumors harboring antigen-positive or mixed antigen-positive and negative tumor cells. Together, these data describe activation of the G2/M cell cycle checkpoint in response to early and late CTL products as a mechanism of resistance to CTL killing, and provide pre-clinical rationale for the clinical combination of agents that inhibit cell cycle checkpoints and activate anti-tumor immunity.
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Affiliation(s)
- Lillian Sun
- Translational Tumor Immunology Program, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, USA
| | - Ellen Moore
- Translational Tumor Immunology Program, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, USA
| | - Rose Berman
- Translational Tumor Immunology Program, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, USA
| | - Paul E Clavijo
- Translational Tumor Immunology Program, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, USA
| | - Anthony Saleh
- Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, USA
| | - Zhong Chen
- Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, USA
| | - Carter Van Waes
- Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, USA
| | - John Davies
- Experimental Transplantation and Immunology Branch, National Cancer Institute, NIH, Bethesda, USA
| | - Jay Friedman
- Translational Tumor Immunology Program, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, USA
| | - Clint T Allen
- Translational Tumor Immunology Program, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, USA
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22
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Zhu J, Liu JQ, Liu Z, Wu L, Shi M, Zhang J, Davis JP, Bai XF. Interleukin-27 Gene Therapy Prevents the Development of Autoimmune Encephalomyelitis but Fails to Attenuate Established Inflammation due to the Expansion of CD11b +Gr-1 + Myeloid Cells. Front Immunol 2018; 9:873. [PMID: 29740452 PMCID: PMC5928207 DOI: 10.3389/fimmu.2018.00873] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Accepted: 04/09/2018] [Indexed: 11/13/2022] Open
Abstract
Interleukin-27 (IL-27) and its subunit P28 (also known as IL-30) have been shown to inhibit autoimmunity and have been suggested as potential immunotherapeutic for autoimmune diseases such as multiple sclerosis (MS). However, the potential of IL-27 and IL-30 as immunotherapeutic, and their mechanisms of action have not been fully understood. In this study, we evaluated the efficacy of adeno-associated viral vector (AAV)-delivered IL-27 (AAV-IL-27) and IL-30 (AAV-IL-30) in a murine model of MS. We found that one single administration of AAV-IL-27, but not AAV-IL-30 completely blocked the development of experimental autoimmune encephalomyelitis (EAE). AAV-IL-27 administration reduced the frequencies of Th17, Treg, and GM-CSF-producing CD4+ T cells and induced T cell expression of IFN-γ, IL-10, and PD-L1. However, experiments involving IL-10-deficient mice and PD-1 blockade revealed that AAV-IL-27-induced IL-10 and PD-L1 expression were not required for the prevention of EAE development. Surprisingly, neither AAV-IL-27 nor AAV-IL-30 treatment inhibited EAE development and Th17 responses when given at disease onset. We found that mice with established EAE had significant expansion of CD11b+Gr-1+ cells, and AAV-IL-27 treatment further expanded these cells and induced their expression of Th17-promoting cytokines such as IL-6. Adoptive transfer of AAV-IL-27-expanded CD11b+Gr-1+ cells enhanced EAE development. Thus, expansion of CD11b+Gr-1+ cells provides an explanation for the resistance to IL-27 therapy in mice with established disease.
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MESH Headings
- Animals
- CD11b Antigen/immunology
- CD11b Antigen/metabolism
- Dependovirus/genetics
- Encephalomyelitis, Autoimmune, Experimental/immunology
- Encephalomyelitis, Autoimmune, Experimental/therapy
- Genetic Therapy/methods
- Genetic Vectors/administration & dosage
- Genetic Vectors/genetics
- Humans
- Interleukin-10/genetics
- Interleukin-10/immunology
- Interleukin-27/administration & dosage
- Interleukin-27/genetics
- Interleukin-27/immunology
- Mice
- Mice, Inbred C57BL
- Multiple Sclerosis/immunology
- Multiple Sclerosis/therapy
- Myeloid Cells/immunology
- Receptors, Chemokine/immunology
- Receptors, Chemokine/metabolism
- Receptors, Cytokine/genetics
- Receptors, Cytokine/immunology
- Receptors, Interleukin
- Treatment Outcome
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Affiliation(s)
- Jianmin Zhu
- Pediatric Translational Medicine Institute, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jin-Qing Liu
- Department of Pathology and Comprehensive Cancer Center, Ohio State University, Columbus, OH, United States
| | - Zhihao Liu
- Department of Pathology and Comprehensive Cancer Center, Ohio State University, Columbus, OH, United States
| | - Lisha Wu
- Department of Pathology and Comprehensive Cancer Center, Ohio State University, Columbus, OH, United States
| | - Min Shi
- Pediatric Translational Medicine Institute, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jianchao Zhang
- Department of Physiology, Ohio State University, Columbus, OH, United States
| | - Jonathan P. Davis
- Department of Physiology, Ohio State University, Columbus, OH, United States
| | - Xue-Feng Bai
- Pediatric Translational Medicine Institute, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Department of Pathology and Comprehensive Cancer Center, Ohio State University, Columbus, OH, United States
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23
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Khong H, Volmari A, Sharma M, Dai Z, Imo CS, Hailemichael Y, Singh M, Moore DT, Xiao Z, Huang XF, Horvath TD, Hawke DH, Overwijk WW. Peptide Vaccine Formulation Controls the Duration of Antigen Presentation and Magnitude of Tumor-Specific CD8 + T Cell Response. THE JOURNAL OF IMMUNOLOGY 2018; 200:3464-3474. [PMID: 29643190 DOI: 10.4049/jimmunol.1700467] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 03/20/2018] [Indexed: 12/22/2022]
Abstract
Despite remarkable progresses in vaccinology, therapeutic cancer vaccines have not achieved their full potential. We previously showed that an excessively long duration of Ag presentation critically reduced the quantity and quality of vaccination-induced T cell responses and subsequent antitumor efficacy. In this study, using a murine model and tumor cell lines, we studied l-tyrosine amino acid-based microparticles as a peptide vaccine adjuvant with a short-term Ag depot function for the induction of tumor-specific T cells. l-Tyrosine microparticles did not induce dendritic cell maturation, and their adjuvant activity was not mediated by inflammasome activation. Instead, prolonged Ag presentation in vivo translated into increased numbers and antitumor activity of vaccination-induced CD8+ T cells. Indeed, prolonging Ag presentation by repeated injection of peptide in saline resulted in an increase in T cell numbers similar to that observed after vaccination with peptide/l-tyrosine microparticles. Our results show that the duration of Ag presentation is critical for optimal induction of antitumor T cells, and can be manipulated through vaccine formulation.
