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Ren XH, Guo T, Xu MF, Huang Y, Liao XR, Qi LJ, Cheng SX. A Multiple Targeting Genome Editing System for Remodulation of Circulating Malignant Cells to Eliminate Cancer Immunosuppression and Restore Immune Responses. Adv Healthc Mater 2025; 14:e2401223. [PMID: 39440615 DOI: 10.1002/adhm.202401223] [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: 05/01/2024] [Revised: 09/29/2024] [Indexed: 10/25/2024]
Abstract
Cancer immunotherapy, which aims to eliminate cancer immunosuppression and reactivate anticancer immunity, holds great promise in oncology treatments. However, it is challenging to accurately study the efficacy of immunotherapy based on human-derived cells through animal experiments due to xenogeneic immune rejection. Herein, a personalized and precise strategy to evaluate the effectiveness of immunotherapy using the blood samples of cancer patients is presented. Through the utilization of multiple cancer-targeting delivery system decorated with the epidermal growth factor receptor (EGFR)-specific aptamer CL4 and the AXL-specific aptamer GL21.T to achieve superior efficiency in delivering the genome editing plasmid for MUC1 knockout, effective modulation on the behavior of circulating malignant cells (CMCs) is realized. After genome editing, both mucin 1 (MUC1) and programmed death-ligand 1 (PD-L1) are significantly downregulated in CMCs. The elimination of immunosuppression results in markedly enhanced secretion of pro-inflammatory anticancer cytokines encompassing interleukins 2, 12, and 15 and interferon-γ by immune cells. The study not only provides a strategy to overcome immunosuppression but also yields critical insights for personalized immunotherapy approaches.
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Affiliation(s)
- Xiao-He Ren
- School of Life Sciences, Anhui Medical University, Hefei, Anhui, 230011, China
- College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei, 430072, China
| | - Tao Guo
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Anhui Medical University, Anhui Public Health Clinical Center, Hefei, Anhui, 230011, China
| | - Ma-Fei Xu
- School of Life Sciences, Anhui Medical University, Hefei, Anhui, 230011, China
| | - Yun Huang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Anhui Public Health Clinical Center, Hefei, Anhui, 230011, China
| | - Xin-Ru Liao
- College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei, 430072, China
| | - Li-Jin Qi
- College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei, 430072, China
| | - Si-Xue Cheng
- College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei, 430072, China
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Lillehoj EP, Yu Y, Verceles AC, Imamura A, Ishida H, Piepenbrink KH, Goldblum SE. Stenotrophomonas maltophilia provokes NEU1-mediated release of a flagellin-binding decoy receptor that protects against lethal infection. iScience 2024; 27:110866. [PMID: 39314239 PMCID: PMC11418149 DOI: 10.1016/j.isci.2024.110866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 08/03/2024] [Accepted: 08/29/2024] [Indexed: 09/25/2024] Open
Abstract
Stenotrophomonas maltophilia (Sm), a multidrug-resistant pathogen often isolated from immunocompromised individuals, presents its flagellin to multimeric tandem repeats within the ectodomain of mucin-1 (MUC1-ED), expressed on airway epithelia. Flagellated Sm increases neuraminidase-1 (NEU1) sialidase association with and desialylation of MUC1-ED. This NEU1-mediated MUC1-ED desialylation unmasks cryptic binding sites for Sm flagellin, increasing flagellin and Sm binding to airway epithelia. MUC1 overexpression increases receptor number whereas NEU1 overexpression elevates receptor binding affinity. Silencing of either MUC1 or NEU1 reduces the flagellin-MUC1 interaction. Sm/flagellin provokes MUC1-ED autoproteolysis at a juxtamembranous glycine-serine peptide bond. MUC1-ED shedding from the epithelium not only occurs in vitro, but in the bronchoalveolar compartments of Sm/flagellin-challenged mice and patients with ventilator-associated Sm pneumonia. Finally, the soluble flagellin-targeting, MUC1-ED decoy receptor dose-dependently inhibits multiple Sm flagellin-driven pathogenic processes, in vitro, including motility, biofilm formation, adhesion, and proinflammatory cytokine production, and protects against lethal Sm lung infection, in vivo.
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Affiliation(s)
- Erik P. Lillehoj
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Yafan Yu
- Department of Biochemistry, University of Nebraska, Lincoln, NE, USA
| | - Avelino C. Verceles
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Akihiro Imamura
- Institute for Glyco-core Research (iGCORE), Gifu University, Gifu, Japan
| | - Hideharu Ishida
- Institute for Glyco-core Research (iGCORE), Gifu University, Gifu, Japan
| | - Kurt H. Piepenbrink
- Department of Biochemistry, University of Nebraska, Lincoln, NE, USA
- Department of Food Science and Technology, University of Nebraska, Lincoln, NE, USA
- Department of Chemistry, University of Nebraska, Lincoln, NE, USA
| | - Simeon E. Goldblum
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
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Mahamad Apandi NI, Chan SW, Toh YF. Differential Expression of Mucin in Salivary Gland Tumours. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:920. [PMID: 38929537 PMCID: PMC11205441 DOI: 10.3390/medicina60060920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 05/28/2024] [Accepted: 05/28/2024] [Indexed: 06/28/2024]
Abstract
Background and Objectives: Mucin has been implicated via various mechanisms in the development and growth of tumour cells. However, mucin expression studies in salivary gland tumours are limited, especially with samples from minor salivary glands. This study aims to investigate and compare mucin expression in benign and malignant salivary gland tumours of minor and major salivary gland origins. Materials and Methods: Special stains were used to stain neutral mucin (Periodic acid Schiff), sialomucin (Alcian Blue) and sulfomucin (Aldehyde Fuschin) within tissues from six normal salivary glands and 73 salivary gland tumours including 31 pleomorphic adenomas, 27 mucoepidermoid carcinomas, and 15 adenoid cystic carcinomas. A semi-quantitative approach was used to evaluate mucin expression within ductal lumens. Sialomucin was the most expressed mucin in all salivary gland tumours, regardless of origin. Results: A significant difference was observed in the mucin expression between benign and malignant salivary gland tumours, as pleomorphic adenoma showed three times significantly higher expression of sialomucin compared to mucoepidermoid carcinoma and adenoid cystic carcinoma (p = 0.028). Pleomorphic adenomas of major glands showed 42 times significantly higher expression of sialomucin compared to those of minor glands (p = 0.000). Conclusions: Sialomucin content in pleomorphic adenomas of major glands was vastly increased compared to that in minor glands. Differential sialomucin expression in benign and malignant salivary gland tumours suggests a role in diagnosing of borderline salivary gland tumours.
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Affiliation(s)
| | - Siew Wui Chan
- Fakulti Pergigian, Universiti Malaya, Kuala Lumpur 50603, Malaysia;
| | - Yen Fa Toh
- Jabatan Patologi, Pusat Perubatan Universiti Malaya, Kuala Lumpur 50603, Malaysia;
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Kembuan GJ, Kim JY, Maus MV, Jan M. Targeting solid tumor antigens with chimeric receptors: cancer biology meets synthetic immunology. Trends Cancer 2024; 10:312-331. [PMID: 38355356 PMCID: PMC11006585 DOI: 10.1016/j.trecan.2024.01.003] [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: 12/05/2022] [Revised: 01/02/2024] [Accepted: 01/05/2024] [Indexed: 02/16/2024]
Abstract
Chimeric antigen receptor (CAR) T cell therapy is a medical breakthrough in the treatment of B cell malignancies. There is intensive focus on developing solid tumor-targeted CAR-T cell therapies. Although clinically approved CAR-T cell therapies target B cell lineage antigens, solid tumor targets include neoantigens and tumor-associated antigens (TAAs) with diverse roles in tumor biology. Multiple early-stage clinical trials now report encouraging signs of efficacy for CAR-T cell therapies that target solid tumors. We review the landscape of solid tumor target antigens from the perspective of cancer biology and gene regulation, together with emerging clinical data for CAR-T cells targeting these antigens. We then discuss emerging synthetic biology strategies and their application in the clinical development of novel cellular immunotherapies.
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Affiliation(s)
- Gabriele J Kembuan
- Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, USA; Harvard Medical School, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Joanna Y Kim
- Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, USA; Harvard Medical School, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Marcela V Maus
- Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
| | - Max Jan
- Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, USA; Harvard Medical School, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
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Li YR, Halladay T, Yang L. Immune evasion in cell-based immunotherapy: unraveling challenges and novel strategies. J Biomed Sci 2024; 31:5. [PMID: 38217016 PMCID: PMC10785504 DOI: 10.1186/s12929-024-00998-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 01/02/2024] [Indexed: 01/14/2024] Open
Abstract
Cell-based immunotherapies (CBIs), notably exemplified by chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy, have emerged as groundbreaking approaches for cancer therapy. Nevertheless, akin to various other therapeutic modalities, tumor cells employ counterstrategies to manifest immune evasion, thereby circumventing the impact of CBIs. This phenomenon is facilitated by an intricately immunosuppression entrenched within the tumor microenvironment (TME). Principal mechanisms underpinning tumor immune evasion from CBIs encompass loss of antigens, downregulation of antigen presentation, activation of immune checkpoint pathways, initiation of anti-apoptotic cascades, and induction of immune dysfunction and exhaustion. In this review, we delve into the intrinsic mechanisms underlying the capacity of tumor cells to resist CBIs and proffer prospective stratagems to navigate around these challenges.
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Affiliation(s)
- Yan-Ruide Li
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
| | - Tyler Halladay
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Lili Yang
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
- Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
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Nakahama K, Izumi M, Yoshimoto N, Fukui M, Sugimoto A, Nagamine H, Ogawa K, Sawa K, Tani Y, Kaneda H, Mitsuoka S, Watanabe T, Asai K, Kawaguchi T. Clinical significance of KL-6 in immune-checkpoint inhibitor treatment for non-small cell lung cancer. Cancer Chemother Pharmacol 2023; 92:381-390. [PMID: 37606723 DOI: 10.1007/s00280-023-04573-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 07/29/2023] [Indexed: 08/23/2023]
Abstract
PURPOSE Krebs von den Lungen-6 (KL-6) functions as a tumor marker, as well as a diagnostic tool for interstitial pneumonia (IP). However, the significance of KL-6 in the immune-checkpoint inhibitor (ICI) treatment of non-small cell lung cancer (NSCLC), especially in patients without IP, is unknown. METHODS This multicenter, retrospective study, which included patients with advanced NSCLC who received ICI therapy, analyzed the association between serum KL-6 values and ICI efficacy and the association between serum KL-6 values and ICI-induced interstitial lung disease (ILD) occurrence, focusing primarily on patients without IP. RESULTS In total, 322 patients had available KL-6 values before ICI therapy. Among 202 patients without IP who received ICI monotherapy, the high-KL-6 group (≥ 500 U/mL) showed significantly shorter progression-free survival (PFS) and overall survival (OS) than the low-KL-6 group (< 500 U/mL) (median: 2.1 vs. 3.6 months, p = 0.048; median: 9.2 vs. 14.5 months, p = 0.035). There was no significant difference in response rate between the KL-6 high and low groups (19% vs. 29%, p = 0.14). In the multivariate analysis, high KL-6 was a significant predictor of poor PFS (hazard ratio [HR], 1.52; 95% confidence interval [CI] 1.10-2.11, p = 0.012) and OS (HR, 1.51; 95% CI 1.07 - 2.13, p = 0.019) for patients treated with ICI monotherapy. There was no significant difference in the occurrence rate of ILD between the high KL-6 and low KL-6 groups in patients with (20% vs. 15%, p = 1.00) or without IP (12% vs. 12%, p = 1.00). CONCLUSION In ICI monotherapy for NSCLC without IP, elevated serum KL-6 levels were associated with poorer outcomes.
