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Feng H, Jin Y, Wu B. Strategies for neoantigen screening and immunogenicity validation in cancer immunotherapy (Review). Int J Oncol 2025; 66:43. [PMID: 40342048 PMCID: PMC12101193 DOI: 10.3892/ijo.2025.5749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2025] [Accepted: 04/11/2025] [Indexed: 05/11/2025] Open
Abstract
Cancer immunotherapy stimulates and enhances antitumor immune responses to eliminate cancer cells. Neoantigens, which originate from specific mutations within tumor cells, are key targets in cancer immunotherapy. Neoantigens manifest as abnormal peptide fragments or protein segments that are uniquely expressed in tumor cells, making them highly immunogenic. As a result, they activate the immune system, particularly T cell‑mediated immune responses, effectively identifying and eliminating tumor cells. Certain tumor‑associated antigens that are abnormally expressed in normal host proteins in cancer cells are promising targets for immunotherapy. Neoantigens derived from mutated proteins in cancer cells offer true cancer specificity and are often highly immunogenic. Furthermore, most neoantigens are unique to each patient, highlighting the need for personalized treatment strategies. The precise identification and screening of neoantigens are key for improving treatment efficacy and developing individualized therapeutic plans. The neoantigen prediction process involves somatic mutation identification, human leukocyte antigen (HLA) typing, peptide processing and peptide‑HLA binding prediction. The present review summarizes the major current methods used for neoantigen screening, available computational tools and the advantages and limitations of various techniques. Additionally, the present review aimed to summarize experimental strategies for validating the immunogenicity of the predicted neoantigens, which will determine whether these neoantigens can effectively trigger immune responses, as well as challenges encountered during neoantigen screening, providing relevant recommendations for the optimization of neoantigen‑based immunotherapy.
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Affiliation(s)
- Hua Feng
- College of Life Sciences, China Jiliang University, Hangzhou, Zhejiang 310018, P.R. China
| | - Yuanting Jin
- College of Life Sciences, China Jiliang University, Hangzhou, Zhejiang 310018, P.R. China
| | - Bin Wu
- Department of Neurosurgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China
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Liu Q, Su J, Chen J, Yang S, Huang Y, Tang R, Jiang Z, Huang S. Bioinspired rational spatial-arrangement of antigens enables the accurate and rapid detection of anti-p53 autoantibody. Mikrochim Acta 2025; 192:123. [PMID: 39890668 DOI: 10.1007/s00604-025-06970-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Accepted: 01/09/2025] [Indexed: 02/03/2025]
Abstract
A highly sensitive antibody detection strategy is presented that leverages the rational spatial arrangement of antigens at the sensing interface. Specifically, we employed rigid benzene ring-based coupling agents, carefully controlling their density and orientation on the biosensing interface to establish a well-defined spatial arrangement of receptor molecules, thereby enhancing antibody binding efficiency. Additionally, we utilized Au-decorated MoS2 nanosheets as an effective electrode modification, which also function as contact points for regulating the coupling agents. By optimizing both the electrode materials and the spatial arrangement of receptor molecules, our strategy enabled the precise and rapid detection of anti-p53 autoantibodies (anti-p53aAbs) in spiked plasma samples, achieving a broad linear range from 0.05 to 10 ng/mL and a low detection limit of 16.67 pg/mL, surpassing the performance of most existing methods. Notably, we introduce a biomimetic strategy for the spatial arrangement of antigens, inspired by the bionic recognition mechanism. This design effectively reduces steric hindrance between antibody molecules, enhances binding efficiency, and provides a novel approach for the rapid and sensitive detection of macromolecules, such as antibodies.
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Affiliation(s)
- Qiwen Liu
- Guangzhou Municipal and Guangdong Provincial KeyLaboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - Jianfen Su
- The Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, 510000, China
| | - Jiamei Chen
- Guangzhou Municipal and Guangdong Provincial KeyLaboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - Shuo Yang
- Guangzhou Municipal and Guangdong Provincial KeyLaboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - Yang Huang
- Guangzhou Municipal and Guangdong Provincial KeyLaboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - Rentao Tang
- Guangzhou Municipal and Guangdong Provincial KeyLaboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - Zhengjin Jiang
- Institute of Pharmaceutical Analysis, College of Pharmacy/State Key Laboratory of Bioactive Molecules and Druggability Assessment/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan University, Guangzhou, 510632, China.
| | - Shengfeng Huang
- Guangzhou Municipal and Guangdong Provincial KeyLaboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
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Wang Y, Ouyang S, Liu M, Si Q, Zhang X, Zhang X, Li J, Wang P, Ye H, Shi J, Song C, Wang K, Dai L. Humoral immune response to tumor-associated antigen Ubiquilin 1 (UBQLN1) and its tumor-promoting potential in lung cancer. BMC Cancer 2024; 24:283. [PMID: 38431566 PMCID: PMC10908023 DOI: 10.1186/s12885-024-12019-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 02/18/2024] [Indexed: 03/05/2024] Open
Abstract
BACKGROUND This study aims to investigate the expression of UBQLN1 in lung cancer (LC) tissue and the diagnostic capability of autoantibody to UBQLN1 (anti-UBQLN1) in the detection of LC and the discrimination of pulmonary nodules (PNs). METHODS Sera from 798 participants were used to discover and validate the level of autoantibodies via HuProt microarray and Enzyme-linked immunosorbent assay (ELISA). Logistic regression analysis was applied to establish model. Receiver operating characteristic curve (ROC) analysis was performed to evaluate the diagnostic potential. Immunohistochemistry was performed to detect UBQLN1 expression in 88 LC tissues and 88 para-tumor tissues. qRT-PCR and western blotting were performed to detect the expression of UBQLN1 at the mRNA and protein levels, respectively. Trans-well assay and cell counting kit-8 (CCK-8) was used to investigate the function of UBQLN1. RESULTS Anti-UBQLN1 was identified with the highest fold change by protein microarray. The level of anti-UBQLN1 in LC patients was obviously higher than that in NC or patients with benign lung disease of validation cohort 1 (P<0.05). The area under the curve (AUC) of anti-UBQLN1 was 0.610 (95%CI: 0.508-0.713) while reached at 0.822 (95%CI: 0.784-0.897) when combining anti-UBQLN1 with CEA, CYFRA21-1, CA125 and three CT indicators (vascular notch sign, lobulation sign and mediastinal lymph node enlargement) in the discrimination of PNs. UBQLN1 protein was overexpressed in lung adenocarcinoma (LUAD) tissues compared to para-tumor tissues. UBQLN1 knockdown remarkably inhibited the migration, invasion and proliferation of LUAD cell lines. CONCLUSIONS Anti-UBQLN1 might be a potential biomarker for the diagnosis of LC and the discrimination of PNs.
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Affiliation(s)
- Yulin Wang
- Henan Institute of Medical and Pharmaceutical Sciences & Henan Key Medical Laboratory of Tumor Molecular Biomarkers, Zhengzhou University, Zhengzhou, Henan, 450052, China
- Henan Key Laboratory of Tumor Epidemiology, Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Songyun Ouyang
- Department of Respiratory and Sleep Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Man Liu
- Henan Institute of Medical and Pharmaceutical Sciences & Henan Key Medical Laboratory of Tumor Molecular Biomarkers, Zhengzhou University, Zhengzhou, Henan, 450052, China
- Henan Key Laboratory of Tumor Epidemiology, Zhengzhou University, Zhengzhou, Henan, 450052, China
- Laboratory of Molecular Biology, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou, China
| | - Qiufang Si
- Henan Institute of Medical and Pharmaceutical Sciences & Henan Key Medical Laboratory of Tumor Molecular Biomarkers, Zhengzhou University, Zhengzhou, Henan, 450052, China
- Henan Key Laboratory of Tumor Epidemiology, Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Xue Zhang
- Henan Institute of Medical and Pharmaceutical Sciences & Henan Key Medical Laboratory of Tumor Molecular Biomarkers, Zhengzhou University, Zhengzhou, Henan, 450052, China
- Henan Key Laboratory of Tumor Epidemiology, Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Xiuzhi Zhang
- Henan Institute of Medical and Pharmaceutical Sciences & Henan Key Medical Laboratory of Tumor Molecular Biomarkers, Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Jiaqi Li
- Henan Institute of Medical and Pharmaceutical Sciences & Henan Key Medical Laboratory of Tumor Molecular Biomarkers, Zhengzhou University, Zhengzhou, Henan, 450052, China
- Henan Key Laboratory of Tumor Epidemiology, Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Peng Wang
- Henan Key Laboratory of Tumor Epidemiology, Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Hua Ye
- Henan Key Laboratory of Tumor Epidemiology, Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Jianxiang Shi
- Henan Institute of Medical and Pharmaceutical Sciences & Henan Key Medical Laboratory of Tumor Molecular Biomarkers, Zhengzhou University, Zhengzhou, Henan, 450052, China
- Henan Key Laboratory of Tumor Epidemiology, Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Chunhua Song
- Henan Key Laboratory of Tumor Epidemiology, Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Kaijuan Wang
- Henan Key Laboratory of Tumor Epidemiology, Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Liping Dai
- Henan Institute of Medical and Pharmaceutical Sciences & Henan Key Medical Laboratory of Tumor Molecular Biomarkers, Zhengzhou University, Zhengzhou, Henan, 450052, China.