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Affiliation(s)
- Hiep Khong
- Immunology Program, University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030.,Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030; and
| | - Annika Volmari
- Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030; and
| | - Meenu Sharma
- Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030; and
| | - Zhimin Dai
- Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030; and
| | - Chinonye S Imo
- Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030; and
| | - Yared Hailemichael
- Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030; and
| | - Manisha Singh
- Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030; and
| | - Derek T Moore
- Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030; and
| | - Zhilan Xiao
- Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030; and
| | - Xue-Fei Huang
- Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030; and
| | - Thomas D Horvath
- Department of Bioinformatics and Computational Biology, Proteomics and Metabolomics Core Facility, University of Texas MD Anderson Cancer Center, Houston, TX 77030
| | - David H Hawke
- Department of Bioinformatics and Computational Biology, Proteomics and Metabolomics Core Facility, University of Texas MD Anderson Cancer Center, Houston, TX 77030
| | - Willem W Overwijk
- Immunology Program, University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030; .,Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030; and
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24
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Liu Z, Wu L, Zhu J, Zhu X, Zhu J, Liu JQ, Zhang J, Davis JP, Varikuti S, Satoskar AR, Zhou J, Li MS, Bai XF. Interleukin-27 signalling induces stem cell antigen-1 expression in T lymphocytes in vivo. Immunology 2017; 152:638-647. [PMID: 28758191 DOI: 10.1111/imm.12805] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 07/21/2017] [Accepted: 07/24/2017] [Indexed: 12/19/2022] Open
Abstract
Stem cell antigen-1 (Sca-1/Ly6A/E) is a cell surface glycoprotein that is often used as a biomarker for stem cells and cell stemness. However, it is not clear what factors can directly induce the expression of Sca-1/Ly6A/E in T lymphocytes in vivo, and if induction of Sca-1 is associated with T cell stemness. In this study, we show that interleukin-27 (IL-27), a member of the IL-12 family of cytokines, directly induces Sca-1 expression in T cells in vivo. We found that mice-deficient for IL-27 (either P28 or EBI3) or its signalling (IL-27Rα) had profound reduction of Sca-1 expression in naive (CD62L+ CD44- ), memory (CD62L+ CD44+ ) and effector (CD62L- CD44+ ) T cells. In contrast, in vivo delivery of IL-27 using adeno-associated viral vectors strongly induced the expression of Sca-1 in naive and memory/effector T-cell populations in an IL-27 receptor- or signal transducer and activator of transcription 1-dependent manner. Interestingly, IL-27-induced Sca-1+ T cells do not express or up-regulate classic stem cell-associated genes such as Nanog, Oct4, Sox2 and Ctnnb1. However, IL-27-induced Sca-1+ T cells had increased expression of effector/memory-associated transcription factor T-bet, Eomes and Blimp1. Hence, IL-27 signalling directly induces the expression of Sca-1/Ly6A/E expression in T cells. Direct expansion of Sca-1+ CD62L+ CD44- T memory stem cells may explain why IL-27 enhances T-cell memory.
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Affiliation(s)
- Zhihao Liu
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology and Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA
| | - Lisha Wu
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology and Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA
| | - Jing Zhu
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology and Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA
| | - Xiaotong Zhu
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology and Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA
| | - Jianmin Zhu
- Paediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jin-Qing Liu
- Department of Pathology and Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA
| | - Jianchao Zhang
- Department of Physiology, Ohio State University, Columbus, OH, USA
| | - Jonathan P Davis
- Department of Physiology, Ohio State University, Columbus, OH, USA
| | - Sanjay Varikuti
- Department of Pathology and Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA
| | - Abhay R Satoskar
- Department of Pathology and Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA
| | - Jie Zhou
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ming-Song Li
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xue-Feng Bai
- Department of Pathology and Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA.,Paediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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25
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Wang M, Zhang C, Song Y, Wang Z, Wang Y, Luo F, Xu Y, Zhao Y, Wu Z, Xu Y. Mechanism of immune evasion in breast cancer. Onco Targets Ther 2017; 10:1561-1573. [PMID: 28352189 PMCID: PMC5359138 DOI: 10.2147/ott.s126424] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Breast cancer (BC) is the most common malignant tumor among women, with high morbidity and mortality. Its onset, development, metastasis, and prognosis vary among individuals due to the interactions between tumors and host immunity. Many diverse mechanisms have been associated with BC, with immune evasion being the most widely studied to date. Tumor cells can escape from the body’s immune response, which targets abnormal components and foreign bodies, using different approaches including modification of surface antigens and modulation of the surrounding environment. In this review, we summarize the mechanisms and factors that impact the immunoediting process and analyze their functions in detail.
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Affiliation(s)
| | - Changwang Zhang
- Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, People's Republic of China
| | - Yongxi Song
- Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, People's Republic of China
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, People's Republic of China
| | | | | | | | - Yi Zhao
- Department of Breast Surgery
| | - Zhonghua Wu
- Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, People's Republic of China
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26
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Melzer MK, Lopez-Martinez A, Altomonte J. Oncolytic Vesicular Stomatitis Virus as a Viro-Immunotherapy: Defeating Cancer with a "Hammer" and "Anvil". Biomedicines 2017; 5:E8. [PMID: 28536351 PMCID: PMC5423493 DOI: 10.3390/biomedicines5010008] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Revised: 01/26/2017] [Accepted: 02/03/2017] [Indexed: 12/17/2022] Open
Abstract
Oncolytic viruses have gained much attention in recent years, due, not only to their ability to selectively replicate in and lyse tumor cells, but to their potential to stimulate antitumor immune responses directed against the tumor. Vesicular stomatitis virus (VSV), a negative-strand RNA virus, is under intense development as an oncolytic virus due to a variety of favorable properties, including its rapid replication kinetics, inherent tumor specificity, and its potential to elicit a broad range of immunomodulatory responses to break immune tolerance in the tumor microenvironment. Based on this powerful platform, a multitude of strategies have been applied to further improve the immune-stimulating potential of VSV and synergize these responses with the direct oncolytic effect. These strategies include: 1. modification of endogenous virus genes to stimulate interferon induction; 2. virus-mediated expression of cytokines or immune-stimulatory molecules to enhance anti-tumor immune responses; 3. vaccination approaches to stimulate adaptive immune responses against a tumor antigen; 4. combination with adoptive immune cell therapy for potentially synergistic therapeutic responses. A summary of these approaches will be presented in this review.
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Affiliation(s)
- Michael Karl Melzer
- Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany.
| | - Arturo Lopez-Martinez
- Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany.
| | - Jennifer Altomonte
- Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany.
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27
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Frankel T, Lanfranca MP, Zou W. The Role of Tumor Microenvironment in Cancer Immunotherapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1036:51-64. [PMID: 29275464 DOI: 10.1007/978-3-319-67577-0_4] [Citation(s) in RCA: 119] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The field of tumor immunology and immunotherapy has undergone a renaissance in the past decade do in large part to a better understanding of the tumor immune microenvironment. After suffering countless successes and setbacks in the twentieth century, immunotherapy has now come to the forefront of cancer research and is recognized as an important tool in the anti-tumor armamentarium. The goal of therapy is to aid the immune system in recognition and destruction of tumor cells by enhancing its ability to react to tumor antigens. This traditionally has been accomplished by induction of adaptive immunity through vaccination or through passive delivery of immunologic effectors as in the case of adoptive cell transfer. The recent discovery of immune "checkpoints" whose purpose is to suppress immune activity and prevent auto-immunity has created a new angle by which reactivity to tumors can be enhanced. Blockers of these checkpoints have yielded impressive clinical results and have recently been approved for use in a wide variety of malignancies. With data showing increasing rates of not only treatment response, but complete remissions, immunotherapy is poised to become an increasingly utilized therapy in the treatment of cancer.
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Affiliation(s)
- Timothy Frankel
- Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA
- Graduate Programs in Immunology and Tumor Biology, University of Michigan, Ann Arbor, MI, USA
| | - Mirna Perusina Lanfranca
- Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA
- Graduate Programs in Immunology and Tumor Biology, University of Michigan, Ann Arbor, MI, USA
| | - Weiping Zou
- Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA.
- Graduate Programs in Immunology and Tumor Biology, University of Michigan, Ann Arbor, MI, USA.