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Affiliation(s)
- Kenji Nakahama
- Department of Respiratory Medicine, Graduate School of Medicine, Osaka Metropolitan University, Asahimachi 1-4-3, Abeno-ku, Osaka City, Osaka, 545-8585, Japan.
| | - Motohiro Izumi
- Department of Pulmonary Medicine, Bell Land General Hospital, Sakai, Japan
| | - Naoki Yoshimoto
- Department of Pulmonary Medicine, Ishikiriseiki Hospital, Higashiosaka, Japan
| | - Mitsuru Fukui
- Department of Laboratory of Statistics, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Akira Sugimoto
- Department of Respiratory Medicine, Graduate School of Medicine, Osaka Metropolitan University, Asahimachi 1-4-3, Abeno-ku, Osaka City, Osaka, 545-8585, Japan
| | - Hiroaki Nagamine
- Department of Respiratory Medicine, Graduate School of Medicine, Osaka Metropolitan University, Asahimachi 1-4-3, Abeno-ku, Osaka City, Osaka, 545-8585, Japan
| | - Koichi Ogawa
- Department of Respiratory Medicine, Graduate School of Medicine, Osaka Metropolitan University, Asahimachi 1-4-3, Abeno-ku, Osaka City, Osaka, 545-8585, Japan
| | - Kenji Sawa
- Department of Respiratory Medicine, Graduate School of Medicine, Osaka Metropolitan University, Asahimachi 1-4-3, Abeno-ku, Osaka City, Osaka, 545-8585, Japan
| | - Yoko Tani
- Department of Clinical Oncology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Hiroyasu Kaneda
- Department of Clinical Oncology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Shigeki Mitsuoka
- Department of Clinical Oncology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Tetsuya Watanabe
- Department of Respiratory Medicine, Graduate School of Medicine, Osaka Metropolitan University, Asahimachi 1-4-3, Abeno-ku, Osaka City, Osaka, 545-8585, Japan
| | - Kazuhisa Asai
- Department of Respiratory Medicine, Graduate School of Medicine, Osaka Metropolitan University, Asahimachi 1-4-3, Abeno-ku, Osaka City, Osaka, 545-8585, Japan
| | - Tomoya Kawaguchi
- Department of Respiratory Medicine, Graduate School of Medicine, Osaka Metropolitan University, Asahimachi 1-4-3, Abeno-ku, Osaka City, Osaka, 545-8585, Japan
- Department of Clinical Oncology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
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Dragon AC, Beermann LM, Umland M, Bonifacius A, Malinconico C, Ruhl L, Kehler P, Gellert J, Weiß L, Mayer-Hain S, Zimmermann K, Riese S, Thol F, Beutel G, Maecker-Kolhoff B, Yamamoto F, Blasczyk R, Schambach A, Hust M, Hudecek M, Eiz-Vesper B. CAR-Ts redirected against the Thomsen-Friedenreich antigen CD176 mediate specific elimination of malignant cells from leukemia and solid tumors. Front Immunol 2023; 14:1219165. [PMID: 37915564 PMCID: PMC10616308 DOI: 10.3389/fimmu.2023.1219165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 09/28/2023] [Indexed: 11/03/2023] Open
Abstract
Introduction Chimeric antigen receptor-engineered T cells (CAR-Ts) are investigated in various clinical trials for the treatment of cancer entities beyond hematologic malignancies. A major hurdle is the identification of a target antigen with high expression on the tumor but no expression on healthy cells, since "on-target/off-tumor" cytotoxicity is usually intolerable. Approximately 90% of carcinomas and leukemias are positive for the Thomsen-Friedenreich carbohydrate antigen CD176, which is associated with tumor progression, metastasis and therapy resistance. In contrast, CD176 is not accessible for ligand binding on healthy cells due to prolongation by carbohydrate chains or sialylation. Thus, no "on-target/off-tumor" cytotoxicity and low probability of antigen escape is expected for corresponding CD176-CAR-Ts. Methods Using the anti-CD176 monoclonal antibody (mAb) Nemod-TF2, the presence of CD176 was evaluated on multiple healthy or cancerous tissues and cells. To target CD176, we generated two different 2nd generation CD176-CAR constructs differing in spacer length. Their specificity for CD176 was tested in reporter cells as well as primary CD8+ T cells upon co-cultivation with CD176+ tumor cell lines as models for CD176+ blood and solid cancer entities, as well as after unmasking CD176 on healthy cells by vibrio cholerae neuraminidase (VCN) treatment. Following that, both CD176-CARs were thoroughly examined for their ability to initiate target-specific T-cell signaling and activation, cytokine release, as well as cytotoxicity. Results Specific expression of CD176 was detected on primary tumor tissues as well as on cell lines from corresponding blood and solid cancer entities. CD176-CARs mediated T-cell signaling (NF-κB activation) and T-cell activation (CD69, CD137 expression) upon recognition of CD176+ cancer cell lines and unmasked CD176, whereby a short spacer enabled superior target recognition. Importantly, they also released effector molecules (e.g. interferon-γ, granzyme B and perforin), mediated cytotoxicity against CD176+ cancer cells, and maintained functionality upon repetitive antigen stimulation. Here, CD176L-CAR-Ts exhibited slightly higher proliferation and mediator-release capacities. Since both CD176-CAR-Ts did not react towards CD176- control cells, their response proved to be target-specific. Discussion Genetically engineered CD176-CAR-Ts specifically recognize CD176 which is widely expressed on cancer cells. Since CD176 is masked on most healthy cells, this antigen and the corresponding CAR-Ts represent a promising approach for the treatment of various blood and solid cancers while avoiding "on-target/off-tumor" cytotoxicity.
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Affiliation(s)
- Anna Christina Dragon
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School (MHH), Hannover, Germany
| | - Luca Marie Beermann
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School (MHH), Hannover, Germany
| | - Melina Umland
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School (MHH), Hannover, Germany
| | - Agnes Bonifacius
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School (MHH), Hannover, Germany
| | - Chiara Malinconico
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School (MHH), Hannover, Germany
| | - Louisa Ruhl
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School (MHH), Hannover, Germany
| | | | | | | | | | - Katharina Zimmermann
- Institute of Experimental Hematology, Hannover Medical School (MHH), Hannover, Germany
| | - Sebastian Riese
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School (MHH), Hannover, Germany
| | - Felicitas Thol
- Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School (MHH), Hannover, Germany
| | - Gernot Beutel
- Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School (MHH), Hannover, Germany
| | - Britta Maecker-Kolhoff
- Department of Pediatric Hematology and Oncology, Hannover Medical School (MHH), Hannover, Germany
| | | | - Rainer Blasczyk
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School (MHH), Hannover, Germany
| | - Axel Schambach
- Institute of Experimental Hematology, Hannover Medical School (MHH), Hannover, Germany
| | - Michael Hust
- Department of Medical Biotechnology, Technical University of Braunschweig, Braunschweig, Germany
| | - Michael Hudecek
- Department of Internal Medicine II, University Hospital of Würzburg, Wuerzburg, Germany
| | - Britta Eiz-Vesper
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School (MHH), Hannover, Germany
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Bruni S, Mercogliano MF, Mauro FL, Cordo Russo RI, Schillaci R. Cancer immune exclusion: breaking the barricade for a successful immunotherapy. Front Oncol 2023; 13:1135456. [PMID: 37284199 PMCID: PMC10239871 DOI: 10.3389/fonc.2023.1135456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 05/10/2023] [Indexed: 06/08/2023] Open
Abstract
Immunotherapy has changed the course of cancer treatment. The initial steps were made through tumor-specific antibodies that guided the setup of an antitumor immune response. A new and successful generation of antibodies are designed to target immune checkpoint molecules aimed to reinvigorate the antitumor immune response. The cellular counterpart is the adoptive cell therapy, where specific immune cells are expanded or engineered to target cancer cells. In all cases, the key for achieving positive clinical resolutions rests upon the access of immune cells to the tumor. In this review, we focus on how the tumor microenvironment architecture, including stromal cells, immunosuppressive cells and extracellular matrix, protects tumor cells from an immune attack leading to immunotherapy resistance, and on the available strategies to tackle immune evasion.
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A phase I study of an adenoviral vector delivering a MUC1/CD40-ligand fusion protein in patients with advanced adenocarcinoma. Nat Commun 2022; 13:6453. [PMID: 36307410 PMCID: PMC9616917 DOI: 10.1038/s41467-022-33834-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 10/05/2022] [Indexed: 12/25/2022] Open
Abstract
Cancer vaccines as immunotherapy for solid tumours are currently in development with promising results. We report a phase 1 study of Ad-sig-hMUC1/ecdCD40L (NCT02140996), an adenoviral-vector vaccine encoding the tumour-associated antigen MUC1 linked to CD40 ligand, in patients with advanced adenocarcinoma. The primary objective of this study is safety and tolerability. We also study the immunome in vaccinated patients as a secondary outcome. This trial, while not designed to determine clinical efficacy, reports an exploratory endpoint of overall response rate. The study meets its pre-specified primary endpoint demonstrating safety and tolerability in a cohort of 21 patients with advanced adenocarcinomas (breast, lung and ovary). The maximal dose of the vaccine is 1 ×1011 viral particles, with no dose limiting toxicities. All drug related adverse events are of low grades, most commonly injection site reactions in 15 (71%) patients. Using exploratory high-dimensional analyses, we find both quantitative and relational changes in the cancer immunome after vaccination. Our data highlights the utility of high-dimensional analyses in understanding and predicting effective immunotherapy, underscoring the importance of immune competency in cancer prognosis.
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Potential Use of CTCs as Biomarkers in Renal Cancer Patients. LIFE (BASEL, SWITZERLAND) 2022; 12:life12010089. [PMID: 35054482 PMCID: PMC8779819 DOI: 10.3390/life12010089] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/22/2021] [Accepted: 01/07/2022] [Indexed: 12/02/2022]
Abstract
We demonstrated that the CellCollector is an appropriate tool for detecting CTCs in RCC patients. We examined EpCAM and MUC1 expression levels in RCC tissues and cell lines and analyzed the detection rate of CTCs in blood samples ex vivo using an anti-EpCAM antibody-covered straight or spiraled CellCollector. Eight matched samples were examined for affinity to the anti-EpCAM vs. anti-EpCAM/anti-MUC1 antibody-covered wire. The use of this combination of antibodies allowed us to classify patients with lung metastasis. Finally, four patients were analyzed in vivo. In conclusion, both straight (ex vivo, in vivo) and spiraled (ex vivo) wires detected CTCs.
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Kumar AR, Devan AR, Nair B, Nair RR, Nath LR. Biology, Significance and Immune Signaling of Mucin 1 in Hepatocellular Carcinoma. Curr Cancer Drug Targets 2022; 22:725-740. [PMID: 35301949 DOI: 10.2174/1568009622666220317090552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 12/14/2021] [Accepted: 12/21/2021] [Indexed: 02/08/2023]
Abstract
Mucin 1 (MUC 1) is a highly glycosylated tumor-associated antigen (TAA) overexpressed in hepatocellular carcinoma (HCC). This protein plays a critical role in various immune-mediated signaling pathways at its transcriptional and post-transcriptional levels, leading to immune evasion and metastasis in HCC. HCC cells maintain an immune-suppressive environment with the help of immunesuppressive tumor-associated antigens, resulting in a metastatic spread of the disease. The development of intense immunotherapeutic strategies to target tumor-associated antigen is critical to overcoming the progression of HCC. MUC 1 remains the most recognized tumor-associated antigen since its discovery over 30 years ago. A few promising immunotherapies targeting MUC 1 are currently under clinical trials, including CAR-T and CAR-pNK-mediated therapies. This review highlights the biosynthesis, significance, and clinical implication of MUC 1 as an immune target in HCC.