- Henan Key Laboratory of Tumor Epidemiology, Zhengzhou University, Zhengzhou, Henan, 450052, China.
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Bryushkova EA, Mushenkova NV, Turchaninova MA, Lukyanov DK, Chudakov DM, Serebrovskaya EO. B cell clonality in cancer. Semin Immunol 2024; 72:101874. [PMID: 38508089 DOI: 10.1016/j.smim.2024.101874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 01/05/2024] [Accepted: 01/05/2024] [Indexed: 03/22/2024]
Abstract
Carcinogenesis in the process of long-term co-evolution of tumor cells and immune environment essentially becomes possible due to incorrect decisions made, remembered, and reproduced by the immune system at the level of clonal populations of antigen-specific T- and B-lymphocytes. Tumor-immunity interaction determines the nature of such errors and, consequently, delineates the possible ways of successful immunotherapeutic intervention. It is generally recognized that tumor-infiltrating B cells (TIL-B) can play both pro-tumor and anti-tumor roles. However, the exact mechanisms that determine the contribution of clonal B cell lineages with different specificities and functions remain largely unclear. This is due to the variability of cancer types, the molecular heterogeneity of tumor cells, and, to a large extent, the individual pattern of each immune response. Further progress requires detailed investigation of the functional properties and phenotypes of clonally heterogeneous B cells in relation to their antigenic specificities, which determine the functionality of both effector B lymphocytes and immunoglobulins produced in the tumor environment. Based on a real understanding of the role of clonal antigen-specific populations of B lymphocytes in the tumor microenvironment, we need to learn how to develop new methods of targeted immunotherapy, as well as adapt existing treatment options to the specific needs of different patients and patient subgroups. In this review, we will cover B cells functional diversity and their multifaceted roles in the tumor environment.
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Affiliation(s)
- E A Bryushkova
- Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russia; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia; Department of Molecular Biology, Lomonosov Moscow State University, Moscow, Russia
| | - N V Mushenkova
- Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russia; Unicorn Capital Partners, Moscow, Russia
| | - M A Turchaninova
- Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russia; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia
| | - D K Lukyanov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia; Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russia
| | - D M Chudakov
- Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russia; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia; Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russia; Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
| | - E O Serebrovskaya
- Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russia; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia; Current position: Miltenyi Biotec B.V. & Co. KG, Bergisch Gladbach, Germany
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Zhuang L, Huang C, Ning Z, Yang L, Zou W, Wang P, Cheng CS, Meng Z. Circulating tumor-associated autoantibodies as novel diagnostic biomarkers in pancreatic adenocarcinoma. Int J Cancer 2023; 152:1013-1024. [PMID: 36274627 DOI: 10.1002/ijc.34334] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 10/03/2022] [Accepted: 10/10/2022] [Indexed: 01/06/2023]
Abstract
To develop a superior diagnostic approach for pancreatic adenocarcinoma (PAAC), the present study prospectively included 338 PAAC patients, 294 normal healthy volunteers (NHV), 122 chronic pancreatitis (CP) patients and 100 patients with non-PAAC malignancies. In the identification phase, HuProt Human Proteome Microarray, comprising 21 065 proteins, was used to identify serum tumor-associated autoantibodies (TAAbs) candidates differentiating PAAC (n = 30) from NHV (n = 30). A PAAC-focused array containing 165 differentially expressed TAAbs identified was subsequently adopted in the validation phase (n = 712) for specificity and sensitivities. The multivariate TAAbs signature for differentiation PAAC from controls (NHV + CP) identified five candidates, namely the IgG-type TAAbs against CLDN17, KCNN3, SLAMF7, SLC22A11 and OR51F2. Multivariate logistic performance model of y = (22.893 × CA19-9 + 0.68 × CLDN17 - 4.012) showed a significant better diagnostic accuracy than that of CA19-9 and CLDN17 in differentiating PAAC from controls (NHV + CP) (AUC = 0.97, 0.92 and 0.82, respectively, P-value < .0001). We further tested the autoantigen level of CLDN17 by ELISA in 82 sera samples from PAAC (n = 42), CP (n = 24) and NHV (n = 16). Similarly, the model showed superior diagnostic performance than that of CA19-9 and CLDN17 (AUC = 0.93, 0.83 and 0.81, respectively, P-value < .0001) in differentiating PAAC from controls. In conclusion, our study is the first to characterize the circulating TAAbs signatures in PAAC. The results showed that CLDN17 combined with CA19-9 provided potentially clinical value and may serve as noninvasive novel biomarkers for PAAC diagnosis.
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Affiliation(s)
- Liping Zhuang
- Minimally Invasive Therapy Center, Shanghai Cancer Center, Fudan University, Shanghai, China.,Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Changjing Huang
- Minimally Invasive Therapy Center, Shanghai Cancer Center, Fudan University, Shanghai, China.,Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhouyu Ning
- Minimally Invasive Therapy Center, Shanghai Cancer Center, Fudan University, Shanghai, China.,Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lina Yang
- Minimally Invasive Therapy Center, Shanghai Cancer Center, Fudan University, Shanghai, China.,Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Shandong Province, China
| | - Wenbin Zou
- Department of Gastroenterology, Digestive Endoscopy Center, Changhai Hospital, the Second Military Medical University, Shanghai, China
| | - Peng Wang
- Minimally Invasive Therapy Center, Shanghai Cancer Center, Fudan University, Shanghai, China.,Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Chien-Shan Cheng
- Minimally Invasive Therapy Center, Shanghai Cancer Center, Fudan University, Shanghai, China.,Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhiqiang Meng
- Minimally Invasive Therapy Center, Shanghai Cancer Center, Fudan University, Shanghai, China.,Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
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Music M, Iafolla M, Soosaipillai A, Batruch I, Prassas I, Pintilie M, Hansen AR, Bedard PL, Lheureux S, Spreafico A, Razak AA, Siu LL, Diamandis EP. Predicting response and toxicity to PD-1 inhibition using serum autoantibodies identified from immuno-mass spectrometry. F1000Res 2020; 9:337. [PMID: 33299547 PMCID: PMC7707117 DOI: 10.12688/f1000research.22715.1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/22/2020] [Indexed: 12/15/2022] Open
Abstract
Background: Validated biomarkers are needed to identify patients at increased risk of immune-related adverse events (irAEs) to immune checkpoint blockade (ICB). Antibodies directed against endogenous antigens can change after exposure to ICB. Methods: Patients with different solid tumors stratified into cohorts received pembrolizumab every 3 weeks in a Phase II trial (INSPIRE study). Blood samples were collected prior to first pembrolizumab exposure (baseline) and approximately 7 weeks (pre-cycle 3) into treatment. In a discovery analysis, autoantibody target immuno-mass spectrometry was performed in baseline and pre-cycle 3 pooled sera of 24 INSPIRE patients based on clinical benefit (CBR) and irAEs. Results: Thyroglobulin (Tg) and thyroid peroxidase (TPO) were identified as the candidate autoantibody targets. In the overall cohort of 78 patients, the frequency of CBR and irAEs from pembrolizumab was 31% and 24%, respectively. Patients with an anti-Tg titer increase ≥1.5x from baseline to pre-cycle 3 were more likely to have irAEs relative to patients without this increase in unadjusted, cohort adjusted, and multivariable models (OR=17.4, 95% CI 1.8-173.8, p=0.015). Similarly, patients with an anti-TPO titer ≥ 1.5x from baseline to pre-cycle 3 were more likely to have irAEs relative to patients without the increase in unadjusted and cohort adjusted (OR=6.1, 95% CI 1.1-32.7, p=0.035) models. Further, the cohort adjusted analysis showed patients with anti-Tg titer greater than median (10.0 IU/mL) at pre-cycle 3 were more likely to have irAEs (OR=4.7, 95% CI 1.2-17.8, p=0.024). Patients with pre-cycle 3 anti-TPO titers greater than median (10.0 IU/mL) had a significant difference in overall survival (23.8 vs 11.5 months; HR=1.8, 95% CI 1.0-3.2, p=0.05). Conclusions: Patient increase ≥1.5x of anti-Tg and anti-TPO titers from baseline to pre-cycle 3 were associated with irAEs from pembrolizumab, and patients with elevated pre-cycle 3 anti-TPO titers had an improvement in overall survival.