- The University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
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28
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Khong H, Overwijk WW. Adjuvants for peptide-based cancer vaccines. J Immunother Cancer 2016; 4:56. [PMID: 27660710 PMCID: PMC5028954 DOI: 10.1186/s40425-016-0160-y] [Citation(s) in RCA: 129] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 08/12/2016] [Indexed: 12/12/2022] Open
Abstract
Cancer therapies based on T cells have shown impressive clinical benefit. In particular, immune checkpoint blockade therapies with anti-CTLA-4 and anti-PD-1/PD-L1 are causing dramatic tumor shrinkage and prolonged patient survival in a variety of cancers. However, many patients do not benefit, possibly due to insufficient spontaneous T cell reactivity against their tumors and/or lacking immune cell infiltration to tumor site. Such tumor-specific T cell responses could be induced through anti-cancer vaccination; but despite great success in animal models, only a few of many cancer vaccine trials have demonstrated robust clinical benefit. One reason for this difference may be the use of potent, effective vaccine adjuvants in animal models, vs. the use of safe, but very weak, vaccine adjuvants in clinical trials. As vaccine adjuvants dictate the type and magnitude of the T cell response after vaccination, it is critical to understand how they work to design safe, but also effective, cancer vaccines for clinical use. Here we discuss current insights into the mechanism of action and practical application of vaccine adjuvants, with a focus on peptide-based cancer vaccines.
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Affiliation(s)
- Hiep Khong
- Department of Melanoma Medical Oncology, University of Texas - MD Anderson Cancer Center, South Campus Research Building 1, 1515 Holcombe Blvd, Houston, TX 77030 USA ; Immunology program - University of Texas - Graduate School of Biomedical Sciences at Houston, 6767 Bertner Ave, Houston, TX 77030 USA
| | - Willem W Overwijk
- Department of Melanoma Medical Oncology, University of Texas - MD Anderson Cancer Center, South Campus Research Building 1, 1515 Holcombe Blvd, Houston, TX 77030 USA ; Immunology program - University of Texas - Graduate School of Biomedical Sciences at Houston, 6767 Bertner Ave, Houston, TX 77030 USA
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29
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Liu JQ, Talebian F, Wu L, Liu Z, Li MS, Wu L, Zhu J, Markowitz J, Carson WE, Basu S, Bai XF. A Critical Role for CD200R Signaling in Limiting the Growth and Metastasis of CD200+ Melanoma. THE JOURNAL OF IMMUNOLOGY 2016; 197:1489-97. [PMID: 27385779 DOI: 10.4049/jimmunol.1600052] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 06/12/2016] [Indexed: 12/29/2022]
Abstract
CD200 is a cell surface glycoprotein that functions through engaging CD200R on cells of the myeloid lineage and inhibits their functions. Expression of CD200 was implicated in a variety of human cancer cells, including melanoma cells; however, its roles in tumor growth and immunity are not clearly understood. In this study, we used CD200R-deficient mice and the B16 tumor model to evaluate this issue. We found that CD200R-deficient mice exhibited accelerated growth of CD200(+), but not CD200(-), B16 tumors. Strikingly, CD200R-deficient mice receiving CD200(+) B16 cells i.v. exhibited massive tumor growth in multiple organs, including liver, lung, kidney, and peritoneal cavity, whereas the growth of the same tumors in wild-type mice was limited. CD200(+) tumors grown in CD200R-deficient mice contained higher numbers of CD11b(+)Ly6C(+) myeloid cells, exhibited increased expression of VEGF and HIF1α genes with increased angiogenesis, and showed significantly reduced infiltration of CD4(+) and CD8(+) T cells, presumably as the result of reduced expression of T cell chemokines, such as CXCL9 and CXCL16. The liver from CD200R-deficient mice, under metastatic growth of CD200(+) tumors, contained significantly increased numbers of CD11b(+)Gr1(-) myeloid cells and Foxp3(+) regulatory T cells and reduced numbers of NK cells. Liver T cells also had a reduced capacity to produce IFN-γ or TNF-α. Taken together, we revealed a critical role for CD200R signaling in limiting the growth and metastasis of CD200(+) tumors. Thus, targeting CD200R signaling may potentially interfere with the metastatic growth of CD200(+) tumors, like melanoma.
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Affiliation(s)
- Jin-Qing Liu
- Department of Pathology and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210
| | - Fatemeh Talebian
- Department of Pathology and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210
| | - Lisha Wu
- Department of Pathology and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210; Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Zhihao Liu
- Department of Pathology and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210; Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Ming-Song Li
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Laichu Wu
- Davis Medical Research Center, Columbus, OH 43210; and
| | - Jianmin Zhu
- Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
| | - Joseph Markowitz
- Department of Pathology and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210
| | - William E Carson
- Department of Pathology and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210
| | - Sujit Basu
- Department of Pathology and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210
| | - Xue-Feng Bai
- Department of Pathology and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210; Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
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30
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Lee SY, Sin JI. MC32 tumor cells acquire Ag-specific CTL resistance through the loss of CEA in a colon cancer model. Hum Vaccin Immunother 2016; 11:2012-20. [PMID: 25902414 DOI: 10.1080/21645515.2015.1016669] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
We previously reported that MC32 cells resist carcinoembryonic antigen (CEA) DNA vaccination by losing their antigen presentation to Ag-specific CTLs in the context of MHC class I antigens in a colon cancer therapeutic model. In this study, we selected 2 tumor cells, MC32-S2-2 and MC32-S4-2, which have the ability to form tumors in CEA DNA vaccine-immunized mice. Wild type MC32 cells grew significantly less in CEA-immunized mice (with Ag-specific CTL lytic activity) than in control mice (with no Ag-specific CTL lytic activity). However, MC32-S2-2 and MC32-S4-2 cells grew at a similar rate in both control and CEA-immunized mice, confirming their resistant status against CEA DNA vaccination. MC32-S2-2 and MC32-S4-2 cells were not susceptible to lysis by CEA-specific CD8+ T cells. Moreover, when MC32-S2-2 and MC32-S4-2 cells were used as stimulating agents of CEA-specific immune cells for IFN-γ production, these cells failed to stimulate the induction of Ag-specific IFN-γ, suggesting a loss of tumor cell recognition by Ag-specific immune cells. However, MC32-S2-2 and MC32-S4-2 cells expressed MHC class I antigens in a manner similar to that of wild type MC32 cells. Finally, Western blot assay confirmed that in MC32-S2-2 and MC32-S4-2 cells, CEA expression remained absent but mouse CEA was expressed. Taken together, these data show that MC32 cells may also be able to achieve resistance to CEA-specific CTLs by antigen loss in this model.
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Key Words
- Antitumor immunity
- CEA
- CEA, carcinoembryonic antigen
- CFSE, carboxyfluorescein diacetate succinimidyl ester
- DNA vaccines
- EP, electroporation
- GAPDH, glyceraldehyde-3-phosphate dehydrogenase
- HLA, human leukocyte antigen
- IM, intramuscular
- LDH, lactate dehydrogenase
- PBS, phosphate-buffered saline
- PCR, polymerase chain reaction
- UV, ultraviolet
- colon cancer
- i.v., intravenously
- immune evasion
- s.c., subcutaneously
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Affiliation(s)
- Sang-Yeul Lee
- a Department of Plastic and Reconstructive Surgery ; School of Medicine; Kangwon National University ; Chuncheon , Gangwon-do , Korea
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31
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Lee SH, Danishmalik SN, Sin JI. DNA vaccines, electroporation and their applications in cancer treatment. Hum Vaccin Immunother 2016; 11:1889-900. [PMID: 25984993 DOI: 10.1080/21645515.2015.1035502] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Numerous animal studies and recent clinical studies have shown that electroporation-delivered DNA vaccines can elicit robust Ag-specific CTL responses and reduce disease severity. However, cancer antigens are generally poorly immunogenic, requiring special conditions for immune response induction. To date, many different approaches have been used to elicit Ag-specific CTL and anti-neoplastic responses to DNA vaccines against cancer. In vivo electroporation is one example, whereas others include DNA manipulation, xenogeneic antigen use, immune stimulatory molecule and immune response regulator application, DNA prime-boost immunization strategy use and different DNA delivery methods. These strategies likely increase the immunogenicity of cancer DNA vaccines, thereby contributing to cancer eradication. However, cancer cells are heterogeneous and might become CTL-resistant. Thus, understanding the CTL resistance mechanism(s) employed by cancer cells is critical to develop counter-measures for this immune escape. In this review, the use of electroporation as a DNA delivery method, the strategies used to enhance the immune responses, the cancer antigens that have been tested, and the escape mechanism(s) used by tumor cells are discussed, with a focus on the progress of clinical trials using cancer DNA vaccines.