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Affiliation(s)
- Ayana R Kumar
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi-682041, Kerala, India
| | - Aswathy R Devan
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi-682041, Kerala, India
| | - Bhagyalakshmi Nair
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi-682041, Kerala, India
| | | | - Lekshmi R Nath
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi-682041, Kerala, India
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Dhasmana A, Dhasmana S, Kotnala S, A A, Kashyap VK, Shaji PD, Laskar P, Khan S, Pellicano R, Fagoonee S, Haque S, Yallapu MM, Chauhan SC, Jaggi M. A topography of immunotherapies against gastrointestinal malignancies. Panminerva Med 2021; 64:56-71. [PMID: 34664484 DOI: 10.23736/s0031-0808.21.04541-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Gastrointestinal (GI) cancers are one of the leading causes of death worldwide. Although various approaches are implemented to improve the health condition of GI patients, none of the treatment protocols promise for eradicating cancer. However, a treatment mechanism against any kind of disease condition is already existing executing inside the human body. The 'immune system' is highly efficient to detect and destroy the unfavourable events of the body including tumor cells. The immune system can restrict the growth and proliferation of cancer. Cancer cells behave much smarter and adopt new mechanisms for hiding from the immune cells. Thus, cancer immunotherapy might play a decisive role to train the immune system against cancer. In this review, we have discussed the immunotherapy permitted for the treatment of GI cancers. We have discussed various methods and mechanisms, periodic development of cancer immunotherapies, approved biologicals, completed and ongoing clinical trials, role of various biopharmaceuticals, and epigenetic factors involved in GI cancer immunotherapies (graphical abstract Figure 1).
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Affiliation(s)
- Anupam Dhasmana
- Department of Immunology and Microbiology, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX, USA.,South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA.,Department of Biosciences and Cancer Research Institute, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Dehradun, India
| | - Swati Dhasmana
- Department of Immunology and Microbiology, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX, USA.,South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Sudhir Kotnala
- Department of Immunology and Microbiology, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX, USA.,South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Anukriti A
- Department of Biosciences, School of Liberal Arts and Sciences, Mody University, Lakshamgarh, Rajasthan, India
| | - Vivek K Kashyap
- Department of Immunology and Microbiology, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX, USA.,South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Poornima D Shaji
- Department of Immunology and Microbiology, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Partha Laskar
- Department of Immunology and Microbiology, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX, USA.,South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Sheema Khan
- Department of Immunology and Microbiology, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX, USA.,South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | | | - Sharmila Fagoonee
- Institute of Biostructure and Bioimaging (CNR), Molecular Biotechnology Center, Turin, Italy
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia.,Bursa Uludağ University Faculty of Medicine, Görükle Campus, Nilüfer, Bursa, Turkey
| | - Murali M Yallapu
- Department of Immunology and Microbiology, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX, USA.,South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Subhash C Chauhan
- Department of Immunology and Microbiology, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX, USA.,South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Meena Jaggi
- Department of Immunology and Microbiology, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX, USA - meena.jaggi @utrgv.edu.,South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
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13
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Lee DH, Choi S, Park Y, Jin HS. Mucin1 and Mucin16: Therapeutic Targets for Cancer Therapy. Pharmaceuticals (Basel) 2021; 14:ph14101053. [PMID: 34681277 PMCID: PMC8537522 DOI: 10.3390/ph14101053] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 01/18/2023] Open
Abstract
The mucin (MUC) family is a group of highly glycosylated macromolecules that are abundantly expressed in mammalian epithelial cells. MUC proteins contribute to the formation of the mucus barrier and thus have protective functions against infection. Interestingly, some MUC proteins are aberrantly expressed in cancer cells and are involved in cancer development and progression, including cell growth, proliferation, the inhibition of apoptosis, chemoresistance, metabolic reprogramming, and immune evasion. With their unique biological and structural features, MUC proteins have been considered promising therapeutic targets and also biomarkers for human cancer. In this review, we discuss the biological roles of the transmembrane mucins MUC1 and MUC16 in the context of hallmarks of cancer and current efforts to develop MUC1- and MUC16-targeted therapies.
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Affiliation(s)
- Dong-Hee Lee
- Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea;
| | - Seunghyun Choi
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea;
| | - Yoon Park
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea;
- Correspondence: (Y.P.); (H.-s.J.)
| | - Hyung-seung Jin
- Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea;
- Correspondence: (Y.P.); (H.-s.J.)
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14
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Hot or cold: Bioengineering immune contextures into in vitro patient-derived tumor models. Adv Drug Deliv Rev 2021; 175:113791. [PMID: 33965462 DOI: 10.1016/j.addr.2021.05.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/02/2021] [Accepted: 05/04/2021] [Indexed: 02/06/2023]
Abstract
In the past decade, immune checkpoint inhibitors (ICI) have proven to be tremendously effective for a subset of cancer patients. However, it is difficult to predict the response of individual patients and efforts are now directed at understanding the mechanisms of ICI resistance. Current models of patient tumors poorly recapitulate the immune contexture, which describe immune parameters that are associated with patient survival. In this Review, we discuss parameters that influence the induction of different immune contextures found within tumors and how engineering strategies may be leveraged to recapitulate these contextures to develop the next generation of immune-competent patient-derived in vitro models.
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15
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Anderluh M, Berti F, Bzducha-Wróbel A, Chiodo F, Colombo C, Compostella F, Durlik K, Ferhati X, Holmdahl R, Jovanovic D, Kaca W, Lay L, Marinovic-Cincovic M, Marradi M, Ozil M, Polito L, Reina JJ, Reis CA, Sackstein R, Silipo A, Švajger U, Vaněk O, Yamamoto F, Richichi B, van Vliet SJ. Recent advances on smart glycoconjugate vaccines in infections and cancer. FEBS J 2021; 289:4251-4303. [PMID: 33934527 PMCID: PMC9542079 DOI: 10.1111/febs.15909] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 04/09/2021] [Accepted: 04/30/2021] [Indexed: 01/01/2023]
Abstract
Vaccination is one of the greatest achievements in biomedical research preventing death and morbidity in many infectious diseases through the induction of pathogen-specific humoral and cellular immune responses. Currently, no effective vaccines are available for pathogens with a highly variable antigenic load, such as the human immunodeficiency virus or to induce cellular T-cell immunity in the fight against cancer. The recent SARS-CoV-2 outbreak has reinforced the relevance of designing smart therapeutic vaccine modalities to ensure public health. Indeed, academic and private companies have ongoing joint efforts to develop novel vaccine prototypes for this virus. Many pathogens are covered by a dense glycan-coat, which form an attractive target for vaccine development. Moreover, many tumor types are characterized by altered glycosylation profiles that are known as "tumor-associated carbohydrate antigens". Unfortunately, glycans do not provoke a vigorous immune response and generally serve as T-cell-independent antigens, not eliciting protective immunoglobulin G responses nor inducing immunological memory. A close and continuous crosstalk between glycochemists and glycoimmunologists is essential for the successful development of efficient immune modulators. It is clear that this is a key point for the discovery of novel approaches, which could significantly improve our understanding of the immune system. In this review, we discuss the latest advancements in development of vaccines against glycan epitopes to gain selective immune responses and to provide an overview on the role of different immunogenic constructs in improving glycovaccine efficacy.
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Affiliation(s)
- Marko Anderluh
- Faculty of Pharmacy, Faculty of Pharmacy, Chair of Pharmaceutical Chemistry, University of Ljubljana, Slovenia
| | | | - Anna Bzducha-Wróbel
- Department of Biotechnology and Food Microbiology, Warsaw University of Life Sciences-SGGW, Warszawa, Poland
| | - Fabrizio Chiodo
- Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, The Netherlands.,Institute of Biomolecular Chemistry (ICB), Italian National Research Council (CNR), Pozzuoli, Italy
| | - Cinzia Colombo
- Department of Chemistry and CRC Materiali Polimerici (LaMPo), University of Milan, Italy
| | - Federica Compostella
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milano, Italy
| | - Katarzyna Durlik
- Department of Microbiology and Parasitology, Jan Kochanowski University, Kielce, Poland
| | - Xhenti Ferhati
- Department of Chemistry 'Ugo Schiff', University of Florence, Sesto Fiorentino, Italy
| | - Rikard Holmdahl
- Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
| | - Dragana Jovanovic
- Vinča Institute of Nuclear Sciences - National Institute of thе Republic of Serbia, University of Belgrade, Serbia
| | - Wieslaw Kaca
- Department of Microbiology and Parasitology, Jan Kochanowski University, Kielce, Poland
| | - Luigi Lay
- Department of Chemistry and CRC Materiali Polimerici (LaMPo), University of Milan, Italy
| | - Milena Marinovic-Cincovic
- Vinča Institute of Nuclear Sciences - National Institute of thе Republic of Serbia, University of Belgrade, Serbia
| | - Marco Marradi
- Department of Chemistry 'Ugo Schiff', University of Florence, Sesto Fiorentino, Italy
| | - Musa Ozil
- Faculty of Arts and Sciences, Department of Chemistry, Recep Tayyip Erdogan University, Rize, Turkey
| | - Laura Polito
- National Research Council, CNR-SCITEC, Milan, Italy
| | - Josè Juan Reina
- Departamento de Química Orgánica, Universidad de Málaga-IBIMA, Spain.,Andalusian Centre for Nanomedicine and Biotechnology-BIONAND, Parque Tecnológico de Andalucía, Málaga, Spain
| | - Celso A Reis
- I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal.,IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Portugal
| | - Robert Sackstein
- Department of Translational Medicine, Translational Glycobiology Institute, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
| | - Alba Silipo
- Department of Chemical Sciences, University of Naples Federico II, Complesso Universitario Monte Sant'Angelo, Napoli, Italy
| | - Urban Švajger
- Blood Transfusion Center of Slovenia, Ljubljana, Slovenia
| | - Ondřej Vaněk
- Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic
| | - Fumiichiro Yamamoto
- Immunohematology & Glycobiology Laboratory, Josep Carreras Leukaemia Research Institute, Badalona, Spain
| | - Barbara Richichi
- Department of Chemistry 'Ugo Schiff', University of Florence, Sesto Fiorentino, Italy
| | - Sandra J van Vliet
- Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, The Netherlands
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16
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Zhang Y, Dong X, Bai L, Shang X, Zeng Y. MUC1-induced immunosuppression in colon cancer can be reversed by blocking the PD1/PDL1 signaling pathway. Oncol Lett 2020; 20:317. [PMID: 33133253 PMCID: PMC7590440 DOI: 10.3892/ol.2020.12180] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 08/20/2020] [Indexed: 12/14/2022] Open
Abstract
Mucin1 (MUC1) upregulation in colon cancer has been linked to poor patient outcomes and advanced stage at diagnosis. This is partially due to MUC1-mediated inhibition of T-cell proliferation affecting efficient lysis by cytotoxic lymphocytes, which contributes to escape from immune surveillance. In the present study, human colorectal cancer tissues were collected, and MUC1-positive and MUC1-negative colon cancer mouse models were prepared; subsequently, the number and function of immune cells in tumor tissues were measured using flow cytometry. The present study revealed that MUC1, as a tumor-associated antigen, can recruit more tumor-infiltrating lymphocytes into the tumor microenvironment compared with MUC1-negative colon cancer, but that these cells could not serve antitumor roles. Conversely, the present study demonstrated that MUC1-positive colon cancer attracted more regulatory T cells (Treg cells), myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) to the tumor site than MUC1-negative colon cancer. Furthermore, the data suggested that programmed death protein 1 (PD1)-programmed death ligand 1 (PDL1) expression is greater in MUC1-positive colon cancer. Blocking the PD1-PDL1 signaling pathway reduced the percentage of Treg cells, MDSCs and TAMs in the tumor microenvironment, enhanced T-cell cytotoxicity and inhibited tumor growth, prolonging the survival time of MUC1-positive tumor-bearing mice. Therefore, the present study elucidated the role of MUC1 in tumor immune escape and provides a foundation for the application of PDL1 inhibitors to MUC1-positive colon cancer.