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Affiliation(s)
- Milena Music
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Marco Iafolla
- Division of Medical Oncology and Hematology, University Health Network, Canada, Toronto, ON, Canada
| | - Antoninus Soosaipillai
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Toronto, ON, Canada
| | - Ihor Batruch
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Toronto, ON, Canada
| | - Ioannis Prassas
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Toronto, ON, Canada
| | - Melania Pintilie
- Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Canada, Toronto, ON, Canada
| | - Aaron R. Hansen
- Division of Medical Oncology and Hematology, University Health Network, Canada, Toronto, ON, Canada
| | - Philippe L. Bedard
- Division of Medical Oncology and Hematology, University Health Network, Canada, Toronto, ON, Canada
| | - Stephanie Lheureux
- Division of Medical Oncology and Hematology, University Health Network, Canada, Toronto, ON, Canada
| | - Anna Spreafico
- Division of Medical Oncology and Hematology, University Health Network, Canada, Toronto, ON, Canada
| | - Albiruni Abdul Razak
- Division of Medical Oncology and Hematology, University Health Network, Canada, Toronto, ON, Canada
| | - Lillian L. Siu
- Division of Medical Oncology and Hematology, University Health Network, Canada, Toronto, ON, Canada
| | - Eleftherios P. Diamandis
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Toronto, ON, Canada
- Department of Clinical Biochemistry, University Health Network, Canada, Toronto, ON, Canada
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Toronto, ON, Canada
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Xu YW, Peng YH, Xu LY, Xie JJ, Li EM. Autoantibodies: Potential clinical applications in early detection of esophageal squamous cell carcinoma and esophagogastric junction adenocarcinoma. World J Gastroenterol 2019; 25:5049-5068. [PMID: 31558856 PMCID: PMC6747294 DOI: 10.3748/wjg.v25.i34.5049] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 07/28/2019] [Accepted: 08/19/2019] [Indexed: 02/06/2023] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) and esophagogastric junction adenocarcinoma (EGJA) are the two main types of gastrointestinal cancers that pose a huge threat to human health. ESCC remains one of the most common malignant diseases around the world. In contrast to the decreasing prevalence of ESCC, the incidence of EGJA is rising rapidly. Early detection represents one of the most promising ways to improve the prognosis and reduce the mortality of these cancers. Current approaches for early diagnosis mainly depend on invasive and costly endoscopy. Non-invasive biomarkers are in great need to facilitate earlier detection for better clinical management of patients. Tumor-associated autoantibodies can be detected at an early stage before manifestations of clinical signs of tumorigenesis, making them promising biomarkers for early detection and monitoring of ESCC and EGJA. In this review, we summarize recent insights into the iden-tification and validation of tumor-associated autoantibodies for the early detection of ESCC and EGJA and discuss the challenges remaining for clinical validation.
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Affiliation(s)
- Yi-Wei Xu
- Department of Clinical Laboratory Medicine, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yu-Hui Peng
- Department of Clinical Laboratory Medicine, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Li-Yan Xu
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong Province, China
- Institute of Oncologic Pathology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jian-Jun Xie
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong Province, China
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - En-Min Li
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong Province, China
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
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Yadav S, Kashaninejad N, Masud MK, Yamauchi Y, Nguyen NT, Shiddiky MJ. Autoantibodies as diagnostic and prognostic cancer biomarker: Detection techniques and approaches. Biosens Bioelectron 2019; 139:111315. [DOI: 10.1016/j.bios.2019.111315] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 05/07/2019] [Accepted: 05/08/2019] [Indexed: 01/25/2023]
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The roles and applications of autoantibodies in progression, diagnosis, treatment and prognosis of human malignant tumours. Autoimmun Rev 2017; 16:1270-1281. [PMID: 29042252 DOI: 10.1016/j.autrev.2017.10.012] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 09/06/2017] [Indexed: 02/07/2023]
Abstract
The existence of autoantibodies towards an individual's own proteins or nucleic acids has been established for more than 100years, and for a long period, these autoantibodies have been believed to be closely associated with autoimmune diseases. However, in recent years, researchers have become more interested in the role and application of autoantibodies in progression, diagnosis, treatment and prognosis of human malignant tumours. Over the past few decades, numerous epidemiological studies have shown that the risk of certain cancers is significantly altered (increased or decreased) in patients with autoimmune diseases, which suggests that autoantibodies may play either promoting or suppressing roles in cancer progression. The idea that autoantibodies are directly involved in tumour progression gains special support by the findings that some antibodies secreted by a variety of cancer cells can promote their proliferation and metastasis. Because the cancer cells generate cell antigenic changes (neoantigens), which trigger the immune system to produce autoantibodies, serum autoantibodies against tumour-associated antigens have been established as a novel type of cancer biomarkers and have been extensively studied in different types of cancer. The autoantibodies as biomarkers in cancer diagnosis are not only more sensitive and specific than antigens, but also could appear before clinical evidences of the tumours, thus disclosing them. The observations that cancer risk is lower in patients with some autoimmune diseases suggest that certain autoantibodies may be protective from certain cancers. Moreover, the presence of autoantibodies in healthy individuals implies that it could be safe to employ autoantibodies to treat cancer. Of note, an autoantibodies derived from lupus murine model received much attention due to their selective cytotoxicity for malignant tumour cell without harming normal ones. These studies showed the therapeutic value of autoantibodies in cancer. In this review, we revisited the pathological or protective role of autoantibodies in cancer progression, summarize the application of autoantibodies in cancer diagnosis and prognosis, and discuss the value of autoantibodies in cancer therapy. The studies established to date suggest that autoantibodies not only regulate cancer progression but also promise to be valuable instruments in oncological diagnosis and therapy.
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Kamta J, Chaar M, Ande A, Altomare DA, Ait-Oudhia S. Advancing Cancer Therapy with Present and Emerging Immuno-Oncology Approaches. Front Oncol 2017; 7:64. [PMID: 28459041 PMCID: PMC5394116 DOI: 10.3389/fonc.2017.00064] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Accepted: 03/20/2017] [Indexed: 12/18/2022] Open
Abstract
Immuno-oncology (I-O) is a young and growing field on the frontier of cancer therapy. Contrary to cancer therapies that directly target malignant cells, I-O therapies stimulate the body’s immune system to target and attack the tumor, which is otherwise invisible to, or inhibiting the immune response. To this end, several methods have been developed: First, passive therapies that enable T-cells to fight the tumor without direct manipulation, typically through binding and modifying the intracellular signaling of surface receptors. Checkpoint inhibitors, perhaps the most well known of I-O therapies; are an example of such. These are monoclonal antibodies that block binding of the tumor cell at receptors that inactivate the T-cell. A variety of small molecules can achieve the same effect by affecting metabolic or signaling pathways to boost the immune response or prevent its attenuation. Drugs originally formulated for unrelated disease states are now being used to treat cancer under the I-O approach. Second, active therapies which often involve direct manipulations that occur in vitro and once introduced to the patient will directly attack the tumor. Adoptive cell transfer is the oldest of these methods. It involves the removal of T-cells from the body, which are then expanded and genetically modified for specificity toward tumor-associated antigens (TAAs), and then reintroduced to the patient. A similar approach is taken with cancer vaccines, where TAAs are identified and reintroduced with adjuvants to stimulate an immune response, sometimes in the context of antigen-presenting cells or viral vectors. Oncolytic viruses are genetically modified natural viruses for selectivity toward tumor cells. The resulting cytotoxicity has the potential to elicit an immune response that furthers tumor cell killing. A final active approach is bi-specific T-cell engagers. These modified antibodies act to link a T-cell and tumor cell through surface receptors and thereby forcibly generate immune recognition. The therapies in each of these subfields are all still very new and ongoing clinical trials could provide even further additions. The full therapeutic potential of the aforementioned therapies, alone or in combination, has yet to be realized, but holds great promise for the future of cancer treatment.