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Key Words
- AFP, α-fetoprotein
- APCs, antigen presenting cells
- CEA, carcinoembryonic antigen
- CTLA-4, cytotoxic T lymphocyte-associated antigen-4
- DCs, dendritic cells
- DNA vaccine
- EP, electroporation
- GITR, glucocorticoid-induced tumor necrosis factor receptor family-related gene
- HPV, human papillomavirus
- HSP, heat shock protein
- HSV, herpes simplex virus
- ID, intradermal
- IM, intramuscular
- MAGE, melanoma-associated antigen
- MART, melanoma antigen recognized by T cells
- PAP, prostatic acid phosphatase
- PD, programmed death
- PRAME, preferentially expressed antigen in melanoma
- PSA, prostate-specific antigen
- PSMA, prostate-specific membrane antigen
- WT1, Wilm's tumor
- anti-tumor immunity
- cancer
- hTERT, human telomerase reverse transcriptase
- tumor immune evasion
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Affiliation(s)
- Si-Hyeong Lee
- a BK21 Plus Graduate Program; Department of Microbiology ; School of Medicine; Kangwon National University ; Chuncheon , Gangwon-do , Korea
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Herrmann VL, Wieland DE, Legler DF, Wittmann V, Groettrup M. The STEAP1(262-270) peptide encapsulated into PLGA microspheres elicits strong cytotoxic T cell immunity in HLA-A*0201 transgenic mice--A new approach to immunotherapy against prostate carcinoma. Prostate 2016; 76:456-68. [PMID: 26715028 DOI: 10.1002/pros.23136] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Accepted: 12/01/2015] [Indexed: 01/24/2023]
Abstract
BACKGROUND PLGA microsphere-based vaccination has been proven to be effective in immunotherapy of syngeneic model tumors in mice. The critical step for the translation to humans is the identification of immunogenic tumor antigens and potent vaccine formulations to overcome immune tolerance. METHODS HLA-A*0201 transgenic mice were immunized with eight different human prostate cancer peptide antigens co-encapsulated with TLR ligands into PLGA microspheres and analyzed for antigen-specific and functional cytotoxic T lymphocyte responses. RESULTS Only vaccination with STEAP1(262-270) peptide encapsulated in PLGA MS could effectively crossprime CTLs in vivo. These CTLs recognized STEAP1(262-270) /HLA-A*0201 complexes on human dendritic cells and prostate cancer cell lines and specifically lysed target cells in vivo. Vaccination with PLGA microspheres was much more potent than with incomplete Freund's adjuvant. CONCLUSIONS Our data suggests that there exist great differences in the immunogenicity of human PCa peptide antigens despite comparable MHC class I binding characteristics. Immunogenic STEAP1(262-270) peptide encapsulated into PLGA microspheres however was able to induce vigorous and functional antigen-specific CTLs and therefore is a promising novel approach for immunotherapy against advanced stage prostate cancer.
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Affiliation(s)
- Valerie L Herrmann
- Division of Immunology, Department of Biology, University of Konstanz, Konstanz, Germany
| | - Daniel E Wieland
- Department of Chemistry, University of Konstanz, Konstanz, Germany
| | - Daniel F Legler
- Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Kreuzlingen, Switzerland
| | | | - Marcus Groettrup
- Division of Immunology, Department of Biology, University of Konstanz, Konstanz, Germany
- Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Kreuzlingen, Switzerland
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33
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Liu Y. Neoantigen: A Long March toward Cancer Immunotherapy. Clin Cancer Res 2016; 22:2602-4. [PMID: 27006495 DOI: 10.1158/1078-0432.ccr-15-3170] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Accepted: 03/06/2016] [Indexed: 01/08/2023]
Abstract
Somatic mutations in cancer give rise to neoantigens. Technology revolutions in cancer genomics and immunology have made it possible to rapidly identify neoantigens for cancer vaccines. Leisegang and colleagues report that it is practical to rapidly identify neoantigens for adoptive T-cell therapy in a mouse tumor model. Clin Cancer Res; 22(11); 2602-4. ©2016 AACRSee related article by Leisegang et al., p. 2734.
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Affiliation(s)
- Yang Liu
- Center for Cancer and Immunology Research, Children's Research Institute, Children's National Health System, and Department of Pediatrics, George Washington University School of Medicine, Washington, DC
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34
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Leisegang M, Engels B, Schreiber K, Yew PY, Kiyotani K, Idel C, Arina A, Duraiswamy J, Weichselbaum RR, Uckert W, Nakamura Y, Schreiber H. Eradication of Large Solid Tumors by Gene Therapy with a T-Cell Receptor Targeting a Single Cancer-Specific Point Mutation. Clin Cancer Res 2015; 22:2734-43. [PMID: 26667491 DOI: 10.1158/1078-0432.ccr-15-2361] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Accepted: 12/07/2015] [Indexed: 11/16/2022]
Abstract
PURPOSE Cancers usually contain multiple unique tumor-specific antigens produced by single amino acid substitutions (AAS) and encoded by somatic nonsynonymous single nucleotide substitutions. We determined whether adoptively transferred T cells can reject large, well-established solid tumors when engineered to express a single type of T-cell receptor (TCR) that is specific for a single AAS. EXPERIMENTAL DESIGN By exome and RNA sequencing of an UV-induced tumor, we identified an AAS in p68 (mp68), a co-activator of p53. This AAS seemed to be an ideal tumor-specific neoepitope because it is encoded by a trunk mutation in the primary autochthonous cancer and binds with highest affinity to the MHC. A high-avidity mp68-specific TCR was used to genetically engineer T cells as well as to generate TCR-transgenic mice for adoptive therapy. RESULTS When the neoepitope was expressed at high levels and by all cancer cells, their direct recognition sufficed to destroy intratumor vessels and eradicate large, long-established solid tumors. When the neoepitope was targeted as autochthonous antigen, T cells caused cancer regression followed by escape of antigen-negative variants. Escape could be thwarted by expressing the antigen at increased levels in all cancer cells or by combining T-cell therapy with local irradiation. Therapeutic efficacies of TCR-transduced and TCR-transgenic T cells were similar. CONCLUSIONS Gene therapy with a single TCR targeting a single AAS can eradicate large established cancer, but a uniform expression and/or sufficient levels of the targeted neoepitope or additional therapy are required to overcome tumor escape. Clin Cancer Res; 22(11); 2734-43. ©2015 AACRSee related commentary by Liu, p. 2602.