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Affiliation(s)
- Yinghui Zhang
- Department of Gastroenterology, The Fourth Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650021, P.R. China
| | - Xiangqian Dong
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Diseases, Kunming, Yunnan 650032, P.R. China
| | - Liping Bai
- Department of Gastroenterology, The Fourth Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650021, P.R. China
| | - Xueqin Shang
- Department of Medical Oncology, The Fourth Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650021, P.R. China
| | - Yujian Zeng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
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17
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Zhang S, Zhang W, Xiao Y, Qin T, Yue Y, Qian W, Shen X, Ma Q, Wang Z. Targeting MUC15 Protein in Cancer: Molecular Mechanisms and Therapeutic Perspectives. Curr Cancer Drug Targets 2020; 20:647-653. [PMID: 32479243 DOI: 10.2174/1568009620666200601140639] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 05/01/2020] [Accepted: 05/11/2020] [Indexed: 11/22/2022]
Abstract
MUC15, a member of the mucin family, is a heavily glycosylated transmembrane protein with the primary functions of lubricating surfaces, establishing a selective molecular barrier at the epithelium and mediating signal transduction. Aberrant expression of MUC15 plays a crucial role in the progression of multiple diseases, including malignant tumors. MUC15 has been identified as a tumor suppressor, but current evidence indicate its function as an oncogene in different types of cancers. MUC15 has been shown to be involved in the development of cancer and influence cellular growth, adhesion, invasion, metastasis and immune immunomodulation. However, the precise role of MUC15 in tumour development has not been thoroughly clarified. Here, we systematically summarize the structure and function of MUC15 in cancer, and discuss its potential role in cancer treatment.
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Affiliation(s)
- Simei Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China
| | - Wunai Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China
| | - Ying Xiao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China
| | - Tao Qin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China
| | - Yangyang Yue
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China
| | - Weikun Qian
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China
| | - Xin Shen
- Department of Anesthesiology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Qingyong Ma
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China
| | - Zheng Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China
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18
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Bhatia R, Gautam SK, Cannon A, Thompson C, Hall BR, Aithal A, Banerjee K, Jain M, Solheim JC, Kumar S, Batra SK. Cancer-associated mucins: role in immune modulation and metastasis. Cancer Metastasis Rev 2020; 38:223-236. [PMID: 30618016 DOI: 10.1007/s10555-018-09775-0] [Citation(s) in RCA: 159] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Mucins (MUC) protect epithelial barriers from environmental insult to maintain homeostasis. However, their aberrant overexpression and glycosylation in various malignancies facilitate oncogenic events from inception to metastasis. Mucin-associated sialyl-Tn (sTn) antigens bind to various receptors present on the dendritic cells (DCs), macrophages, and natural killer (NK) cells, resulting in overall immunosuppression by either receptor masking or inhibition of cytolytic activity. MUC1-mediated interaction of tumor cells with innate immune cells hampers cross-presentation of processed antigens on MHC class I molecules. MUC1 and MUC16 bind siglecs and mask Toll-like receptors (TLRs), respectively, on DCs promoting an immature DC phenotype that in turn reduces T cell effector functions. Mucins, such as MUC1, MUC2, MUC4, and MUC16, interact with or form aggregates with neutrophils, macrophages, and platelets, conferring protection to cancer cells during hematological dissemination and facilitate their spread and colonization to the metastatic sites. On the contrary, poor glycosylation of MUC1 and MUC4 at the tandem repeat region (TR) generates cancer-specific immunodominant epitopes. The presence of MUC16 neo-antigen-specific T cell clones and anti-MUC1 antibodies in cancer patients suggests that mucins can serve as potential targets for developing cancer therapeutics. The present review summarizes the molecular events involved in mucin-mediated immunomodulation, and metastasis, as well as the utility of mucins as targets for cancer immunotherapy and radioimmunotherapy.
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Affiliation(s)
- Rakesh Bhatia
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Shailendra K Gautam
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Andrew Cannon
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Christopher Thompson
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Bradley R Hall
- Department of Surgery, University of Nebraska Medical Center, Omaha, NE, USA
| | - Abhijit Aithal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Kasturi Banerjee
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA.,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Joyce C Solheim
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sushil Kumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA. .,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. .,Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
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19
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Agrawal B. New therapeutic targets for cancer: the interplay between immune and metabolic checkpoints and gut microbiota. Clin Transl Med 2019; 8:23. [PMID: 31468283 PMCID: PMC6715761 DOI: 10.1186/s40169-019-0241-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Accepted: 08/16/2019] [Indexed: 02/07/2023] Open
Abstract
Transformation and growth of tumor cells are associated with profound alterations in neighbouring cells and their environment, together forming the tumor microenvironment (TME). The TME provides a conducive but complex milieu for the tumors to thrive while incapacitating the immune cells that home there as part of our natural immunosurveillance mechanism. The orchestration of this successful survival strategy by tumor cells is associated with exploitation of numerous metabolic and immune checkpoints, as well as metabolic reprogramming in the tumor cells. Together these form an intricate network of feedback mechanisms that favor the growing tumor. In addition, an ecosystem of microbiota, proximal or distal to tumors, influences the successful survival or elimination of tumor cells mediated by immune cells. Discovery and clinical application of immune checkpoint inhibitors (ICIs) i.e., monoclonal antibodies (mAbs) blocking specific immune checkpoints CTLA-4 and PD-1/PD-L1, have revolutionized therapy of various cancers. However, they are still associated with limited response rates, severe immune-related adverse events, development of resistance, and more serious exacerbation of cancer progression termed hyper-progressive disease. Checkpoint inhibitors only represent a milestone and not the finish-line in the quest for treating and curing cancer. Efforts are underway to investigate and develop inhibitors of other immune as well as metabolic checkpoint molecules. Future therapy for various cancers is projected to target immune and metabolic checkpoints and the microbiota together.
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Affiliation(s)
- Babita Agrawal
- Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
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20
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Taverna C, Maggiore G, Cannavicci A, Bonomo P, Santucci M, Franchi A. Immunohistochemical profiling of mucins in sinonasal adenocarcinomas. Pathol Res Pract 2019; 215:152439. [DOI: 10.1016/j.prp.2019.152439] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 04/18/2019] [Accepted: 05/03/2019] [Indexed: 02/03/2023]
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21
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Dréau D, Moore LJ, Wu M, Roy LD, Dillion L, Porter T, Puri R, Momin N, Wittrup KD, Mukherjee P. Combining the Specific Anti-MUC1 Antibody TAB004 and Lip-MSA-IL-2 Limits Pancreatic Cancer Progression in Immune Competent Murine Models of Pancreatic Ductal Adenocarcinoma. Front Oncol 2019; 9:330. [PMID: 31114758 PMCID: PMC6503151 DOI: 10.3389/fonc.2019.00330] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 04/11/2019] [Indexed: 12/19/2022] Open
Abstract
Immunotherapy regimens have shown success in subsets of cancer patients; however, their efficacy against pancreatic ductal adenocarcinoma (PDA) remain unclear. Previously, we demonstrated the potential of TAB004, a monoclonal antibody targeting the unique tumor-associated form of MUC1 (tMUC1) in the early detection of PDA. In this study, we evaluated the therapeutic benefit of combining the TAB004 antibody with Liposomal-MSA-IL-2 in immune competent and human MUC1 transgenic (MUC1.Tg) mouse models of PDA and investigated the associated immune responses. Treatment with TAB004 + Lip-MSA-IL-2 resulted in significantly improved survival and slower tumor growth compared to controls in MUC1.Tg mice bearing an orthotopic PDA.MUC1 tumor. Similarly, in the spontaneous model of PDA that expresses human MUC1, the combination treatment stalled the progression of pancreatic intraepithelial pre-neoplastic (PanIN) lesion to adenocarcinoma. Treatment with the combination elicited a robust systemic and tumor-specific immune response with (a) increased percentages of systemic and tumor infiltrated CD45+CD11b+ cells, (b) increased levels of myeloperoxidase (MPO), (c) increased antibody-dependent cellular cytotoxicity/phagocytosis (ADCC/ADCP), (d) decreased percentage of immune regulatory cells (CD8+CD69+ cells), and (e) reduced circulating levels of immunosuppressive tMUC1. We report that treatment with a novel antibody against tMUC1 in combination with a unique formulation of IL-2 can improve survival and lead to stable disease in appropriate models of PDA by reducing tumor-induced immune regulation and promoting recruitment of CD45+CD11b+ cells, thereby enhancing ADCC/ADCP.
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Affiliation(s)
- Didier Dréau
- Department of Biological Sciences, UNC Charlotte, Charlotte, NC, United States
| | | | - Mike Wu
- OncoTab Inc., Charlotte, NC, United States
| | | | | | - Travis Porter
- Department of Biological Sciences, UNC Charlotte, Charlotte, NC, United States
| | - Rahul Puri
- OncoTab Inc., Charlotte, NC, United States
| | - Noor Momin
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - K Dane Wittrup
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - Pinku Mukherjee
- Department of Biological Sciences, UNC Charlotte, Charlotte, NC, United States.,OncoTab Inc., Charlotte, NC, United States
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22
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A first-in-human study of the novel metabolism-based anti-cancer agent SM-88 in subjects with advanced metastatic cancer. Invest New Drugs 2019; 38:392-401. [PMID: 30929156 PMCID: PMC7066285 DOI: 10.1007/s10637-019-00758-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 03/06/2019] [Indexed: 12/31/2022]
Abstract
Purpose SM-88 (D,L-alpha-metyrosine; racemetyrosine) is a novel anti-cancer agent, used with melanin, phenytoin, and sirolimus (SMK Therapy). This pilot first-in-human study characterized the safety, tolerability, and efficacy of SMK Therapy in subjects with advanced metastatic cancer. Methods All subjects (n = 30) received SMK Therapy for an initial 6 week Cycle (5 days on, 2 off per week) and continued if well tolerated. Safety signals, clinical response, overall survival, progression free survival (PFS), and quality of life changes were assessed. Results The most common drug related adverse events were hyperpigmentation and rash. All drug related adverse events were mild to moderate in intensity. Following treatment with SMK Therapy, 4 subjects achieved complete response, 6 partial response, and 17 stable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (total clinical benefit 90%). Responses were observed within 6 weeks, and continued to improve, with 3 complete and 3 partial responders achieving best response after at least 3.2 months. Durable stable disease was observed, lasting a median duration of 11 months (range 1–31 months). Median overall survival for all subjects was 29.8 months, and median PFS was 13 months. Following 6 weeks of treatment, most (83.3%) subjects showed an improvement in Eastern Cooperative Oncology Group (ECOG) score and an improvement in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ 30) global health status (baseline 61.2 ± 25.0; end of Cycle 1 80.7 ± 14.7; n = 29; p < 0.001). Conclusions The results of this study support continued development of SM-88.