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Affiliation(s)
- Jeff Kamta
- Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA
| | - Maher Chaar
- Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA
| | - Anusha Ande
- Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA
| | - Deborah A Altomare
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA
| | - Sihem Ait-Oudhia
- Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA
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Macdonald IK, Parsy-Kowalska CB, Chapman CJ. Autoantibodies: Opportunities for Early Cancer Detection. Trends Cancer 2017; 3:198-213. [PMID: 28718432 DOI: 10.1016/j.trecan.2017.02.003] [Citation(s) in RCA: 91] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Revised: 02/06/2017] [Accepted: 02/07/2017] [Indexed: 12/18/2022]
Abstract
Cancer cells can induce an immunological response resulting in the production of tumor-associated (TA) autoantibodies. These serum immunobiomarkers have been detected for a range of cancers at an early stage before the development of clinical symptoms. Their measurement is minimally invasive and cost effective using established technologies. TA autoantibodies are present in a clinically significant number of individuals and could supplement current screening modalities to aid early diagnosis of high-risk populations and assist the clinical management of patients. Here we review their production, discovery, and validation as biomarkers for cancer and their current and future potential as clinical tools.
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Ardelt PU, Ebbing J, Adams F, Reiss C, Arap W, Pasqualini R, Bachmann A, Wetterauer U, Riedmiller H, Kneitz B. An anti-ubiquitin antibody response in transitional cell carcinoma of the urinary bladder. PLoS One 2015; 10:e0118646. [PMID: 25742283 PMCID: PMC4351094 DOI: 10.1371/journal.pone.0118646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Accepted: 01/08/2015] [Indexed: 12/05/2022] Open
Abstract
Background To use combinatorial epitope mapping (“fingerprinting”) of the antibody response to identify targets of the humoral immune response in patients with transitional cell carcinoma (TCC) of the bladder. Methods A combinatorial random peptide library was screened on the circulating pool of immunoglobulins purified from an index patient with a high risk TCC (pTa high grade plus carcinoma in situ) to identify corresponding target antigens. A patient cohort was investigated for antibody titers against ubiquitin. Results We selected, isolated, and validated an immunogenic peptide motif from ubiquitin as a dominant epitope of the humoral response. Patients with TCC had significantly higher antibody titers against ubiquitin than healthy donors (p<0.007), prostate cancer patients (p<0.0007), and all patients without TCC taken together (p<0.0001). Titers from superficial tumors were not significantly different from muscle invasive tumors (p = 0.0929). For antibody response against ubiquitin, sensitivity for detection of TCC was 0.44, specificity 0.96, positive predictive value 0.96 and negative predictive value 0.41. No significant titer changes were observed during the standard BCG induction immunotherapy. Conclusions This is the first report to demonstrate an anti-ubiquitin antibody response in patients with TCC. Although sensitivity of antibody production was low, a high specificity and positive predictive value make ubiquitin an interesting candidate for further diagnostic and possibly immune modulating studies.
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Affiliation(s)
- Peter U. Ardelt
- Department of Urology, University Hospital Basel, Basel, Switzerland
- Department of Urology and Pediatric Urology, Medical School, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
- Department of Urology, Bavarian Julius Maximilians-University Medical School, Würzburg, Germany
- * E-mail:
| | - Jan Ebbing
- Department of Urology, University Hospital Basel, Basel, Switzerland
| | - Fabian Adams
- Department of Urology and Pediatric Urology, Medical School, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
| | - Cora Reiss
- Center for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany
| | - Wadih Arap
- Division of Hematology/Oncology and Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico, United States of America
| | - Renata Pasqualini
- Division of Hematology/Oncology and Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico, United States of America
| | | | - Ulrich Wetterauer
- Department of Urology and Pediatric Urology, Medical School, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
| | - Hubertus Riedmiller
- Department of Urology, Bavarian Julius Maximilians-University Medical School, Würzburg, Germany
| | - Burkhard Kneitz
- Department of Urology, Bavarian Julius Maximilians-University Medical School, Würzburg, Germany
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Kobayashi M, Nagashio R, Ryuge S, Murakami Y, Yanagita K, Nakashima H, Matsumoto T, Jiang SX, Saegusa M, Satoh Y, Masuda N, Sato Y. Acquisition of useful sero-diagnostic autoantibodies using the same patients'sera and tumor tissues. Biomed Res 2014; 35:133-43. [PMID: 24759181 DOI: 10.2220/biomedres.35.133] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Cancer tissues are comprised of various components including tumor cells and the surrounding tumor stroma, which consists of the extracellular matrix and inflammatory cells. Since the tumor stroma plays critical roles in tumor development, investigation of the tumor stroma in addition to tumor cells is important to identify useful tumor-associated markers. To discover novel and useful sero-diagnostic markers, a comparative study of tumor-associated autoantibodies (AAbs) in sera from lung adenocarcinoma (AC) patients was investigated by two-dimensional immunoblotting with AC cell lines or each autologous AC tissues. Autoantigens identified from tissue and cell line samples comprised 58 (45 antigens) and 53 spots (41 antigens), respectively. Thirty-six proteins including Transforming growth factor-beta-induced protein ig-h3 (BIGH3) and Hyaluronan and proteoglycan link protein 1 (HAPLN1) were detected only from tissues, 32 proteins only from cell lines, and 9 proteins from both. BIGH3 and HAPLN1 expressions were confirmed in the tumor stroma, but not in AC cell lines by immunostaining and immunoblotting. These data suggest that autologous tumor tissue and serum are important to coincidently detect AAbs derived from the tumor stroma in addition to tumor cells.
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Affiliation(s)
- Makoto Kobayashi
- Department of Applied Tumor Pathology, Graduate School of Medical Sciences, Kitasato University, Kanagawa, Japan
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Abstract
In the process of tumorigenesis, normal cells are remodeled to cancer cells and protein expression patterns are changed to those of tumor cells. A newly formed tumor microenvironment elicits the immune system and, as a result, a humoral immune response takes place. Although the tumor antigens are undetectable in sera at the early stage of tumorigenesis, the nature of an antibody amplification response to antigens makes tumor-associated autoantibodies as promising early biomarkers in cancer diagnosis. Moreover, the recent development of proteomic techniques that make neo-epitopes of tumor-associated autoantigens discovered concomitantly has opened a new area of ‘immuno-proteomics’, which presents tumor-associated autoantibody signatures and confers information to redefine the process of tumorigenesis. In this article, the strategies recently used to identify and validate serum autoantibodies are outlined and tumor-associated antigens suggested until now as diagnostic/prognostic biomarkers in various tumor types are reviewed. Also, the meaning of autoantibody signatures and their clinical utility in personalized medicine are discussed. [BMB Reports 2012; 45(12): 677-685]
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Affiliation(s)
- Chang-Kyu Heo
- Cancer Biomarkers Development Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Korea
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Macdonald IK, Murray A, Healey GF, Parsy-Kowalska CB, Allen J, McElveen J, Robertson C, Sewell HF, Chapman CJ, Robertson JFR. Application of a high throughput method of biomarker discovery to improvement of the EarlyCDT(®)-Lung Test. PLoS One 2012; 7:e51002. [PMID: 23272083 PMCID: PMC3521770 DOI: 10.1371/journal.pone.0051002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Accepted: 10/29/2012] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND The National Lung Screening Trial showed that CT screening for lung cancer led to a 20% reduction in mortality. However, CT screening has a number of disadvantages including low specificity. A validated autoantibody assay is available commercially (EarlyCDT®-Lung) to aid in the early detection of lung cancer and risk stratification in patients with pulmonary nodules detected by CT. Recent advances in high throughput (HTP) cloning and expression methods have been developed into a discovery pipeline to identify biomarkers that detect autoantibodies. The aim of this study was to demonstrate the successful clinical application of this strategy to add to the EarlyCDT-Lung panel in order to improve its sensitivity and specificity (and hence positive predictive value, (PPV)). METHODS AND FINDINGS Serum from two matched independent cohorts of lung cancer patients were used (n = 100 and n = 165). Sixty nine proteins were initially screened on an abridged HTP version of the autoantibody ELISA using protein prepared on small scale by a HTP expression and purification screen. Promising leads were produced in shake flask culture and tested on the full assay. These results were analyzed in combination with those from the EarlyCDT-Lung panel in order to provide a set of re-optimized cut-offs. Five proteins that still displayed cancer/normal differentiation were tested for reproducibility and validation on a second batch of protein and a separate patient cohort. Addition of these proteins resulted in an improvement in the sensitivity and specificity of the test from 38% and 86% to 49% and 93% respectively (PPV improvement from 1 in 16 to 1 in 7). CONCLUSION This is a practical example of the value of investing resources to develop a HTP technology. Such technology may lead to improvement in the clinical utility of the EarlyCDT--Lung test, and so further aid the early detection of lung cancer.