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Affiliation(s)
| | - Boris Engels
- Department of Pathology, The University of Chicago, Illinois
| | - Karin Schreiber
- Department of Pathology, The University of Chicago, Illinois
| | - Poh Yin Yew
- Department of Medicine, The University of Chicago, Illinois
| | | | - Christian Idel
- Department of Pathology, The University of Chicago, Illinois
| | - Ainhoa Arina
- Department of Pathology, The University of Chicago, Illinois
| | | | - Ralph R Weichselbaum
- Department of Radiation and Cellular Oncology, The Ludwig Center for Metastasis Research, The University of Chicago, Illinois
| | - Wolfgang Uckert
- Molecular Cell Biology and Gene Therapy, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany. Institute of Biology, Humboldt University Berlin, Berlin, Germany
| | | | - Hans Schreiber
- Institute of Immunology, Charité, Campus Buch, Berlin, Germany. Department of Pathology, The University of Chicago, Illinois
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Tan M, Zhu L, Zhuang H, Hao Y, Gao S, Liu S, Liu Q, Liu D, Liu J, Lin B. Lewis Y antigen modified CD47 is an independent risk factor for poor prognosis and promotes early ovarian cancer metastasis. Am J Cancer Res 2015; 5:2777-2787. [PMID: 26609483 PMCID: PMC4633904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Accepted: 07/08/2015] [Indexed: 06/05/2023] Open
Abstract
CD47 is a membrane receptor that belongs to the immunoglobulin superfamily and plays an important role in the mechanisms of tumor immune escape. CD47 participates in tumor immune escape by combining with SIRPα to reduce the phagocytic activity of macrophages. There are six potential N-glycosylation sites on CD47, and glycosylation is known to be necessary for its membrane localization. However, it is still unknown to what extent glycosylation influences CD47 ligand binding properties and subsequent signaling. By using immunoprecipitation and confocal laser scanning microscopy, we showed that CD47 contains Lewis y antigen. Immunohistochemical analysis demonstrated that both the positive expression and the overexpression of CD47 and Lewis y antigen in cancer tissues and borderline tumors were significantly higher than those in benign ovarian tumors and normal ovarian tissues (P < 0.05). A linear correlation between the expression patterns of CD47 and Lewis y antigen was evident (r = 0.47, P < 0.01). The high expression of CD47 and Lewis y antigen showed significant correlations with the clinical pathological parameters of ovarian cancer [International Federation of Gynecology and Obstetrics (FIGO) standards, lymph node metastasis, and degree of differentiation] (P < 0.05). The Cox model and Kaplan-Meier tests showed that high expression of CD47 was an independent adverse risk factor for the prognosis of ovarian cancer. Cases with both high CD47 and Lewis y antigen expression had poor prognoses. Our study demonstrates that Lewis y antigens of CD47 may play a crucial role in the development of ovarian cancer, and could be new targets for immunotherapy for ovarian cancer.
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Affiliation(s)
- Mingzi Tan
- Department of Gynecology and Obstetrics, Shengjing Hospital Affiliated to China Medical UniversityLiaoning, China
| | - Liancheng Zhu
- Department of Gynecology and Obstetrics, Shengjing Hospital Affiliated to China Medical UniversityLiaoning, China
| | - Huiyu Zhuang
- Department of Gynecology and Obstetrics, Shengjing Hospital Affiliated to China Medical UniversityLiaoning, China
- Department of Gynecology and Obstetrics, Beijing Chaoyang Hospital Affiliated to Capital Medical UniversityBeijing, China
| | - Yingying Hao
- Department of Gynecology and Obstetrics, Shengjing Hospital Affiliated to China Medical UniversityLiaoning, China
| | - Song Gao
- Department of Gynecology and Obstetrics, Shengjing Hospital Affiliated to China Medical UniversityLiaoning, China
| | - Shuice Liu
- Department of Gynecology and Obstetrics, Shengjing Hospital Affiliated to China Medical UniversityLiaoning, China
| | - Qing Liu
- Department of Gynecology and Obstetrics, Shengjing Hospital Affiliated to China Medical UniversityLiaoning, China
| | - Dawo Liu
- Department of Gynecology and Obstetrics, Shengjing Hospital Affiliated to China Medical UniversityLiaoning, China
| | - Juanjuan Liu
- Department of Gynecology and Obstetrics, Shengjing Hospital Affiliated to China Medical UniversityLiaoning, China
| | - Bei Lin
- Department of Gynecology and Obstetrics, Shengjing Hospital Affiliated to China Medical UniversityLiaoning, China
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Wang L, Liu JQ, Talebian F, Liu Z, Yu L, Bai XF. IL-10 enhances CTL-mediated tumor rejection by inhibiting highly suppressive CD4 + T cells and promoting CTL persistence in a murine model of plasmacytoma. Oncoimmunology 2015; 4:e1014232. [PMID: 26140236 DOI: 10.1080/2162402x.2015.1014232] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Revised: 01/23/2015] [Accepted: 01/27/2015] [Indexed: 01/28/2023] Open
Abstract
Interleukin-10 (IL-10) is a potent anti-inflammatory cytokine that regulates immune responses. IL-10 has also been shown to enhance antitumor CD8+ T-cell responses in tumor models although the underlying mechanisms are not fully understood. In this study, we used a series of genetic mouse models and the mouse plasmacytoma J558 model to investigate this issue. J558 tumors grew significantly faster in IL-10-/- mice than in wild type (WT) mice, but similarly in IL-10 -/- Rag2 -/- and Rag2 -/- mice. Tumors from IL-10 -/- mice contained fewer IFN-γ-producing CD8+ and CD4+ T cells than tumors from WT mice. Strikingly, depletion of total CD4+ T cells, but not CD25+ cells, resulted in tumor eradication in IL-10 -/- mice. Adoptive transfer studies revealed that CD4+ T cells from IL-10 -/- mice exhibited more potent suppression of cytotoxic T lymphocyte (CTL)-mediated tumor rejection than their WT counterparts, and IL-10-deficient tumor-infiltrating CD4+ T cells expressed higher levels of PD-L1 and CTLA-4 inhibitory molecules. Although IL-10-deficient CD8+ T cells are not defective in activation and initial rejection of tumors, adoptive transfer studies using IL-10-deficient P1CTL transgenic T cells that recognize the tumor rejection antigen P1A reveal that IL-10 is required for long-term persistence of CTLs and control of tumor growth. Thus, we have found that IL-10 enhances antitumor CTL responses by inhibiting highly suppressive CD4+ T cells and promoting CTL persistence. These data have important implications for the design of immunotherapy for human cancer.
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Affiliation(s)
- Lixin Wang
- Department of Hematology; Chinese Navy General Hospital ; Beijing, China ; Department of Pathology and Comprehensive Cancer Center; The Ohio State University Medical Center ; Columbus, OH USA ; Department of Hematology; Chinese PLA General Hospital ; Beijing, China
| | - Jin-Qing Liu
- Department of Pathology and Comprehensive Cancer Center; The Ohio State University Medical Center ; Columbus, OH USA
| | - Fatemeh Talebian
- Department of Pathology and Comprehensive Cancer Center; The Ohio State University Medical Center ; Columbus, OH USA
| | - Zhenzhen Liu
- Department of Pathology and Comprehensive Cancer Center; The Ohio State University Medical Center ; Columbus, OH USA
| | - Li Yu
- Department of Hematology; Chinese PLA General Hospital ; Beijing, China
| | - Xue-Feng Bai
- Department of Pathology and Comprehensive Cancer Center; The Ohio State University Medical Center ; Columbus, OH USA
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Wu AA, Drake V, Huang HS, Chiu S, Zheng L. Reprogramming the tumor microenvironment: tumor-induced immunosuppressive factors paralyze T cells. Oncoimmunology 2015; 4:e1016700. [PMID: 26140242 DOI: 10.1080/2162402x.2015.1016700] [Citation(s) in RCA: 205] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Revised: 02/02/2015] [Accepted: 02/03/2015] [Indexed: 02/08/2023] Open
Abstract
It has become evident that tumor-induced immuno-suppressive factors in the tumor microenvironment play a major role in suppressing normal functions of effector T cells. These factors serve as hurdles that limit the therapeutic potential of cancer immunotherapies. This review focuses on illustrating the molecular mechanisms of immunosuppression in the tumor microenvironment, including evasion of T-cell recognition, interference with T-cell trafficking, metabolism, and functions, induction of resistance to T-cell killing, and apoptosis of T cells. A better understanding of these mechanisms may help in the development of strategies to enhance the effectiveness of cancer immunotherapies.