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Saltos A, Khalil F, Smith M, Li J, Schell M, Antonia SJ, Gray JE. Clinical associations of mucin 1 in human lung cancer and precancerous lesions. Oncotarget 2018; 9:35666-35675. [PMID: 30479696 PMCID: PMC6235019 DOI: 10.18632/oncotarget.26278] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 10/06/2018] [Indexed: 12/18/2022] Open
Abstract
Mucin 1 (MUC1) is a cell membrane glycoprotein overexpressed in non-small cell lung cancer (NSCLC) and has been implicated in carcinogenesis of premalignant lung lesions. Thus, MUC1 has been a target of interest for vaccine strategies for lung cancer treatment and prevention. Here, we assessed MUC1 expression by immunohistochemistry using tumor samples from patients with biopsy-proven NSCLC. Levels of expression in areas of dysplasia, metaplasia, adenocarcinoma in situ, and carcinoma within the same tissue sample were characterized independently on a scale of 0-3 for paired comparison. We also assessed clinical data for correlations with MUC1 expression. Our analysis included 16 samples from patients with squamous lesions and 19 from patients with adenocarcinoma lesions. Among squamous lesions, MUC1 expression score was significantly increased in dysplastic compared with metaplastic areas (mean difference = 0.83, 95% confidence interval [CI], 0.21-infinity; P = 0.021). MUC1 expression was also increased among areas of squamous cell carcinoma versus dysplastic areas (mean difference = 0.44, 95% CI, -0.006-infinity; P = 0.052). In the adenocarcinoma lesions, MUC1 expression was increased in adenocarcinoma versus adenocarcinoma in situ, although not significantly (mean difference = 0.20, 95% CI, -0.055-infinity; P = 0.094). The increase in MUC1 expression with the progression of premalignant lung lesions to invasive carcinoma in patients with NSCLC supports MUC1 as a possible therapeutic target for the prevention and treatment of lung cancer.
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Affiliation(s)
- Andreas Saltos
- Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Farah Khalil
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Michelle Smith
- Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Jiannong Li
- Department of Biostatistics/Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Michael Schell
- Department of Biostatistics/Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Scott J Antonia
- Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Jhanelle E Gray
- Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
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Agrawal B, Gupta N, Konowalchuk JD. MUC1 Mucin: A Putative Regulatory (Checkpoint) Molecule of T Cells. Front Immunol 2018; 9:2391. [PMID: 30405607 PMCID: PMC6204366 DOI: 10.3389/fimmu.2018.02391] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Accepted: 09/26/2018] [Indexed: 01/30/2023] Open
Abstract
T lymphocytes are at the center of inducing an effective adaptive immune response and maintaining homeostasis. T cell responses are initiated through interactions between antigen presenting cells (APCs) and T cells. The type and strength of signals delivered through the T cell receptor (TCR) may modulate how the cells respond. The TCR-MHC (T cell receptor-major histocompatibility complex molecules) complex dictates the specificity, whereas co-stimulatory signals induced by interaction of various accessory cell surface molecules strengthen and optimize T cell responses. Multiple immune regulatory mechanisms brought about by co-inhibitory molecules expressed on T cells play a key role in orchestrating successful and non-damaging immunity. These co-inhibitory molecules are also referred to as initiators of immune check-points or co-inhibitory pathways. Knowledge of co-inhibitory pathways associated with activated T lymphocytes has allowed a better understanding of (a) the inflammatory and anti-inflammatory processes associated with infectious diseases and autoimmune diseases, and (b) mechanisms by which tumors evade immune attack. Many of these regulatory pathways are non-redundant and function in a highly concerted manner. Targeting them has provided effective approaches in treating cancer and autoimmune diseases. For this reason, it is valuable to identify any co-inhibitory molecules that affect these pathways. MUC1 mucin (CD227) has long been known to be expressed by epithelial cells and overexpressed by a multitude of adenocarcinomas. As long ago as 1998 we made a surprising discovery that MUC1 is also expressed by activated human T cells and we provided the first evidence of the role of MUC1 as a novel T cell regulator. Subsequent studies from different laboratories, as well as ours, supported an immuno-regulatory role of MUC1 in infections, inflammation, and autoimmunity that corroborated our original findings establishing MUC1 as a novel T cell regulatory molecule. In this article, we will discuss the experimental evidence supporting MUC1 as a putative regulatory molecule or a “checkpoint molecule” of T cells with implications as a novel biomarker and therapeutic target in chronic diseases such as autoimmunity, inflammation and cancer, and possibly infections.
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Affiliation(s)
- Babita Agrawal
- Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Nancy Gupta
- Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Jeffrey D Konowalchuk
- Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
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Cramer DW, Fichorova RN, Terry KL, Yamamoto H, Vitonis AF, Ardanaz E, Aune D, Boeing H, Brändstedt J, Boutron-Ruault MC, Chirlaque MD, Dorronsoro M, Dossus L, Duell EJ, Gram IT, Gunter M, Hansen L, Idahl A, Johnson T, Khaw KT, Krogh V, Kvaskoff M, Mattiello A, Matullo G, Merritt MA, Nodin B, Orfanos P, Onland-Moret NC, Palli D, Peppa E, Quirós JR, Sánchez-Perez MJ, Severi G, Tjønneland A, Travis RC, Trichopoulou A, Tumino R, Weiderpass E, Fortner RT, Kaaks R. Anti-CA15.3 and Anti-CA125 Antibodies and Ovarian Cancer Risk: Results from the EPIC Cohort. Cancer Epidemiol Biomarkers Prev 2018; 27:790-804. [PMID: 29661801 PMCID: PMC6309875 DOI: 10.1158/1055-9965.epi-17-0744] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 10/26/2017] [Accepted: 04/06/2018] [Indexed: 11/16/2022] Open
Abstract
Background: Neoplastic and non-neoplastic events may raise levels of mucins, CA15.3, and CA125, and generate antibodies against them, but their impact on epithelial ovarian cancer (EOC) risk has not been fully defined.Methods: CA15.3, CA125, and IgG1 antibodies against them were measured in 806 women who developed EOC and 1,927 matched controls from the European Prospective Investigation of Nutrition and Cancer. Associations between epidemiologic factors and anti-mucin antibodies were evaluated using generalized linear models; EOC risks associated with anti-mucin antibodies, by themselves or in combination with respective antigens, were evaluated using conditional logistic regression.Results: In controls, lower antibodies against both mucins were associated with current smoking; and, in postmenopausal women, higher levels with longer oral contraceptive use and later-age-at and shorter-interval-since last birth. Lower anti-CA15.3 antibodies were associated with higher body mass and, in premenopausal women, more ovulatory cycles. Higher anti-CA15.3 and anti-CA125 antibodies were associated with higher risk for mucinous EOC occurring ≥ 3 years from enrollment. Long-term risk for serous EOC was reduced in women with low CA125 and high anti-CA125 antibodies relative to women with low concentrations of both.Conclusions: We found general support for the hypothesis that anti-mucin antibody levels correlate with risk factors for EOC. Antibodies alone or in combinations with their antigen may predict longer term risk of specific EOC types.Impact: Anti-CA125 and anti-CA15.3 antibodies alone or in perspective of antigens may be informative in the pathogenesis of EOC subtypes, but less useful for informing risk for all EOC. Cancer Epidemiol Biomarkers Prev; 27(7); 790-804. ©2018 AACR.
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Affiliation(s)
- Daniel W Cramer
- Epidemiology Center, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, Massachusetts.
- Harvard Medical School, Boston, Massachusetts
- Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
| | - Raina N Fichorova
- Harvard Medical School, Boston, Massachusetts
- Laboratory of Genital Tract Biology, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Kathryn L Terry
- Epidemiology Center, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
- Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
| | - Hidemi Yamamoto
- Laboratory of Genital Tract Biology, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Allison F Vitonis
- Epidemiology Center, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Eva Ardanaz
- Navarra Public Health Institute, Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
- CIBER Epidemiology and Public Health CIBERESP, Madrid, Spain
| | - Dagfinn Aune
- School of Public Health, Imperial College London, London, United Kingdom
| | - Heiner Boeing
- German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Jenny Brändstedt
- Department of Clinical Sciences, Lund University, Sweden
- Division of Surgery, Skåne University Hospital, Lund, Sweden
| | | | - Maria-Dolores Chirlaque
- Department of Epidemiology, Regional Health Council, IMIB-Arrixaca, Murcia, Spain
- CIBER in Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Department of Health and Social Sciences, Universidad de Murcia, Murcia, Spain
| | - Miren Dorronsoro
- Public Health Direction and Biodonostia Research Institute and Ciberesp, Basque Regional Health Department, San Sebastian, Spain
| | - Laure Dossus
- International Agency for Research on Cancer, Lyon, France
| | - Eric J Duell
- Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), Barcelona, Spain
| | - Inger T Gram
- Faculty of Health Sciences, Department of Community Medicine, University of Tromsø, The Arctic University of Norway, Tromsø, Norway
| | - Marc Gunter
- International Agency for Research on Cancer, Lyon, France
| | - Louise Hansen
- Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Annika Idahl
- Department of Clinical Sciences, Obstetrics and Gynecology, Umeå University, Umeå, Sweden
| | - Theron Johnson
- Division of Cancer Epidemiology, German Cancer Research Center, (DKFZ) Heidelberg, Germany
| | - Kay-Tee Khaw
- School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Vittorio Krogh
- Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Marina Kvaskoff
- CESP, INSERM U1018, Univ. Paris-Sud, UVSQ, Université Paris-Saclay, Villejuif, France
- Gustave Roussy, Villejuif, France
| | - Amalia Mattiello
- Diparmento di Medicina Clinica e Chirugria Federico II University, Naples, Italy
| | - Giuseppe Matullo
- Department of Medical Sciences, University of Torino, Italian Institute for Genomic Medicine -IIGM (FKA HuGeF), Torino, Italy
| | - Melissa A Merritt
- School of Public Health, Imperial College London, London, United Kingdom
| | - Björn Nodin
- Department of Clinical Sciences Lund, Oncology and Pathology, Lund University, Lund, Sweden
| | - Philippos Orfanos
- Hellenic Health Foundation, Athens, Greece
- WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - N Charlotte Onland-Moret
- Julis Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Domenico Palli
- Cancer Risk Factors and Life-Style Epidemiology Unit, Cancer Research and Prevention Institute - ISPO, Florence, Italy
| | | | | | - Maria-Jose Sánchez-Perez
- Escuela Andaluza de Salud Pública. Instituto de Investigación Biosanitaria ibs.Granada, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain
- CIBER de Epidemiología y Salud Pública (CIBERESP), Spain
| | - Gianluca Severi
- CESP, INSERM U1018, Univ. Paris-Sud, UVSQ, Université Paris-Saclay, Villejuif, France
- Gustave Roussy, Villejuif, France
| | - Anne Tjønneland
- Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Ruth C Travis
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Antonia Trichopoulou
- Hellenic Health Foundation, Athens, Greece
- WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Rosario Tumino
- Cancer Registry and Histopathology Department, "Civic - M.P. Arezzo" Hospital, ASP Ragusa, Italy
| | - Elisabete Weiderpass
- Department of Community Medicine, University of Tromsø, The Arctic University of Norway, Tromsø, Norway
- Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Genetic Epidemiology Group, Folkhälsan Research Center, Helsinki, Finland
| | - Renée T Fortner
- Division of Cancer Epidemiology, German Cancer Research Center, (DKFZ) Heidelberg, Germany
| | - Rudolf Kaaks
- Division of Cancer Epidemiology, German Cancer Research Center, (DKFZ) Heidelberg, Germany.
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Seregni E, Botti C, Bajetta E, Ferrari L, Martinetti A, Nerini-Molteni S, Bombardieri E. Hormonal Regulation of MUC1 Expression. Int J Biol Markers 2018; 14:29-35. [PMID: 10367247 DOI: 10.1177/172460089901400106] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Several circulating mucinous markers, including CA 15.3, MCA, CA 459, CASA, and Truquant BR, are secreted products of the polymorphic MUC1 gene, and are used as diagnostic tools in patients with breast cancer. In clinical practice the measurement of the levels of these markers in the blood can give important information on the tumor's response to treatment and its biological behavior during disease monitoring. Since the marker levels reflect the activity of the tumor, it is important to know all factors influencing the production/secretion and the blood concentrations of MUC1 mucin. Recent findings suggest that MUC1 gene expression is regulated by steroid hormones and other substances present in the serum. Such observations are very important not only because of their biological significance but also for their clinical implications, as one approach to breast cancer therapy is based on chemical hormone manipulation. Nevertheless, we have preliminarily demonstrated that endocrine treatment in breast cancer patients does not influence the circulating CA 15.3 serum levels, so changes in marker levels are related only to the clinical evolution of the tumor.