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Yao Y, Fan Y, Wu J, Wan H, Wang J, Lam S, Lam WL, Girard L, Gazdar AF, Wu Z, Zhou Q. Potential application of non-small cell lung cancer-associated autoantibodies to early cancer diagnosis. Biochem Biophys Res Commun 2012; 423:613-9. [PMID: 22713465 PMCID: PMC4512951 DOI: 10.1016/j.bbrc.2012.06.050] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2012] [Accepted: 06/10/2012] [Indexed: 10/28/2022]
Abstract
To identify a panel of tumor associated autoantibodies which can potentially be used as biomarkers for the early diagnosis of non-small cell lung cancer (NSCLC). Thirty-five unique and in-frame expressed phage proteins were isolated. Based on the gene expression profiling, four proteins were selected for further study. Both receiver operating characteristic curve analysis and leave-one-out method revealed that combined measurements of four antibodies produced have better predictive accuracies than any single marker alone. Leave-one-out validation also showed significant relevance with all stages of NSCLC patients. The panel of autoantibodies has a high potential for detecting early stage NSCLC.
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Affiliation(s)
- Yibing Yao
- Tianjin Lung Cancer Institute, Tianjin General Hospital, Tianjin Medical University, Tianjin 300070, China
- Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Yu Fan
- Tianjin Lung Cancer Institute, Tianjin General Hospital, Tianjin Medical University, Tianjin 300070, China
| | - Jun Wu
- Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Haisu Wan
- Tianjin Lung Cancer Institute, Tianjin General Hospital, Tianjin Medical University, Tianjin 300070, China
| | - Jing Wang
- Tianjin Lung Cancer Institute, Tianjin General Hospital, Tianjin Medical University, Tianjin 300070, China
| | - Stephen Lam
- British Columbia Cancer Research Centre, Vancouver, BC, Canada V5Z 1L3
| | - Wan L. Lam
- British Columbia Cancer Research Centre, Vancouver, BC, Canada V5Z 1L3
| | - Luc Girard
- Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Adi F. Gazdar
- Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Zhihao Wu
- Tianjin Lung Cancer Institute, Tianjin General Hospital, Tianjin Medical University, Tianjin 300070, China
| | - Qinghua Zhou
- Tianjin Lung Cancer Institute, Tianjin General Hospital, Tianjin Medical University, Tianjin 300070, China
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Desmetz C, Mange A, Maudelonde T, Solassol J. Autoantibody signatures: progress and perspectives for early cancer detection. J Cell Mol Med 2012; 15:2013-24. [PMID: 21651719 PMCID: PMC4394213 DOI: 10.1111/j.1582-4934.2011.01355.x] [Citation(s) in RCA: 100] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Becoming invasive is a crucial step in cancer development, and the early spread of tumour cells is usually undetected by current imaging technologies. In patients with cancer and no signs of overt metastases, sensitive methods have been developed to identify circulating autoantibodies and their antigen counterparts in several cancers. These technologies are often based on proteomic approaches, and recent advances in protein and antibody microarrays have greatly facilitated the discovery of new antibody biomarkers in sera from cancer patients. Interestingly, in a clinical application setting, combinations of multiple autoantibody reactivities into panel assays have recently been proposed as relevant screening tests and validated in several independent trials. In addition, autoantibody signatures seem to be particularly relevant for early detection of cancer in high-risk cancer patients. In this review, we highlight the concept that immunogenic epitopes associated with the humoural response and key pathogenic pathways elicit serum autoantibodies that can be considered as relevant cancer biomarkers. We outline the proteomic strategies employed to identify and validate their use in clinical practice for cancer screening and diagnosis. We particularly emphasize the clinical utility of autoantibody signatures in several cancers. Finally, we discuss the challenges remaining for clinical validation.
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Affiliation(s)
- C Desmetz
- CHU Montpellier, Laboratoire de biologie cellulaire et hormonale, Hôpital Arnaud de Villeneuve, Montpellier, France
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18
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Shih NY, Lai HL, Chang GC, Lin HC, Wu YC, Liu JM, Liu KJ, Tseng SW. Anti-alpha-enolase autoantibodies are down-regulated in advanced cancer patients. Jpn J Clin Oncol 2010; 40:663-9. [PMID: 20395242 DOI: 10.1093/jjco/hyq028] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVE Elevation of serum autoantibodies to alpha-enolase (ENO1) is often seen in inflammation diseases. However, it is unclear whether the levels of serum ENO1 autoantibodies could be affected during tumor progression. Hence, we attempted to determine the relative serum ENO1 autoantibody levels in healthy individuals and various stages of patients with lung and breast cancers. METHODS Sera were obtained from 99 normal individuals, 21 patients with non-cancer-associated diseases and 178 cancer patients, including Stage I, II and IV non-small cell lung cancer, small cell lung cancer and breast cancer. The ENO1 autoantibody levels were determined by enzyme-linked immunosorbent assay. RESULTS Compared with the healthy individuals, the levels of ENO1 autoantibodies were significantly decreased in Stage IV non-small cell lung cancer, small cell lung cancer and breast cancer patients. Consistently, this phenomenon was also observed in tumor-grafted mice. Using logistic regression analyses, data show that the titer status of ENO1 autoantibody level is highly associated with the late stage of lung and breast cancers when compared with those of healthy controls. In contrast, there were no statistic differences between healthy controls and early stages of non-small cell lung cancer patients, and total amounts of serum immunoglobulin A, immunoglobulin G and immunoglobulin M levels in Stage IV non-small cell lung cancer patients were not significantly distinct from those of the healthy controls. Thus, the decreased ENO1 autoantibody event in malignant stage of cancer patients is not contributed by reduction in total immunoglobulin. CONCLUSIONS Marked decrease in the basal level of serum ENO1 autoantibodies is a common malignant event of lung and breast cancers, suggesting that ENO1 autoantibody may serve as a prognostic marker to monitor the disease progression of these cancer patients.
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Affiliation(s)
- Neng-Yao Shih
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
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Tan HT, Low J, Lim SG, Chung MCM. Serum autoantibodies as biomarkers for early cancer detection. FEBS J 2009; 276:6880-904. [DOI: 10.1111/j.1742-4658.2009.07396.x] [Citation(s) in RCA: 243] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Desmetz C, Maudelonde T, Mangé A, Solassol J. Identifying autoantibody signatures in cancer: a promising challenge. Expert Rev Proteomics 2009; 6:377-86. [PMID: 19681673 DOI: 10.1586/epr.09.56] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Biomarkers that show high sensitivity and specificity are needed for the early diagnosis and prognosis of cancer. An immune response to cancer is elicited in humans, as demonstrated, in part, by the identification of autoantibodies against a number of tumor-associated antigen (TAAs) in sera from patients with different types of cancer. Identification of TAAs and their cognate autoantibodies is a promising strategy for the discovery of relevant biomarkers. During the past few years, three proteomic approaches, including serological identification of antigens by recombinant expression cloning (SEREX), serological proteome analysis (SERPA) and, more recently, protein microarrays, have been the dominant strategies used to identify TAAs and their cognate autoantibodies. In this review, we aim to describe the advantages, drawbacks and recent improvements of these approaches for the study of humoral responses. Finally, we discuss the definition of autoantibody signatures to improve sensitivity for the development of clinically relevant tests.
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Affiliation(s)
- Caroline Desmetz
- CHU Montpellier, Laboratoire de Biologie Cellulaire et Hormonale, Hôpital Arnaud de Villeneuve, 371 Avenue du Doyen Giraud, Montpellier, F-34295, France.
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Desmetz C, Cortijo C, Mangé A, Solassol J. Humoral response to cancer as a tool for biomarker discovery. J Proteomics 2009; 72:982-8. [PMID: 19539066 DOI: 10.1016/j.jprot.2009.06.004] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2009] [Revised: 06/03/2009] [Accepted: 06/05/2009] [Indexed: 01/08/2023]
Abstract
There is an important need to find relevant biomarkers that show high sensitivity and specificity for early diagnosis and prognosis of cancer. An immune response to cancer is elicited in humans, as demonstrated in part by the identification of autoantibodies against a number of tumor-associated antigens in sera from patients with different types of cancer. Identification of tumor-associated antigens and their cognate autoantibodies is a promising strategy for the discovery of relevant biomarkers. During the past few years, proteomic approaches, including SEREX, SERPA and, more recently, protein microarrays, have been the dominant strategies used to identify tumor-associated antigens and their cognate autoantibodies. In this review, we aim to describe advantages, drawbacks, and recent improvements of these approaches for the study of humoral responses.