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Key Words
- 1MT, 1-methyltryptophan
- COX2, cyclooxygenase-2
- GM-CSF, granulocyte macrophage colony-stimulating factor
- GPI, glycosylphosphatidylinositol
- Gal1, galectin-1
- HDACi, histone deacetylase inhibitor
- HLA, human leukocyte antigen
- IDO, indoleamine-2,3- dioxygenase
- IL-10, interleukin-10
- IMC, immature myeloid cell
- MDSC, myeloid-derived suppressor cells
- MHC, major histocompatibility
- MICA, MHC class I related molecule A
- MICB, MHC class I related molecule B
- NO, nitric oxide
- PARP, poly ADP-ribose polymerase
- PD-1, program death receptor-1
- PD-L1, programmed death ligand 1
- PGE2, prostaglandin E2
- RCAS1, receptor-binding cancer antigen expressed on Siso cells 1
- RCC, renal cell carcinoma
- SOCS, suppressor of cytokine signaling
- STAT3, signal transducer and activator of transcription 3
- SVV, survivin
- T cells
- TCR, T-cell receptor
- TGF-β, transforming growth factor β
- TRAIL, TNF-related apoptosis-inducing ligand
- VCAM-1, vascular cell adhesion molecule-1
- XIAP, X-linked inhibitor of apoptosis protein
- iNOS, inducible nitric-oxide synthase
- immunosuppression
- immunosuppressive factors
- immunotherapy
- tumor microenvironment
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Affiliation(s)
- Annie A Wu
- Department of Oncology; The Johns Hopkins University School of Medicine ; Baltimore, MD USA
| | - Virginia Drake
- School of Medicine; University of Maryland ; Baltimore, MD USA
| | | | - ShihChi Chiu
- College of Medicine; National Taiwan University ; Taipei, Taiwan
| | - Lei Zheng
- Department of Oncology; The Johns Hopkins University School of Medicine ; Baltimore, MD USA
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Abstract
BACKGROUND Viral gene therapy is a promising new treatment modality for head and neck cancer. This paper provides the reader with a review of the relevant literature in this field. RESULTS There are government licensed viral gene therapy products currently in use for head and neck cancer, utilised in conjunction with established treatment modalities. The viruses target tumour-associated genes, with the first licensed virus replacing p53 gene function, which is frequently lost in tumourigenesis. Oncolytic viruses selectively destroy cancer cells through viral replication and can be armed with therapeutic transgenes. CONCLUSION Despite considerable advances in this field over the last 40 years, further research is needed to improve the overall efficacy of the viruses and allow their widespread utilisation in the management of head and neck cancer.
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Bhatia A, Kumar Y. Cellular and molecular mechanisms in cancer immune escape: a comprehensive review. Expert Rev Clin Immunol 2013; 10:41-62. [PMID: 24325346 DOI: 10.1586/1744666x.2014.865519] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Immune escape is the final phase of cancer immunoediting process wherein cancer modulates our immune system to escape from being destroyed by it. Many cellular and molecular events govern the cancer's evasion of host immune response. The tumor undergoes continuous remodeling at the genetic, epigenetic and metabolic level to acquire resistance to apoptosis. At the same time, it effectively modifies all the components of the host's immunome so as to escape from its antitumor effects. Moreover, it induces accumulation of suppressive cells like Treg and myeloid derived suppressor cells and factors which also enable it to elude the immune system. Recent research in this area helps in defining the role of newer players like miRNAs and exosomes in immune escape. The immunotherapeutic approaches developed to target the escape phase appear quite promising; however, the quest for a perfect therapeutic agent that can achieve maximum cure with minimal toxicity continues.
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Affiliation(s)
- Alka Bhatia
- Department of Experimental Medicine & Biotechnology, PGIMER, Chandigarh-160012, India
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Viral Vector Vaccines To Treat Colorectal Cancer. CURRENT COLORECTAL CANCER REPORTS 2013. [DOI: 10.1007/s11888-013-0185-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Lakshmi Narendra B, Eshvendar Reddy K, Shantikumar S, Ramakrishna S. Immune system: a double-edged sword in cancer. Inflamm Res 2013; 62:823-34. [PMID: 23868500 DOI: 10.1007/s00011-013-0645-9] [Citation(s) in RCA: 133] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2013] [Accepted: 06/27/2013] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE The objective of the review is to examine the role of innate and adaptive immune cells in cancer. INTRODUCTION Immune system functions as a host defensive mechanism protecting against invading pathogens and transformed cells, including cancer. However, a body of research carried out over the last few decades has disclosed the unexpected role of immune system in fostering the tumor growth. METHODS A computer-based online search was performed in the PubMed, Scopus and Web of Science databases for articles published, concerning natural killer (NK) cells, Macrophages, CD4+ and CD8+ T cells with relevance to cancer. After finding relevant articles within these search limits, a manual search was conducted through the references from these articles. RESULTS AND CONCLUSIONS This review summarizes the role of immune system in Immunosurveillance and Immunoediting. It then focused mainly on role of macrophages, regulatory T cells (Treg), TH17 cells and on the immunosuppressive mechanisms, which facilitate immune evasion of tumor cells. Our results shows that, immune cells, such as CD8+ cytotoxic T lymphocytes (CTL), CD4+ T helper (TH)1 cells and NK cells along with their characteristic cytokine interferon (IFN)-γ, function as major antitumor effector cells. Whereas CD4+TH2 cells, myeloid-derived suppressor cells (MDSCs) and their derived cytokines function as dominant tumor-promoting forces. In contrast to these cells, macrophages, Treg, and TH17 cells show a dual effect in cancer. Thus, it appears that most components of the immune system are potentially endowed with dual functions i.e., promoting tumor development on the one hand and restraining tumor development on the other and hence immune system can be considered as a double-edged sword in cancer.
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Affiliation(s)
- Bodduluru Lakshmi Narendra
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, 500037 Hyderabad, India
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Tüting T. T cell immunotherapy for melanoma from bedside to bench to barn and back: how conceptual advances in experimental mouse models can be translated into clinical benefit for patients. Pigment Cell Melanoma Res 2013; 26:441-56. [PMID: 23617831 DOI: 10.1111/pcmr.12111] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Accepted: 04/18/2013] [Indexed: 12/27/2022]
Abstract
A solid scientific basis now supports the concept that cytotoxic T lymphocytes can specifically recognize and destroy melanoma cells. Over the last decades, clinicians and basic scientists have joined forces to advance our concepts of melanoma immunobiology. This has catalyzed the rational development of therapeutic approaches to enforce melanoma-specific T cell responses. Preclinical studies in experimental mouse models paved the way for their successful translation into clinical benefit for patients with metastatic melanoma. A more thorough understanding of how melanomas develop resistance to T cell immunotherapy is necessary to extend this success. This requires a continued interdisciplinary effort of melanoma biologists and immunologists that closely connects clinical observations with in vitro investigations and appropriate in vivo mouse models: From bedside to bench to barn and back.
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Affiliation(s)
- Thomas Tüting
- Laboratory of Experimental Dermatology, Department of Dermatology, University Hospital Bonn, Bonn, Germany.