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Affiliation(s)
- E Seregni
- Nuclear Medicine Department, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy
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27
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von Mensdorff-Pouilly S, Snijdewint FG, Verstraeten AA, Verheijen RH, Kenemans P. Human MUC1 Mucin: A Multifaceted Glycoprotein. Int J Biol Markers 2018; 15:343-56. [PMID: 11192832 DOI: 10.1177/172460080001500413] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Human MUC1 mucin, a membrane-bound glycoprotein, is a major component of the ductal cell surface of normal glandular cells. MUC1 is overexpressed and aberrantly glycosylated in carcinoma cells. The role MUC1 plays in cancer progression represents two sides of one coin: on the one hand, loss of polarity and overexpression of MUC1 in cancer cells interferes with cell adhesion and shields the tumor cell from immune recognition by the cellular arm of the immune system, thus favoring metastases; on the other hand, MUC1, in essence a self-antigen, is displaced and altered in malignancy and induces immune responses. Tumor-associated MUC1 has short carbohydrate sidechains and exposed epitopes on its peptide core; it gains access to the circulation and comes into contact with the immune system provoking humoral and cellular immune responses. Natural antibodies to MUC1 present in the circulation of cancer patients may be beneficial to the patient by restricting tumor growth and dissemination: early stage breast cancer patients with a humoral response to MUC1 have a better disease-specific survival. Several MUC1 peptide vaccines, differing in vectors, carrier proteins and adjuvants, have been tested in phase I clinical trials. They are capable of inducing predominantly humoral responses to the antigen, but evidence that these immune responses may be effective against the tumor in humans is still scarce.
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Affiliation(s)
- S von Mensdorff-Pouilly
- Department of Obstetrics and Gynecology, Academic Hospital Vrije Universiteit, Amsterdam, The Netherlands
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Botti C, Seregni E, Ferrari L, Martinetti A, Bombardieri E. Immunosuppressive Factors: Role in Cancer Development and Progression. Int J Biol Markers 2018; 13:51-69. [PMID: 9803353 DOI: 10.1177/172460089801300201] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The concept of the immunological surveillance against neoplastic cells was initially proposed by Erlich in 1909 and later elaborated by Burnet. This hypothesis states that the normal function of the immune system, in particular the cell-mediated immunity, is to recognize and destroy the transformed and proliferating tumor cells. The role of cell-mediated immunity during the first steps of tumorigenesis remains controversial. However, there is certain evidence about its importance in the progression and dissemination of cancer. The frequent immunosuppressed condition of cancer patients at tumor relapse or recurrence of secondary tumors is a clinical sign supporting this hypothesis, and many studies have demonstrated a defective immune response in patients diagnosed with advanced cancer. Several mechanisms of escape from the immune surveillance have been described, including the immunoselection of tumor antigen-negative variants, the downregulation of MHC class I expression, suppressive T cells, and the elaboration of immunosuppressive cytokines and other factors. Because of the technical difficulty of isolating the very small amounts from culture supernatants or body fluids, only a few of these substances have been characterized and studied with respect to their biological activity: transforming growth factor-β (TGF-β), the protein p15E, interleukin 10 (IL-10), prostaglandin E2 (PGE2), mucins, suppressive E-receptor (SER), immunosuppressive acidic protein (IAP), and adhesion molecules. The possibility of monitoring cancer patients by testing biochemical factors related to cancer growth led to a proposal to measure a number of these factors as tumor markers. Some of them, e.g mucins, enjoy the consensus of the oncologic community, as for some indications they can help the clinician in the management of cancer patients. Except for the class of mucins, the other above-mentioned immunosuppressive factors have not found any clinical application in the laboratory routine because the information deriving from their measurement, although of speculative and scientific interest, has limited clinical value at present. Nevertheless, even if they have no impact on patient management, these substances do have a potential role to play in the study of cancer patients, and should be taken into account when developing new therapeutic strategies.
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Affiliation(s)
- C Botti
- Nuclear Medicine Department, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy
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29
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Eguchi T, Sogawa C, Okusha Y, Uchibe K, Iinuma R, Ono K, Nakano K, Murakami J, Itoh M, Arai K, Fujiwara T, Namba Y, Murata Y, Ohyama K, Shimomura M, Okamura H, Takigawa M, Nakatsura T, Kozaki KI, Okamoto K, Calderwood SK. Organoids with cancer stem cell-like properties secrete exosomes and HSP90 in a 3D nanoenvironment. PLoS One 2018; 13:e0191109. [PMID: 29415026 PMCID: PMC5802492 DOI: 10.1371/journal.pone.0191109] [Citation(s) in RCA: 94] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Accepted: 12/28/2017] [Indexed: 12/12/2022] Open
Abstract
Ability to form cellular aggregations such as tumorspheres and spheroids have been used as a morphological marker of malignant cancer cells and in particular cancer stem cells (CSC). However, the common definition of the types of cellular aggregation formed by cancer cells has not been available. We examined morphologies of 67 cell lines cultured on three dimensional morphology enhancing NanoCulture Plates (NCP) and classified the types of cellular aggregates that form. Among the 67 cell lines, 49 cell lines formed spheres or spheroids, 8 cell lines formed grape-like aggregation (GLA), 8 cell lines formed other types of aggregation, and 3 cell lines formed monolayer sheets. Seven GLA-forming cell lines were derived from adenocarcinoma among the 8 lines. A neuroendocrine adenocarcinoma cell line PC-3 formed asymmetric GLA with ductal structures on the NCPs and rapidly growing asymmetric tumors that metastasized to lymph nodes in immunocompromised mice. In contrast, another adenocarcinoma cell line DU-145 formed spheroids in vitro and spheroid-like tumors in vivo that did not metastasize to lymph nodes until day 50 after transplantation. Culture in the 3D nanoenvironment and in a defined stem cell medium enabled the neuroendocrine adenocarcinoma cells to form slowly growing large organoids that expressed multiple stem cell markers, neuroendocrine markers, intercellular adhesion molecules, and oncogenes in vitro. In contrast, the more commonly used 2D serum-contained environment reduced intercellular adhesion and induced mesenchymal transition and promoted rapid growth of the cells. In addition, the 3D stemness nanoenvironment promoted secretion of HSP90 and EpCAM-exosomes, a marker of CSC phenotype, from the neuroendocrine organoids. These findings indicate that the NCP-based 3D environment enables cells to form stem cell tumoroids with multipotency and model more accurately the in vivo tumor status at the levels of morphology and gene expression.
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Affiliation(s)
- Takanori Eguchi
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan
- Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Dental School, Okayama, Japan
| | - Chiharu Sogawa
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Yuka Okusha
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Kenta Uchibe
- Department of Oral Morphology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | | | - Kisho Ono
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Keisuke Nakano
- Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Dental School, Okayama, Japan
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Jun Murakami
- Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Dental School, Okayama, Japan
- Department of Oral Diagnosis and Dent-maxillofacial Radiology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Manabu Itoh
- JSR Life Sciences Corporation, Tsukuba, Japan
| | - Kazuya Arai
- JSR Life Sciences Corporation, Tsukuba, Japan
| | - Toshifumi Fujiwara
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Yuri Namba
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Yoshiki Murata
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Kazumi Ohyama
- Radio Isotope Research Center, Okayama University Dental School, Okayama, Japan
| | - Manami Shimomura
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Hirohiko Okamura
- Department of Oral Morphology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Masaharu Takigawa
- Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Dental School, Okayama, Japan
| | - Tetsuya Nakatsura
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Ken-ichi Kozaki
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Kuniaki Okamoto
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Stuart K. Calderwood
- Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States of America
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Ono E, Uede T. Implication of Soluble Forms of Cell Adhesion Molecules in Infectious Disease and Tumor: Insights from Transgenic Animal Models. Int J Mol Sci 2018; 19:ijms19010239. [PMID: 29342882 PMCID: PMC5796187 DOI: 10.3390/ijms19010239] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2017] [Revised: 01/10/2018] [Accepted: 01/12/2018] [Indexed: 12/26/2022] Open
Abstract
Cell adhesion molecules (CAMs) are surface ligands, usually glycoproteins, which mediate cell-to-cell adhesion. They play a critical role in maintaining tissue integrity and mediating migration of cells, and some of them also act as viral receptors. It has been known that soluble forms of the viral receptors bind to the surface glycoproteins of the viruses and neutralize them, resulting in inhibition of the viral entry into cells. Nectin-1 is one of important CAMs belonging to immunoglobulin superfamily and herpesvirus entry mediator (HVEM) is a member of the tumor necrosis factor (TNF) receptor family. Both CAMs also act as alphaherpesvirus receptor. Transgenic mice expressing the soluble form of nectin-1 or HVEM showed almost complete resistance against the alphaherpesviruses. As another CAM, sialic acid-binding immunoglobulin-like lectins (Siglecs) that recognize sialic acids are also known as an immunoglobulin superfamily member. Siglecs play an important role in the regulation of immune cell functions in infectious diseases, inflammation, neurodegeneration, autoimmune diseases and cancer. Siglec-9 is one of Siglecs and capsular polysaccharide (CPS) of group B Streptococcus (GBS) binds to Siglec-9 on neutrophils, leading to suppress host immune response and provide a survival advantage to the pathogen. In addition, Siglec-9 also binds to tumor-produced mucins such as MUC1 to lead negative immunomodulation. Transgenic mice expressing the soluble form of Siglec-9 showed significant resistance against GBS infection and remarkable suppression of MUC1 expressing tumor proliferation. This review describes recent developments in the understanding of the potency of soluble forms of CAMs in the transgenic mice and discusses potential therapeutic interventions that may alter the outcomes of certain diseases.
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Affiliation(s)
- Etsuro Ono
- Department of Biomedicine, Center of Biomedical Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
| | - Toshimitsu Uede
- Division of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
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Matsuda A, Higashi M, Nakagawa T, Yokoyama S, Kuno A, Yonezawa S, Narimatsu H. Assessment of tumor characteristics based on glycoform analysis of membrane-tethered MUC1. J Transl Med 2017; 97:1103-1113. [PMID: 28581490 DOI: 10.1038/labinvest.2017.53] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Revised: 03/29/2017] [Accepted: 04/01/2017] [Indexed: 12/12/2022] Open
Abstract
Clinical tissue specimens are useful for pathological diagnosis, which is, in some cases, supported by visualization of biomolecule localization. In general, diagnostic specificity in molecular pathology is increased by the acquisition of a probe to distinguish the modification of isomers. Although glycosylation is one of the candidate modifications in a protein, comparative glycan analysis of disease-associated proteins derived from a single tissue section is still challenging because of the lack of analytical sensitivity. Here we demonstrate a possible method for differential glycoform analysis of an endogenous tumor-associated glycoprotein MUC1 by an antibody-overlay lectin microarray. Tissue sections (5 μm thick) of patients with cholangiocarcinoma (CCA; n=21) and pancreatic ductal adenocarcinoma (PDAC; n=50) were stained with an anti-MUC1 antibody MY.1E12 that was established as a monoclonal antibody recognizing an MUC1 glycosylation isoform with a sialyl-core 1 structure (NeuAcα2-3galactosyl β1-3-N-acetylgalactosamine). MY.1E12-positive tissue areas (2.5 mm2) were selectively dissected with a laser capture microdissection procedure. The membrane MUC1 was enriched by immunoprecipitation with MY.1E12 and subjected to lectin microarray analysis. Even though the reactivities of MY.1E12 between CCA and PDAC were similar, the lectin-binding patterns varied. We found Maackia amurensis leukoagglutinin and pokeweed lectin distinguished MY.1E12-reactive MUC1 of CCA from that of PDAC. Moreover, MUC1 with M. amurensis hemagglutinin (MAH) reactivity potentially reflected the degree of malignancy. These results were confirmed with MAH-MY.1E12 double fluorescent immunostaining. These glycan changes on MUC1 were detected with high sensitivity owing to the cluster effect of immobilized lectins on a tandem repeat peptide antigen covered with highly dense glycosylation such as mucin. Our approach provides the information to investigate novel glycodynamics in biology, for example, glycoalteration, as well as diseases related to not only MUC1 but also other membrane proteins.