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Affiliation(s)
- C Desmetz
- CHU Montpellier, Hôpital Arnaud de Villeneuve, Laboratoire de biologie cellulaire et hormonale, Montpellier, France
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Desmetz C, Mangé A, Solassol J. Étude de la réaction immunitaire humorale aux cancers par des approches protéomiques. Med Sci (Paris) 2008; 24:1071-6. [DOI: 10.1051/medsci/200824121071] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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Gunawardana CG, Diamandis EP. High throughput proteomic strategies for identifying tumour-associated antigens. Cancer Lett 2007; 249:110-9. [PMID: 17306453 DOI: 10.1016/j.canlet.2007.01.002] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2006] [Accepted: 01/04/2007] [Indexed: 10/23/2022]
Abstract
Tumours elicit an immune response in the host organism and this area has been studied for decades. Initially, tumour-associated antigens were studied by examining a few proteins at a time using techniques such as 1-D SDS-PAGE and sandwich ELISAs. Now, however, with the development of high-throughput strategies, multiple potential antigens in a single experiment could be uncovered. The prevailing view is that these antigens can be used as biosensors for cancers. In addition, some of these antigens may indeed be used as targets for immunotherapy. SEREX, SERPA, and protein microarray technology have been the three dominant strategies employed to identify tumour-associated antigens. In this mini-review, we aim to describe these three techniques and provide their advantages and disadvantages. In addition, we aim to address some of the challenges of cancer immunomics.
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Affiliation(s)
- C Geeth Gunawardana
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ont., Canada
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Razani-Boroujerdi S, Sopori ML. Early manifestations of NNK-induced lung cancer: role of lung immunity in tumor susceptibility. Am J Respir Cell Mol Biol 2006; 36:13-9. [PMID: 16873770 PMCID: PMC1899301 DOI: 10.1165/rcmb.2005-0330oc] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
A strong correlation exists between smoking and lung cancer; however, susceptibility to lung cancer among smokers is not uniform. Similarly, mice show differential susceptibility to the tobacco carcinogen nitrosamine 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which produces lung tumors in A/J but not in C3H mice. Host immunity may play a role in the susceptibility to cancer, and cigarette smoke/nicotine suppresses the immune system through activation of nicotinic acetylcholine receptors (nAChRs). Mammalian lungs express alpha7-nAChRs, and NNK is a high-affinity agonist for alpha7-nAChRs. To examine whether NNK differentially modulates lung immunity in susceptible and resistant mouse strains, A/J and C3H mice were treated with NNK and/or immunized with sheep red blood cells. Lung tissues and RNA of treated and untreated animals were analyzed by immunohistochemistry and RT-PCR for alpha7-nAChR and COX-2 expression. Spleen- and the lung-associated lymph node cells from control and immunized animals were assessed for immunologic responses, including anti-sheep red blood cell antibody plaque-forming cells, concanavalin A-induced T-cell proliferation, and the anti-CD3/CD28 antibody-induced rise in intracellular calcium. NNK strongly suppressed these responses in A/J but not in C3H mice. Similar NNK-induced immunologic changes were seen in another pair of carcinogen-sensitive (NGP) and relatively carcinogen-resistant (B10.A) mouse strains. Moreover, NNK stimulates a significantly higher expression of COX-2 and alpha7-nAChRs in A/J than in C3H lungs. These results suggest that the susceptibility to chemical carcinogenesis among various mouse strains might be influenced by their immunologic response to the carcinogen.
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Wu TY, Fleischmann WR. Efficacy of B16 melanoma cells exposed in vitro to long-term IFN-alpha treatment (B16alpha cells) as a tumor vaccine in mice. J Interferon Cytokine Res 1998; 18:829-39. [PMID: 9809618 DOI: 10.1089/jir.1998.18.829] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
B16 melanoma cells exposed to >2 weeks of in vitro interferon-alpha (IFN-alpha) treatment (B16alpha cells) were UV inactivated and used for vaccination. This vaccination was efficacious against challenge with parental B16 cells in the absence of adjuvant therapy. Vaccinations based on parental cells and B16 cells exposed to short-term in vitro IFN-alpha treatment were not effective. The efficacy of B16alpha vaccination was evaluated using three B16 tumor models. Using intraperitoneal (i.p.) tumor challenge given after vaccination, vaccination efficacy depended on the concentration of IFN-alpha to which B16alpha cells were exposed, the number of inactivated B16alpha cells inoculated, the number of inoculations administered, and the amount of tumor burden. A significant fraction (30%) of vaccinated mice surviving initial challenge had durable immunity against a second parental tumor challenge. This immunity increased to 92% with administration of a single booster vaccination. Using metastatic tumor challenge given after vaccination, vaccination reduced lung metastases by approximately 67%. Using vaccination begun 3 days after subcutaneous (s.c.) tumor challenge, regression of established tumor occurred when vaccination was given i.p. (39%) or contralaterally s.c. (53%). Taken together, the results suggest that vaccination with inactivated B16alpha cells may serve as a model for induction of host tumor immunity against primary or secondary tumors.
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Affiliation(s)
- T Y Wu
- Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston 77555, USA
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Fleischmann CM, Wu TY, Fleischmann WR. B16 melanoma cells exposed in vitro to long-term IFN-alpha treatment (B16 alpha cells) as activators of tumor immunity in mice. J Interferon Cytokine Res 1997; 17:37-43. [PMID: 9041470 DOI: 10.1089/jir.1997.17.37] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Mice inoculated with B16 melanoma cells exposed to long-term in vitro IFN-alpha treatment (> or = 14 days, B16 alpha cells) but not short-term in vitro IFN-alpha treatment (24 h) exhibited an enhanced survival time. Enhanced survival time also occurred when inactivated B16 alpha cells were inoculated at the same time as live B16 cells. Further, an even greater improvement in survival time was observed when the inactivated B16 alpha cells were inoculated before live B16 cell challenge. No enhancement in survival time was observed when mice were inoculated with inactivated, untreated B16 cells. Enhancement of survival time by B16 alpha cells was unrelated to retrovirus surface antigen expression. Long-lasting protective immunity to B16 cells was observed in mice that survived B16 alpha cell, but not normal B16 cell, challenge and subsequent IFN treatment. It is evident that inoculation with inactivated B16 alpha cells, but not with inactivated untreated B16 cells, was able to prolong significantly the survival time of mice either simultaneously or subsequently challenged with live B16 cells. Additionally, survival of B16 alpha-inoculated but not B16-inoculated mice was accompanied by a durable immunity. Inoculation of inactivated B16 alpha cells may serve as a model for the induction of host immunity to a parental primary or secondary tumor.
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Affiliation(s)
- C M Fleischmann
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston 77555, USA
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Abstract
It has been observed that in human breast cancer transposition of the greater omentum to cover the excision site after removal of recurrent tumor appears to inhibit further recurrences at the site, without affecting spread to other sites. To establish an experimental model of this, inbred rats were transplanted in two sites on the chest with pieces of either an epithelioma or a mammary tumor. A flap of the omentum was then drawn through the peritoneal wall and then secured over one of the implants. In one group, this omentoplasty was carried out 1 week after tumor implantation. In most rats, the tumor in contact with the omentum was actually larger than the control, in contrast to the clinical observations. In many animals, the omentum was also a route of metastasis of the tumor.
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Pearson HJ, Anderson J, Chamberlain J, Bell PR. The effect of Kupffer cell stimulation or depression on the development of liver metastases in the rat. Cancer Immunol Immunother 1986; 23:214-6. [PMID: 3024833 PMCID: PMC11038908 DOI: 10.1007/bf00205652] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/1986] [Accepted: 07/08/1986] [Indexed: 01/03/2023]
Abstract
Tumour cells from a squamous carcinoma (approximately 2.5 X 10(5)) were injected intraportally into a syngeneic strain of rats to produce liver metastases 14 days later. Kupffer cells were stimulated by Corynebacterium parvum (7 mg or 1 mg i.v.) and zymosan (10 mg intraportally). Kupffer cell activity was depressed by the administration of silica, gadolinium chloride or human red cells. The animals in each group were sacrificed at 14 days, the livers removed and the number of visible surface metastases counted and compared. (Mann-Whitney U-test). Kupffer cell stimulation significantly reduced the number of surface liver metastases in all animals (P 0.0048). In contrast depression of Kupffer cell activity significantly increased the number of metastases in all animals (P 0.0045), suggesting that the activity of these cells has an important effect on the development of liver metastases.