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Cui N, Xu Y, Cao Z, Xu F, Zhang P, Jin L. Effects of heat stress on the level of heat shock protein 70 on the surface of hepatocellular carcinoma Hep G2 cells: implications for the treatment of tumors. Tumour Biol 2012. [PMID: 23208674 DOI: 10.1007/s13277-012-0603-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
The ability to distinguish tumor cells from normal cells is vital to allow the immune system to selectively destroy tumor cells. In order to find an effective marker, we used enzyme-linked immunosorbent assay, immunocytochemistry, immunofluorescence, and flow cytometry to investigate the effects of heat stress on the amount of heat shock protein 70 on the surface of tumor cells (Hep G2 cells). Heat shock protein 70 is the major stress-induced heat shock protein found on the surface of tumor cells. Our results indicate that the percentage of Hep G2 cells with a detectable level of heat shock protein 70 on their cell surface increased significantly (P < 0.05) following heat stress at 42 °C for 2 h (up to 1.92 times the level before heat treatment). The detectable level of heat shock protein 70 on the surface of Hep G2 cells reached its peak 12 h after treatment. However, the fluorescent intensity of stressed and unstressed Hep G2 cells was not significantly different (P > 0.05). The increase in the level of heat shock protein 70 on the surface of tumor cells following heat stress could provide a basis for finding novel immunotoxins as targets for drug action and may have application to be used in conjunction with hyperthermia in the treatment of tumors.
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Affiliation(s)
- Naizhong Cui
- Ministry of Education Center for Food Safety of Animal Origin, School of Life Science and Biotechnology, Dalian University of Technology, Dalian, Liaoning, 116024, China
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Vaccination with embryonic stem cells protects against lung cancer: is a broad-spectrum prophylactic vaccine against cancer possible? PLoS One 2012; 7:e42289. [PMID: 22860107 PMCID: PMC3409174 DOI: 10.1371/journal.pone.0042289] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2012] [Accepted: 07/05/2012] [Indexed: 12/22/2022] Open
Abstract
The antigenic similarity between tumors and embryos has been appreciated for many years and reflects the expression of embryonic gene products by cancer cells and/or cancer-initiating stem cells. Taking advantage of this similarity, we have tested a prophylactic lung cancer vaccine composed of allogeneic murine embryonic stem cells (ESC). Naïve C57BL/6 mice were vaccinated with ESC along with a source of granulocyte macrophage-colony stimulating factor (GM-CSF) in order to provide immunostimulatory adjuvant activity. Vaccinated mice were protected against subsequent challenge with implantable Lewis lung carcinoma (LLC). ESC-induced anti-tumor immunity was not due to a non-specific “allo-response” as vaccination with allogeneic murine embryonic fibroblasts did not protect against tumor outgrowth. Vaccine efficacy was associated with robust tumor-reactive primary and memory CD8+ T effector responses, Th1 cytokine response, higher intratumoral CD8+ T effector/CD4+CD25+Foxp3+ T regulatory cell ratio, and reduced myeloid derived suppressor cells in the spleen. Prevention of tumorigenesis was found to require a CD8-mediated cytotoxic T lymphocyte (CTL) response because in vivo depletion of CD8+ T lymphocytes completely abrogated the protective effect of vaccination. Importantly, this vaccination strategy also suppressed the development of lung cancer induced by the combination of carcinogen administration and chronic pulmonary inflammation. Further refinement of this novel vaccine strategy and identification of shared ESC/tumor antigens may lead to immunotherapeutic options for lung cancer patients and, perhaps more importantly, could represent a first step toward the development of prophylactic cancer vaccines.
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Wang LX, Talebian F, Liu JQ, Khattabi M, Yu L, Bai XF. IL-10 contributes to the suppressive function of tumour-associated myeloid cells and enhances myeloid cell accumulation in tumours. Scand J Immunol 2012; 75:273-81. [PMID: 22050574 DOI: 10.1111/j.1365-3083.2011.02662.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Studies have revealed that tumour-associated myeloid cells (TAMC) are one of the major sources of IL-10 in tumour-bearing mice. However, the significance of TAMC-derived IL-10 in tumour immunity is poorly understood. Here, we show that IL-10 blockade or IL-10 deficiency reduces the capacity of TAMC in suppressing the proliferation of P1A-specific CD8 T cells. In the spleen, IL-10-deficient and wild-type (WT) mice bearing large tumour burdens have similar TAMC populations. The tumours from IL-10-deficient mice, however, have reduced numbers of TAMC compared with tumours from their WT counterparts. IL-10⁻/⁻ RAG-2⁻/⁻ mice also had reduced numbers of TAMC compared with tumours from IL-10⁺/⁺ RAG-2⁻/⁻ mice; therefore, the reduction in TAMC in IL-10-deficient tumours was not because of adaptive immune response in tumours. Adoptively transferred tumour antigen-specific CD8 T cells expanded more efficiently within tumours in IL-10⁻/⁻ RAG-2⁻/⁻ mice than in tumours from IL-10⁺/⁺ RAG-2⁻/⁻ mice. Cytotoxic T lymphocyte adoptive transfer therapy prevented tumour evasion in IL-10⁻/⁻ RAG-2⁻/⁻ mice more efficiently than in IL-10⁺/⁺ RAG-2⁻/⁻ mice. Thus, IL-10 enhances the accumulation of myeloid cells in tumours, and TAMC-derived IL-10 suppresses the activation and expansion of tumour antigen-specific T cells.
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Affiliation(s)
- L-X Wang
- Department of Pathology and Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, OH, USA
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Jazirehi AR, Economou JS. Proteasome inhibition blocks NF-κB and ERK1/2 pathways, restores antigen expression, and sensitizes resistant human melanoma to TCR-engineered CTLs. Mol Cancer Ther 2012; 11:1332-41. [PMID: 22532603 DOI: 10.1158/1535-7163.mct-11-0814] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Adoptive cell transfer (ACT) of ex vivo engineered autologous lymphocytes encoding high-affinity MART-1/HLA-A*0201-specific T-cell receptor (TCR)α/β chains (F5 CTL), densely infiltrate into sites of metastatic disease, mediating dramatic but partial clinical responses in patients with melanoma. We hypothesized that MART-1 downmodulation in addition to aberrant apoptotic/survival signaling could confer resistance to death signals delivered by transgenic CTLs. To explore this hypothesis, we established an in vitro model of resistant (R) lines from MART-1(+)/HLA-A*0201(+) F5 CTL-sensitive parental (P) lines under serial F5 CTL-selective pressure. We have recently reported that several melanoma R lines, while retaining MART-1 expression, exhibited constitutive NF-κB activation and overexpression of NF-κB-dependent resistance factors. Another established melanoma cell line M244, otherwise sensitive to F5 CTL, yielded R lines after serial F5 CTL-selective pressure, which had both reduced MART-1 expression levels, thus, could not be recognized, and were resistant to CTL-delivered apoptotic death signals. The proteasome inhibitor bortezomib blocked NF-κB activity, decreased phospho-ERK1/2, increased phospho-c-jun-NH(2)-kinase (p-JNK) levels, reduced expression of resistance factors, restored MART-1 expression to sufficient levels, which in combination allowed M244R lines be sensitized to F5 CTL killing. These findings suggest that proteasome inhibition in immune resistant tumors can restore proapoptotic signaling and improve tumor antigen expression.
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Affiliation(s)
- Ali R Jazirehi
- Department of Surgery and the Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, CA 90095, USA.