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Affiliation(s)
- Atsushi Matsuda
- Glycomedicine Technology Research Center (GTRC), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan
| | - Michiyo Higashi
- Department of Pathology, Field of Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka, Kagoshima, Japan
| | - Tomomi Nakagawa
- Glycomedicine Technology Research Center (GTRC), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan
| | - Seiya Yokoyama
- Department of Pathology, Field of Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka, Kagoshima, Japan
| | - Atsushi Kuno
- Glycomedicine Technology Research Center (GTRC), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan
| | - Suguru Yonezawa
- Department of Pathology, Field of Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka, Kagoshima, Japan
| | - Hisashi Narimatsu
- Glycomedicine Technology Research Center (GTRC), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan
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Tao Z, Li S, Ichim TE, Yang J, Riordan N, Yenugonda V, Babic I, Kesari S. Cellular immunotherapy of cancer: an overview and future directions. Immunotherapy 2017; 9:589-606. [DOI: 10.2217/imt-2016-0086] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The clinical success of checkpoint inhibitors has led to a renaissance of interest in cancer immunotherapies. In particular, the possibility of ex vivo expanding autologous lymphocytes that specifically recognize tumor cells has attracted much research and clinical trial interest. In this review, we discuss the historical background of tumor immunotherapy using cell-based approaches, and provide some rationale for overcoming current barriers to success of autologous immunotherapy. An overview of adoptive transfer of lymphocytes, tumor infiltrating lymphocytes and dendritic cell therapies is provided. We conclude with discussing the possibility of gene-manipulating immune cells in order to augment therapeutic activity, including silencing of the immune-suppressive zinc finger orphan nuclear receptor, NR2F6, as an attractive means of overcoming tumor-associated immune suppression.
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Affiliation(s)
- Ziqi Tao
- The Affiliated XuZhou Center Hospital of Nanjing University of Chinese Medicine, The Affiliated XuZhou Hospital of Medical College of Southeast University, Jiangsu, China
| | - Shuang Li
- Department of Endocrinology, the Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | | | - Junbao Yang
- Department of Translational Neurosciences and Neurotherapeutics, Pacific Neuroscience Institute, John Wayne Cancer Institute, Providence Saint John’s Health Center, Santa Monica, CA 90404, USA
| | - Neil Riordan
- Medistem Panama, Inc., City of Knowledge, Clayton, Republic of Panama
| | - Venkata Yenugonda
- Department of Translational Neurosciences and Neurotherapeutics, Pacific Neuroscience Institute, John Wayne Cancer Institute, Providence Saint John’s Health Center, Santa Monica, CA 90404, USA
| | - Ivan Babic
- Department of Translational Neurosciences and Neurotherapeutics, Pacific Neuroscience Institute, John Wayne Cancer Institute, Providence Saint John’s Health Center, Santa Monica, CA 90404, USA
| | - Santosh Kesari
- Department of Translational Neurosciences and Neurotherapeutics, Pacific Neuroscience Institute, John Wayne Cancer Institute, Providence Saint John’s Health Center, Santa Monica, CA 90404, USA
- John Wayne Cancer Institute, 2200 Santa Monica Blvd, Santa Monica, CA 90404, USA
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Aldarouish M, Wang C. Trends and advances in tumor immunology and lung cancer immunotherapy. J Exp Clin Cancer Res 2016; 35:157. [PMID: 27686848 PMCID: PMC5043622 DOI: 10.1186/s13046-016-0439-3] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Accepted: 09/24/2016] [Indexed: 02/06/2023] Open
Abstract
Among several types of tumor, lung cancer is considered one of the most fatal and still the main cause of cancer-related deaths. Although chemotherapeutic agents can improve survival and quality of life compared with symptomatic treatment, cancers usually still progress after chemotherapy and are often aggravated by serious side effects. In the last few years there has been a growing interest in immunotherapy for lung cancer based on promising preliminary results in achieving meaningful and durable treatments responses with minimal manageable toxicity. This article is divided into two parts, the first part discusses the role of human immune system in controlling and eradicating cancer and the mechanisms of immune response evasion by tumor. The second part reviews the recent progress made in immunotherapy for lung cancer with results from trials evaluating therapeutic vaccines in addition to immune checkpoint blockade, specifically cytotoxic T lymphocyte associated protein 4, programmed death receptor 1 pathway, using monoclonal antibodies.
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Affiliation(s)
- Mohanad Aldarouish
- Department of Oncology, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjiaqiao Rd, Nanjing, Jiangsu Province, People's Republic of China.
| | - Cailian Wang
- Department of Oncology, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjiaqiao Rd, Nanjing, Jiangsu Province, People's Republic of China.
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Zaenker P, Gray E, Ziman M. Autoantibody Production in Cancer—The Humoral Immune Response toward Autologous Antigens in Cancer Patients. Autoimmun Rev 2016; 15:477-83. [DOI: 10.1016/j.autrev.2016.01.017] [Citation(s) in RCA: 141] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Accepted: 01/23/2016] [Indexed: 12/21/2022]
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Codony-Servat J, Rosell R. Cancer stem cells and immunoresistance: clinical implications and solutions. Transl Lung Cancer Res 2016; 4:689-703. [PMID: 26798578 DOI: 10.3978/j.issn.2218-6751.2015.12.11] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Tumor cells can be contained, but not eliminated, by traditional cancer therapies. A cell minor subpopulation is able to evade attack from therapies and may have cancer stem cell (CSC) characteristics, including self-renewal, multiple differentiation and tumor initiation (tumor initiating cells, or TICs). Thus, CSCs/TICs, aided by the microenvironment, produce more differentiated, metastatic cancer cells which the immune system detects and interacts with. There are three phases to this process: elimination, equilibrium and escape. In the elimination phase the immune system recognizes and destroys most of the tumor cells. Then the latency phase begins, consisting of equilibrium between immunological elimination and tumor cell growth. Finally, a minor attack-resistant subpopulation escapes and forms a clinically detectable tumor mass. Herein we review current knowledge of immunological characterization of CSCs/TICs. Due to the correlation between CTCs/TICs and drug resistance and metastasis, we also comment on the crucial role of key molecules involved in controlling CSCs/TICs properties; such molecules are essential to detect and destroy CSCs/TICs. Monoclonal antibodies, antibody constructs and vaccines have been designed to act against CSCs/TICs, with demonstrated efficacy in human cancer xenografts and some antitumor activity in human clinical studies. Therefore, therapeutic strategies that selectively target CSCs/TICs warrant further investigation. Better understanding of the interaction between CSCs and tumor immunology may help to identify strategies to eradicate the minor subpopulation that escapes conventional therapy attack, thus providing a solution to the problem of drug resistance and metastasis.
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Affiliation(s)
- Jordi Codony-Servat
- 1 Pangaea Biotech S.L., Quirón-Dexeus University Hospital, Barcelona, Spain ; 2 Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain ; 3 Instituto Oncológico Dr Rosell, Quirón-Dexeus University Hospital, Barcelona, Spain ; 4 Fundación Molecular Oncology Research, Barcelona, Spain
| | - Rafael Rosell
- 1 Pangaea Biotech S.L., Quirón-Dexeus University Hospital, Barcelona, Spain ; 2 Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain ; 3 Instituto Oncológico Dr Rosell, Quirón-Dexeus University Hospital, Barcelona, Spain ; 4 Fundación Molecular Oncology Research, Barcelona, Spain
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Rivalland G, Loveland B, Mitchell P. Update on Mucin-1 immunotherapy in cancer: a clinical perspective. Expert Opin Biol Ther 2015; 15:1773-87. [PMID: 26453294 DOI: 10.1517/14712598.2015.1088519] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Mucin 1 (MUC1) is particularly well suited as a cancer immunotherapy target due to the elevated protein expression and aberrant forms associated with malignancy. A variety of therapeutic strategies have been explored, including antibodies intended to induce cancer cell destruction, and vaccinations with peptides, tumor extracts, and gene expression systems. AREAS COVERED MUC1 immunotherapeutic strategies have included vaccination with peptide sequences, glycan molecules, viruses, and dendritic cells, monoclonal antibodies and monoclonal antibody conjugates. Here we review the relevant clinical trials in each field of immunotherapy with particular focus on large and recently published trials. EXPERT OPINION Long clinical experience in the trial setting has reduced concerns of immunotherapy associated toxicities and inappropriate immune responses, with the main limitation (common to many experimental approaches) being a lack of clinical efficacy. However, there have been sufficient treatment-associated responses to justify continued pursuit of MUC1 targeted immunotherapies. The focus now should be on application to the relevant cancers under appropriate circumstances and combination with the emerging non-specific immunotherapy approaches such as the PD-1 pathway inhibitors.
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Affiliation(s)
- Gareth Rivalland
- a 1 Austin Health, Olivia Newton-John Cancer and Wellness Centre , Studley Rd, Heidelberg VIC 3084, Australia
| | - Bruce Loveland
- b 2 Burnet Institute, Centre for Biomedical Research , Melbourne VIC 3004, Australia
| | - Paul Mitchell
- c 3 Austin Health, Level 4, Olivia Newton-John Cancer and Wellness Centre , Studley Rd, Heidelberg VIC 3084, Australia +613 94 96 57 63 ; +613 94 57 66 98 ;
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Fremd C, Stefanovic S, Beckhove P, Pritsch M, Lim H, Wallwiener M, Heil J, Golatta M, Rom J, Sohn C, Schneeweiss A, Schuetz F, Domschke C. Mucin 1-specific B cell immune responses and their impact on overall survival in breast cancer patients. Oncoimmunology 2015; 5:e1057387. [PMID: 26942066 DOI: 10.1080/2162402x.2015.1057387] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Revised: 05/26/2015] [Accepted: 05/28/2015] [Indexed: 02/07/2023] Open
Abstract
Considering the diverse functions of B cells, responses to tumor-associated antigens (TAA) have been thought to be the main source of B cell-mediated antitumor immunity. Polymorphic epithelial mucin (MUC1) is considered one of the most specific TAA in patients with breast cancer. The present study aims to dissect the level and subclasses of naturally occurring anti-MUC1 antibodies in regard to tumor biologic parameters, clinical characteristics and overall survival. In 288 primary, non-metastatic breast cancer patients, pretreatment serum levels of anti-MUC1 immunoglobulin G (IgG) and its subclasses G1-4 as well as immunoglobulin M (IgM) were analyzed via ELISA. With respect to overall survival (Kaplan-Meier analysis), tumor biologic parameters as hormone receptor status, human epidermal growth factor receptor 2 (Her2), Ki-67 expression and tumor grading have been correlated as well as clinical characteristics as nodal involvement, tumor stage and patients' age at the time of diagnosis. Median follow-up time was 148 mo (IQR: 73.1-158.5 mo). A significant increase in IgG antibody titers was correlated highly significantly with an improved overall survival of patients. In multivariate analysis, total IgG proved to be an independent prognostic marker for overall survival (p = 0.002). IgG subclass analysis did not reveal any correlation of IgG1, IgG3 and IgG4 levels with overall survival, while increased immunoglobulin G2 (IgG2) values, although statistically not significant, tended to correlate with prolonged patient survival. MUC1-specific IgM antibodies were shown not to be predictive of overall survival. Altogether, humoral immune responses appear to play a crucial part in the tumor immunity of breast cancer patients. The present data confirms the positive impact of tumor-specific IgG on prolonged overall survival in breast cancer patients. MUC1-antibody testing might be a useful tool to identify high-risk patients who may need adjuvant therapy and potentially might benefit from MUC1-directed immunotherapy.