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Zöller M. Evaluation of in vivo and in vitro effectivity of immune defense against a spontaneously arising, nonlymphoid rat tumor. II. T cell response after induction of immunogenicity. Cancer Immunol Immunother 1985; 19:189-97. [PMID: 2408743 PMCID: PMC11039298 DOI: 10.1007/bf00199225] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/1984] [Accepted: 01/09/1985] [Indexed: 12/31/2022]
Abstract
It was evaluated in vitro whether it is possible to induce immunogenicity by haptenization of a nonlymphoid rat tumor, BSp6AS, which is known to be antigenic, but non-immunogenic, in the syngeneic host. The effectivity of 'induced immunogenicity' was tested in vivo. BSp6AS, an NK- and macrophage-resistant variant of a spontaneously arising fibrosarcoma in the BDX rat strain, does not induce a primary or a secondary T cell response after in vivo or in vitro priming. This deficiency in cytotoxic response is due solely to failure of activation of helper T cells (TH), since (a) cytotoxic T cells (CTL) can be detected after in vitro stimulation in the presence of interleukin 2 (IL-2)-containing medium; and (b) there are no indications for down-regulation of a potential specific immune response by suppressor T cells (TS). The lack of activation of tumor-specific TH can be bypassed by activation of hapten-specific TH. Upon coculture with haptenized tumor cells as a stimulator population, both hapten-specific and tumor-specific CTL are activated by hapten-specific TH. In line with the findings in vitro, no transplant rejection of naive tumor cells was seen after a variety of immunization schedules. But immunized F1 hybrids did reject tumor grafts, supporting the hypothesis of lacking help in the syngeneic situation. This could be confirmed in the syngeneic system by adoptive transfer experiments. Tumor-specific CTL, educated in vitro in the presence of IL-2, were ineffective. But complete protection against haptenized, and partial protection against native tumor cells was achieved in the additional presence of hapten-specific TH. To our knowledge these experiments prove for the first time that hapten-specific TH are efficient in inducing an immune response even against a nonlymphoid, nonimmunogenic tumor, i.e., it is possible (a) to activate tumor-specific CTL and (b) to initiate tumor graft rejection via hapten-specific TH.
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Zöller M. Evaluation of in vivo and in vitro effectivity of immune defense against a spontaneously arising, nonlymphoid rat tumor. I. Analysis of natural immune defense. Cancer Immunol Immunother 1985; 19:183-8. [PMID: 3847288 PMCID: PMC11039115 DOI: 10.1007/bf00199224] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/1984] [Accepted: 01/09/1985] [Indexed: 01/07/2023]
Abstract
Possible mechanisms of natural defense against a nonimmunogenic, nonlymphoid rat tumor were evaluated in vitro and examined for effectivity in vivo, using BSp6S, the subcutaneously grown transplantation line of a spontaneously arising fibrosarcoma in the BDX rat strain, which is highly susceptible to natural killer (NK) cells and macrophages (Mø). The role of nonspecific immune defense in vivo was demonstrated by eliminating NK cells by irradiation and Mø by silica treatment. Especially after depletion of NK cells a significant acceleration of tumor growth and a reduction in the number of cells required for tumor takes was observed. Activation of Mø by Corynebacterium parvum (CP) did lead to retardation of tumor growth; prevention of tumor growth was only achieved after inoculation of a marginal dose of tumor cells. Activation of NK cells was of minor influence. It is concluded that NK cells and Mø are the main influences on survival time, the effectiveness of NK cells being limited to early periods of tumor growth.
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Bursuker I, North RJ. Generation and decay of the immune response to a progressive fibrosarcoma. II. Failure to demonstrate postexcision immunity after the onset of T cell-mediated suppression of immunity. J Exp Med 1984; 159:1312-21. [PMID: 6232336 PMCID: PMC2187291 DOI: 10.1084/jem.159.5.1312] [Citation(s) in RCA: 63] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
This study shows that surgical removal of the meth A fibrosarcoma from its semisyngeneic host fails to result in postexcision immunity to growth of a tumor implant unless the host already has acquired a mechanism of concomitant immunity to growth of an implant. Therefore, tumor excision does not cause immunity to be generated but preserves a mechanism of concomitant immunity that already exists and which otherwise would eventually undergo down-regulation under the influence of suppressor T cells. Removal of the tumor after it has grown large enough to cause the T cell-mediated suppression of concomitant immunity does not result in the reemergence of immunity. Instead, the host remains unable to generate concomitant immunity to a second tumor for a long period of time and retains, for at least 31 d, suppressor T cells able to passively transfer suppression to appropriate recipients. Like the suppressor T cells responsible for active suppression of concomitant immunity, the suppressor T cells responsible for "memory" suppression are of the Ly-1+2- phenotype. The results indicate that progressive tumor growth results in a state of immunological tolerance of tumor-specific, transplantation antigens that can persist in the apparent absence of tumor antigens.
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Zöller M, Matzku S. Solid tumor-derived target cell susceptibility to macrophages and natural killer/natural cytotoxic cells in the rat. Immunobiology 1983; 164:349-60. [PMID: 6603412 DOI: 10.1016/s0171-2985(83)80031-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Cytotoxic capacity of rat macrophages (M phi) and natural killer (NK)/natural cytotoxic cells (NC) against adherent growing, solid tumor-derived target cells was evaluated, modulating the activation status of effector cells and growth conditions of target cells. Testing a panel of target cells, cytotoxicity of NK/NC and M phi was strikingly correlated so that besides of target-cell binding structures basic lysability seems to be of influence with respect to cytotoxicity rates. Varying the in vivo growth conditions of target cells altered their lysability by M phi and NK/NC cells in the sense that ascitic versus subcutaneously (sc) grown tumors were more resistant to lysis. On the other hand, in vitro culturing did not influence susceptibility for M phi, but with some tumor lines increased lysis by NK/NC cells was observed. In the rat, the activation status of M phi and NC was not age-dependent, and NK cell activity only declined slowly with age. But cytotoxic potential of M phi obviously presents a strain characteristic, different from NK/NC cell activity, only the latter two correlating in different rat strains. Experiments to augment natural cytotoxic capacity revealed that application of Corynebacterium parvum (CP) activated M phi and NK/NC cells, while sc tumor implantation only resulted in increased NK/NC cell cytotoxicity, leaving M phi unaltered.
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Abstract
The application of immunologic methods to the treatment of neoplasia has been a goal of research in tumor immunology. Unfortunately, no clearly defined success for such therapy has been achieved. However, the most recent advances in tumor biology have provided for a more valid conceptual framework upon which to plan further research in this area. The more general awareness of tumor progression and heterogeneity, particularly in the context of tumor metastasis, while imposing a sense of gloom regarding all therapeutic modalities, shifted immunologic thinking toward the development of nonspecific modalities. We herein propose that this 'shift' may be premature and that immunotherapy using cytolygic T cells could still be feasible. Our views are based on newer approaches for selecting immunogenic variants of malignant tumors and a better understanding of the relationship of the immune response to metastases.
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Iglehart JD, Weinhold KJ, Ward EC, Matthews TJ, Langlois AJ, Schäfer W, Bolognesi DP. Prospects for the immunological management of lethal tumors. Cancer Invest 1983; 1:409-21. [PMID: 6365274 DOI: 10.3109/07357908309048509] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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Chandradasa KD, Blears J. Studies with a spontaneous murine tumour--II. Transformation of non-inhibitory lymph node cells (LNC) of tumour bearers into tumour inhibitor cells in vitro. EUROPEAN JOURNAL OF CANCER & CLINICAL ONCOLOGY 1982; 18:1063-8. [PMID: 6891649 DOI: 10.1016/0277-5379(82)90084-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Syngeneic BALB/c mice repeatedly pre-exposed to mitomycin-c-treated cells of a 'spontaneous' tumour SP/N-1 failed to develop resistance against the same tumour when tested by cell transfer assays. No difference could be observed between tumour-bearer, tumour-pretreated or normal donor LNC, or spleen cells by this assay system. When tumour-bearer LNC were cultured in vitro for 45 hr in the absence of tumour cells, these LNC generated a relatively strong ability to suppress tumour outgrowth in vivo following cell transfers. The tumour suppression appears to be due to tumour cell destruction since observation over four months or more in some experiments failed to reveal the presence of tumours at the site of inoculation. These findings clearly demonstrate that naturally arising tumours so often considered as devoid of, or weak in, tumour-associated transplantation antigens (TATA) may not necessarily be so. Despite the fact that the syngeneic host may be capable of recognizing TATA as foreign, the immune response initiated may not progress to completion in at least a proportion of these tumour-host systems. The defect appears to reside in the failure of differentiation of the pre-effector cells into the mature effector form. We interpret this as being due to a strong activation of certain inhibitors of essential lymphokine mediators such as interleukin 2, needed for differentiation and expansion of effector cell clones. It remains to be seen whether the mechanism of non-responsiveness or weakness of the response against many other members of this category of tumours--the 'spontaneous' or natural tumours--can be explained on the same basis as that of the SP/N-1 system studied here.