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Talebian F, Liu JQ, Liu Z, Khattabi M, He Y, Ganju R, Bai XF. Melanoma cell expression of CD200 inhibits tumor formation and lung metastasis via inhibition of myeloid cell functions. PLoS One 2012; 7:e31442. [PMID: 22319630 PMCID: PMC3272017 DOI: 10.1371/journal.pone.0031442] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2011] [Accepted: 01/10/2012] [Indexed: 12/30/2022] Open
Abstract
CD200 is a cell surface glycoprotein that functions through engaging CD200 receptor on cells of the myeloid lineage and inhibits their functions. Expression of CD200 has been implicated in a variety of human cancer cells including melanoma cells and has been thought to play a protumor role. To investigate the role of cancer cell expression of CD200 in tumor formation and metastasis, we generated CD200-positive and CD200-negative B16 melanoma cells. Subcutaneous injection of CD200-positive B16 melanoma cells inhibited tumor formation and growth in C57BL/6 mice but not in Rag1−/−C57BL/6 mice. However, i.v. injection of CD200-positive B16 melanoma cells dramatically inhibited tumor foci formation in the lungs of both C57BL/6 and Rag1−/−C57BL6 mice. Flow cytometry analysis revealed higher expression of CD200R in Gr1+ myeloid cells in the lung than in peripheral myeloid cells. Depletion of Gr1+ cells or stimulation of CD200R with an agonistic antibody in vivo dramatically inhibited tumor foci formation in the lungs. In addition, treatment with tumor antigen specific CD4 or CD8 T cells or their combination yielded a survival advantage for CD200 positive tumor bearing mice over mice bearing CD200-negative tumors. Taken together, we have revealed a novel role for CD200-CD200R interaction in inhibiting tumor formation and metastasis. Targeting CD200R may represent a novel approach for cancer immunotherapy.
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Affiliation(s)
- Fatemeh Talebian
- Department of Pathology and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America
- Integrated Biomedical Science Graduate Program, The Ohio State University, Columbus, Ohio, United States of America
| | - Jin-Qing Liu
- Department of Pathology and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America
| | - Zhenzhen Liu
- Department of Pathology and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America
- The Ohio State Biochemistry Program, The Ohio State University, Columbus, Ohio, United States of America
| | - Mazin Khattabi
- Department of Pathology and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America
| | - Yukai He
- Immunology/Immunotherapy Program, Georgia Health Sciences University, Augusta, Georgia, United States of America
| | - Ramesh Ganju
- Department of Pathology and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America
| | - Xue-Feng Bai
- Department of Pathology and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America
- * E-mail:
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Characterization of human endogenous retroviral elements in the blood of HIV-1-infected individuals. J Virol 2011; 86:262-76. [PMID: 22031938 DOI: 10.1128/jvi.00602-11] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
We previously reported finding the RNA of a type K human endogenous retrovirus, HERV-K (HML-2), at high titers in the plasma of HIV-1-infected and cancer patients (R. Contreras-Galindo et al., J. Virol. 82:9329-9236, 2008.). The extent to which the HERV-K (HML-2) proviruses become activated and the nature of their activated viral RNAs remain important questions. Therefore, we amplified and sequenced the full-length RNA of the env gene of the type 1 and 2 HERV-K (HML-2) viruses collected from the plasma of seven HIV-1-infected patients over a period of 1 to 3 years and from five breast cancer patients in order to reconstruct the genetic evolution of these viruses. HERV-K (HML-2) RNA was found in plasma fractions of HIV-1 patients at a density of ∼1.16 g/ml that contained both immature and correctly processed HERV-K (HML-2) proteins and virus-like particles that were recognized by anti-HERV-K (HML-2) antibodies. RNA sequences from novel HERV-K (HML-2) proviruses were discovered, including K111, which is specifically active during HIV-1 infection. Viral RNA arose from complete proviruses and proviruses devoid of a 5' long terminal repeat, suggesting that the expression of HERV-K (HML-2) RNA in these patients may involve sense and antisense transcription. In HIV-1-infected individuals, the HERV-K (HML-2) viral RNA showed evidence of frequent recombination, accumulation of synonymous rather than nonsynonymous mutations, and conserved N-glycosylation sites, suggesting that some of the HERV-K (HML-2) viral RNAs have undergone reverse transcription and are under purifying selection. In contrast, HERV-K (HML-2) RNA sequences found in the blood of breast cancer patients showed no evidence of recombination and exhibited only sporadic viral mutations. This study suggests that HERV-K (HML-2) is active in HIV-1-infected patients, and the resulting RNA message reveals previously undiscovered HERV-K (HML-2) genomic sequences.
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Russ AJ, Xu K, Wentworth L, Alam S, Meyers JV, Macklin MD, Rakhmilevich AL, Rajamanickam V, Suresh M, Cho CS. Melanoma-induced suppression of tumor antigen-specific T cell expansion is comparable to suppression of global T cell expansion. Cell Immunol 2011; 271:104-9. [PMID: 21741629 DOI: 10.1016/j.cellimm.2011.06.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2011] [Revised: 06/02/2011] [Accepted: 06/10/2011] [Indexed: 01/28/2023]
Abstract
We have observed that in vivo interaction between melanoma and resting T cells promotes suppression of antigen-driven proliferative T cell expansion. We hypothesized that this suppression would affect tumor antigen-specific T cell populations more potently than tumor-unrelated T cell populations. A B16F10 cell line was stably transfected to express low levels of the lymphocytic choriomeningitis virus (LCMV) glycoprotein GP33 (B16GP33). Mice bearing B16F10 or B16GP33 tumors were infected with LCMV, and proliferative expansion of LCMV epitope-specific T cell populations was quantified. In vitro and in vivo assays confirmed low levels of antigenic GP33 expression by B16GP33 tumors. Suppressed expansion of GP33-specific T cells was equivalent between mice bearing B16F10 and B16GP33 tumors. These observations suggest that the ability of growing melanoma tumors to impair antigen-driven proliferative expansion of activated T cells is global and not antigen-specific, and provide further insight into the influence of cancer on activated T cell homeostasis.
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Affiliation(s)
- Andrew J Russ
- Section of Surgical Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792-7375, USA
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Jazirehi AR, Baritaki S, Koya RC, Bonavida B, Economou JS. Molecular mechanism of MART-1+/A*0201+ human melanoma resistance to specific CTL-killing despite functional tumor-CTL interaction. Cancer Res 2010; 71:1406-17. [PMID: 21159666 DOI: 10.1158/0008-5472.can-10-1296] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Durable responses in metastatic melanoma patients remain generally difficult to achieve. Adoptive cell therapy (ACT) with ex vivo engineered lymphocytes expressing high affinity T-cell receptors (TCRα/β) for the melanoma antigen MART-1₂₇₋₃₅/HLA-A*0201 [recognized by F5 cytotoxic T lymphocytes (F5 CTL)] has been found to benefit certain patients. However, many other patients are inherently unresponsive and/or relapse for unknown reasons. To analyze the basis for the acquired resistance and strategies to reverse it, we established F5 CTL-resistant (R) human melanoma clones from relatively sensitive parental lines under selective F5 CTL pressure. Surface MART-1₂₇₋₃₅/HLA-A*0201 in these clones was unaltered and F5 CTLs recognized and interacted with them similar to the parental lines. Nevertheless, the R clones were resistant to F5 CTL killing, exhibited hyperactivation of the NF-κB survival pathway, and overexpression of the antiapoptotic genes B cell lymphoma protein 2 (Bcl-2), Bcl-2 related gene (long alternatively spliced variant of Bcl-x gene; Bcl-(xL)), and myeloid cell differentiation 1 (Mcl-1). Sensitivity to F5 CTL-killing could be increased by pharmacological inhibition of the NF-κB pathway, Bcl-2 family members, or the proteasome, the latter of which reduced NF-κB activity and diminished antiapoptotic gene expression. Specific gene-silencing (by siRNA) confirmed the protective role of antiapoptotic factors by reversing R clone resistance. Together, our findings suggest that long-term immunotherapy may impose a selection for the development of resistant cells that are unresponsive to highly avid and specific melanoma-reactive CTLs, despite maintaining expression of functional peptide:MHC complexes, due to activation of antiapoptotic signaling pathways. Though unresponsive to CTL, our results argue that resistant cells can be resensitized to immunotherapy with coadministration of targeted inhibitors to antiapoptotic survival pathways.
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Affiliation(s)
- Ali R Jazirehi
- Department of Surgery, Molecular and Medical Pharmacology, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
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