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Zöller M, Matzku S. Mechanisms of cellular cytotoxicity mediated by effector cells from rats with spontaneous tumors. Int J Cancer 1982; 30:181-5. [PMID: 7129672 DOI: 10.1002/ijc.2910300209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
We have previously shown that effector cells from BD X rats bearing spontaneous tumors display increased cytotoxicity towards syngeneic tumor cells compared to effector cells from untreated rats (Zöller and Matzku, 1980 a). The increased in vitro cytotoxicity of lymphoid cells from tumor-bearing (TB) animals was not T-cell mediated and the question was raised, whether it was due solely to increased natural killer (NK) cell activity, or whether humoral factors could also be involved. We now prove that in a long-term assay, the presence of B cells is indeed mainly responsible for increased TB cytotoxicity, since: (1) After depletion of surface immunoglobulin positive cells (s-Ig+), TB cytotoxicity no longer exceeds cytotoxicity of effector cells from untreated rats; (2) Mixtures of s-Ig+ cells from TB animals with Fc-receptor positive (Fc-R+) cells from untreated rats restore the increased TB cytotoxicity; (3) Addition of rabbit Fab' anti rat F(ab')2 reduces TB-effector cell cytoxicity. A minor contribution of the increased TB cytotoxicity by activation/numerical increase of NK cells will be discussed.
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Chalmers PJ, Pullen GR, Nind AP, Nairn RC. Position-dependent cell survival and the microcytotoxicity assay. J Immunol Methods 1982; 51:81-8. [PMID: 7108230 DOI: 10.1016/0022-1759(82)90384-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
For microcytotoxicity, when numbers of effector or target cells are limited, the method of Takasugi and Klein (1970) is at present the most convenient way of assessing cytotoxicity. In this procedure, target cell survival is affected by minor variations in culture conditions or washing vigour and the variations may be greater in some areas of the plate than in others, notably at the sides and especially the corners. A randomized block design for allotment of treatments to the plate is less affected by these position effects than the conventional row by row design. Statistical significance of acquired data may then be assessed by two-way analysis of variance, which is more sensitive than Student's t test in these circumstances. The use of the randomized procedure for the microcytotoxicity assay is strongly recommended.
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Flannery GR, Brooks CG. Quantitative studies of natural immunity to solid tumours in rats. NK activity in animals with primary or transplanted spontaneous tumours. Int J Cancer 1981; 28:747-55. [PMID: 7333706 DOI: 10.1002/ijc.2910280614] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Natural killer (NK) cell activity was measured in a quantitative 6 h chromium release assay using sarcoma MC7 cells as targets. The total NK lytic activity present in the spleen and blood of tumour-bearing animals was compared with the corresponding values for age/sex/parity-matched animals. Rats with primary spontaneous tumours in the breast or subcutaneous sites showed normal levels of NK activity, while rats with primary spontaneous kidney tumours had elevated NK activity, the degree of augmentation being greater with increasing tumour size. A similar elevation of NK activity was generally found in animals with large, transplanted, spontaneous or chemically-induced tumours. This augmentation could only detected when total lytic activity was considered: when NK activity was measured merely on a cell-for-cell basis, it often appeared to be depressed in such animals, in agreement with previous reports. However, with one rapidly metastasizing spontaneous tumour, a real depression of both spleen and blood NK activity was found. Small inocula of cells from non-immunogenic spontaneous mammary tumours or from other non-immunogenic spontaneous tumours caused no early increase in systemic NK activity when injected into the mammary pad, a site where spontaneous tumours frequently arise. However, cells from one immunogenic spontaneous tumour and 2/3 immunogenic chemically-induced tumours did occasionally stimulate significant early increases in NK activity when placed at this site. Early changes in peritoneal exudate NK activity were also investigated using small inocula of these tumours injected intraperitoneally. Augmentation of NK activity occurred with a 3-fold greater frequency following inoculation with immunogenic tumour cells than with non-immunogenic cells in this system. It can be concluded from these studies that: (1) spontaneous tumours do not selectively arise in members of an inbred strain with subnormal NK activity; (2) most large tumours in rats stimulate rather than depress NK activity; (3) early boosting of NK activity by small inocula of tumour cells placed in the mammary pad does not occur with non-immunogenic spontaneous tumours; (4) early boosting of NK activity in the peritoneal site does occur with non-immunogenic tumours, but with a very low frequency. The latter findings suggest that developing spontaneous tumours are unlikely to stimulate the NK system, and emphasize the importance of using syngeneic, spontaneous tumours for studying tumour-host relationships in animals.
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Yarkoni E, Rapp HJ. Regression by active specific immunotherapy of established dermal tumor transplants and lymph node metastases in guinea pigs. Infect Immun 1981; 31:514-6. [PMID: 7216457 PMCID: PMC351814 DOI: 10.1128/iai.31.1.514-516.1981] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Guinea pigs, each with an established, syngeneic dermal tumor (line-10) and microscopic lymph node metastasis, were treated by intradermal inoculation of living line-10 tumor cells admixed with emulsified heat-killed Mycobacterium bovis BCG cells. This treatment caused complete regression of established dermal tumors (about 10 mm in diameter) and prevented the growth of microscopic lymph node metastases in 25 of 39 treated animals (64%). All control animals treated by intradermal inoculation with heat-killed M. bovis BCG cells attached to oil droplets died with progressive dermal and lymphatic tumor growth.
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Abstract
Attempts were made to induce immunity to 5 spontaneous rat sarcomas transplanted into syngeneic recipients. Rats were immunized by surgical removal of growing tumour transplants or by treatment with attenuated tumour, followed by challenge with tumour cells in suspension. Two tumours wee apparently not immunogenic, but a low level of immunity was induced against 2, and weak evidence of immunity was observed with another. Induced immunity was individually specific rather than cross-reactive. It is concluded that, contrary to some reports, some spontaneous animal tumours are immunogenic in the strain of origin.
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Brown DG, Wagner JC, Wagner MM. Failure to demonstrate tumour-associated transplantation antigens on asbestos-induced mesotheliomas in rats. Br J Cancer 1980; 42:797-801. [PMID: 7459217 PMCID: PMC2010543 DOI: 10.1038/bjc.1980.316] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
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Hay KA, Lausch RN. Uninhibited growth and metastases of herpes simplex virus-transformed cells in virus-sensitized hosts. Int J Cancer 1979; 23:337-43. [PMID: 86519 DOI: 10.1002/ijc.2910230311] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Four established tumour lines of hamster cells transformed by herpes simplex virus (HSV) but not shedding the virus were examined for continued expression of virus-associated antigens. Hamster or rabbits, appropriately immunized to the tumour cells, produced virus-neutralizing antibody. The serum titres were invariably low, suggesting that only small quantities of virion antigen were present in the cells. Hamster sensitized to HSV and resistant to virulent virus challenge did not reject low numbers of tumour cells, nor was the incidence of lung metastases significantly reduced. Virus-sensitized lymph-node cells, readily cytotoxic for HSV-infected hamster embryo fibroblasts, did not lyse any of three transformed lines tested in an 18-h 51chromium release test. Animals that had their tumour excised demonstrated no or only modest resistance to tumour rechallenge. Thus, virus-specific transplantation rejection antigen could not be detected in the HSV tumour lines although low levels of virus structural antigens were present.
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Pimm MV, Cook AJ, Hopper DG, Dickinson AM, Baldwin RW. BCG treatment of transplanted rat tumours of spontaneous origin. Int J Cancer 1978; 22:426-32. [PMID: 700898 DOI: 10.1002/ijc.2910220410] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Six transplanted rat tumours (three mammary carcinomas and three fibrosarcomas), all of spontaneous origin and of limited immunogenicity, have been examined for susceptibility to immunotherapy with BCG (Glaxo). Growth of limited numbers of cells from five tumours was suppressed when cells were injected subcutaneously in admixture with BCG organisms. There was no clear correlation between the immunogenicity of tumour lines and their susceptibility to regionally applied BCG. Active specific immunotherapy, using vaccines of viable or radiation-attenuated tumour cells in admixture with BCG, was reproducibly successful with only one tumour, the mammary carcinoma Sp4, this being the most immunogenic of the tumours examined. These studies indicate that naturally arising tumours are less susceptible to BCG-mediated suppression than carcinogen-induced tumours widely used for experimental immunotherapy, but indicate that local application of BCG may give the best therapeutic response.
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Pimm MV, Cook AJ, Baldwin RW. Failure of neuraminidase treatment to influence tumorigenicity or immunogenicity of syngeneically transplanted rat tumour cells. Eur J Cancer 1978; 14:869-78. [PMID: 689056 DOI: 10.1016/0014-2964(78)90103-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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