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Affiliation(s)
- Carlo Fremd
- Department of Gynecology and Obstetrics; National Center for Tumor Diseases; Heidelberg University Hospital ; Heidelberg, Germany
| | - Stefan Stefanovic
- Department of Gynecology and Obstetrics; National Center for Tumor Diseases; Heidelberg University Hospital ; Heidelberg, Germany
| | - Philipp Beckhove
- Division of Translational Immunology; Tumor Immunology Program; German Cancer Research Center ; Heidelberg, Germany
| | - Maria Pritsch
- Division of Translational Immunology; Tumor Immunology Program; German Cancer Research Center ; Heidelberg, Germany
| | - Hendry Lim
- Division of Translational Immunology; Tumor Immunology Program; German Cancer Research Center ; Heidelberg, Germany
| | - Markus Wallwiener
- Department of Gynecology and Obstetrics; National Center for Tumor Diseases; Heidelberg University Hospital ; Heidelberg, Germany
| | - Joerg Heil
- Department of Gynecology and Obstetrics; National Center for Tumor Diseases; Heidelberg University Hospital ; Heidelberg, Germany
| | - Michael Golatta
- Department of Gynecology and Obstetrics; National Center for Tumor Diseases; Heidelberg University Hospital ; Heidelberg, Germany
| | - Joachim Rom
- Department of Gynecology and Obstetrics; National Center for Tumor Diseases; Heidelberg University Hospital ; Heidelberg, Germany
| | - Christof Sohn
- Department of Gynecology and Obstetrics; National Center for Tumor Diseases; Heidelberg University Hospital ; Heidelberg, Germany
| | - Andreas Schneeweiss
- Department of Gynecology and Obstetrics; National Center for Tumor Diseases; Heidelberg University Hospital ; Heidelberg, Germany
| | - Florian Schuetz
- Department of Gynecology and Obstetrics; National Center for Tumor Diseases; Heidelberg University Hospital ; Heidelberg, Germany
| | - Christoph Domschke
- Department of Gynecology and Obstetrics; National Center for Tumor Diseases; Heidelberg University Hospital ; Heidelberg, Germany
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Mitchell P, Thatcher N, Socinski MA, Wasilewska-Tesluk E, Horwood K, Szczesna A, Martín C, Ragulin Y, Zukin M, Helwig C, Falk M, Butts C, Shepherd FA. Tecemotide in unresectable stage III non-small-cell lung cancer in the phase III START study: updated overall survival and biomarker analyses. Ann Oncol 2015; 26:1134-1142. [PMID: 25722382 DOI: 10.1093/annonc/mdv104] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Accepted: 02/12/2015] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Tecemotide is a MUC1-antigen-specific cancer immunotherapy. The phase III START study did not meet its primary end point but reported notable survival benefit with tecemotide versus placebo in an exploratory analysis of the predefined patient subgroup treated with concurrent chemoradiotherapy. Here, we attempted to gain further insight into the effects of tecemotide in START. PATIENTS AND METHODS START recruited patients who did not progress following frontline chemoradiotherapy for unresectable stage III non-small-cell lung cancer. We present updated overall survival (OS) data and exploratory analyses of OS for baseline biomarkers: soluble MUC1 (sMUC1), antinuclear antibodies (ANA), neutrophil/lymphocyte ratio (NLR), lymphocyte count, and HLA type. RESULTS Updated OS data are consistent with the primary analysis: median 25.8 months (tecemotide) versus 22.4 months (placebo) (HR 0.89, 95% CI 0.77-1.03, P = 0.111), with ∼20 months additional median follow-up time compared with the primary analysis. Exploratory analysis of the predefined subgroup treated with concurrent chemoradiotherapy revealed clinically relevant prolonged OS with tecemotide versus placebo (29.4 versus 20.8 months; HR 0.81, 95% CI 0.68-0.98, P = 0.026). No improvement was seen with sequential chemoradiotherapy. High sMUC1 and ANA correlated with a possible survival benefit with tecemotide (interaction P = 0.0085 and 0.0022) and might have future value as biomarkers. Interactions between lymphocyte count, NLR, or prespecified HLA alleles and treatment effect were not observed. CONCLUSION Updated OS data support potential treatment benefit with tecemotide in patients treated with concurrent chemoradiotherapy. Exploratory biomarker analyses suggest that elevated sMUC1 or ANA levels correlate with tecemotide benefit. CLINICALTRIALSGOV NUMBER NCT00409188.
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Affiliation(s)
- P Mitchell
- Olivia Newton-John Cancer and Wellness Centre, Austin Hospital, Melbourne, Australia.
| | - N Thatcher
- Christie Hospital NHS Trust, Manchester, UK
| | | | | | - K Horwood
- Princess Alexandra Hospital, Woolloongabba, Australia
| | - A Szczesna
- Mazowieckie Centrum Leczenia Chorób Pluc i Gruzlicy, Otwock, Poland
| | - C Martín
- Division of Clinical Oncology, Instituto Especializado Alexander Fleming, Buenos Aires, Argentina
| | - Y Ragulin
- Medical Radiological Research Center, Obninsk, Russia
| | - M Zukin
- Clinical Oncology, Instituto Nacional do Câncer-INCA, Rio de Janeiro, Brazil
| | | | - M Falk
- Merck KGaA, Darmstadt, Germany
| | - C Butts
- Cancer Care, Cross Cancer Institute, Edmonton
| | - F A Shepherd
- University Health Network, Princess Margaret Cancer Centre, Toronto, Canada
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Ramlogan-Steel CA, Steel JC, Morris JC. Lung cancer vaccines: current status and future prospects. Transl Lung Cancer Res 2015; 3:46-52. [PMID: 25806280 DOI: 10.3978/j.issn.2218-6751.2013.12.01] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2013] [Accepted: 12/03/2013] [Indexed: 12/31/2022]
Abstract
Designing a cancer treatment that very specifically targets and kills tumor cells with little to no side effects is the "holy grail" of oncology. Cancer vaccines have this potential. Vaccines utilize the immune system to specifically target and eliminate tumor cells. Historically, vaccination approaches against lung cancer have been disappointing. However, over the past decade, a greater understanding of the immune system and of the antigens expressed by tumors, coupled with advances in immunoadjuvants and improved delivery systems, has led to advances in the use of immunotherapy including vaccines to target lung cancer. Proof of principle phase I/II clinical trials targeting the MAGE-A3 and MUC1 tumor antigens, as well as cell-based vaccines such as belagenpumatucel-L have suggested improved survival, leading to larger scale phase III clinical trials. This review will discuss cancer vaccines in relation to lung cancer and present clinical data supporting their use.
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Affiliation(s)
| | - Jason C Steel
- University of Cincinnati Cancer Center, University of Cincinnati, Cincinnati, OH 45267, USA
| | - John C Morris
- University of Cincinnati Cancer Center, University of Cincinnati, Cincinnati, OH 45267, USA
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Carmon L, Avivi I, Kovjazin R, Zuckerman T, Dray L, Gatt ME, Or R, Shapira MY. Phase I/II study exploring ImMucin, a pan-major histocompatibility complex, anti-MUC1 signal peptide vaccine, in multiple myeloma patients. Br J Haematol 2014; 169:44-56. [DOI: 10.1111/bjh.13245] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Accepted: 10/24/2014] [Indexed: 01/01/2023]
Affiliation(s)
- Lior Carmon
- Vaxil BioTherapeutics Ltd.; Nes-Ziona Israel
| | - Irit Avivi
- Department of Haematology; Rambam Medical Campus; Haifa Israel
- Technion; Israel Institute of Technology; Haifa Israel
| | | | - Tsila Zuckerman
- Department of Haematology; Rambam Medical Campus; Haifa Israel
- Technion; Israel Institute of Technology; Haifa Israel
| | - Lillian Dray
- Department of Bone Marrow Transplantation & Cancer Immunotherapy; Hadassah Medical Centre; Jerusalem Israel
| | - Moshe E. Gatt
- Department of Bone Marrow Transplantation & Cancer Immunotherapy; Hadassah Medical Centre; Jerusalem Israel
| | - Reuven Or
- Department of Bone Marrow Transplantation & Cancer Immunotherapy; Hadassah Medical Centre; Jerusalem Israel
| | - Michael Y. Shapira
- Department of Bone Marrow Transplantation & Cancer Immunotherapy; Hadassah Medical Centre; Jerusalem Israel
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Rahma OE, Myint ZW, Estfan B. Dendritic Cell Cancer Vaccines for Treatment of Colon Cancer. CURRENT COLORECTAL CANCER REPORTS 2014. [DOI: 10.1007/s11888-014-0243-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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Abstract
PURPOSE OF REVIEW Recent advances in our understanding of cancer immunology resulted in the development of promising therapeutic agents for either nonantigen-specific immunotherapy, for example, monoclonal antibodies targeting immune checkpoints on the T-cell lymphocyte, and antigen-specific immunotherapy or vaccination. Here, we review the recently reported results from randomized controlled trials (RCTs) with the latter approach. RECENT FINDINGS Several trials indicated feasibility, safety, and potential for better patient outcomes. In resected early stage non-small-cell lung cancer, a phase II RCT with the MAGE-A3 vaccine showed a trend for improved disease-free interval (hazard ratio 0.75), now further evaluated in the large MAGRIT (MAGE-A3 as Adjuvant NSCLC Immunotherapy Trial) study. In stage III after chemoradiotherapy, the phase III START (Stimulating Targeted Antigenic Responses to NSCLC) trial with L-BLP25 vaccine resulted in a remarkable 10-month improvement in median survival in the concurrent chemoradiotherapy subgroup. In the advanced setting, the phase III study with the allogeneic tumor cell vaccine belagenpumatucel-L did not improve survival in the whole study, but interesting effects were seen in subgroups. SUMMARY Recent non-small-cell lung cancer vaccination trials did not meet their primary endpoint, but showed clear patient benefits in subgroup analyses. Confirmatory trials and identifying patients who will benefit using predictive factors, will hopefully bring these approaches in the clinic in the near future.
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Rolfo C, Sortino G, Smits E, Passiglia F, Bronte G, Castiglia M, Russo A, Santos ES, Janssens A, Pauwels P, Raez L. Immunotherapy: is a minor god yet in the pantheon of treatments for lung cancer? Expert Rev Anticancer Ther 2014; 14:1173-87. [PMID: 25148289 DOI: 10.1586/14737140.2014.952287] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Immunotherapy has been studied for many years in lung cancer without significant results, making the majority of oncologists quite skeptical about its possible application for non-small cell lung cancer treatment. However, the recent knowledge about immune escape and subsequent 'cancer immunoediting' has yielded the development of new strategies of cancer immunotherapy, heralding a new era of lung cancer treatment. Cancer vaccines, including both whole-cell and peptide vaccines have been tested both in early and advanced stages of non-small cell lung cancer. New immunomodulatory agents, including anti-CTLA4, anti-PD1/PDL1 monoclonal antibodies, have been investigated as monotherapy in metastatic lung cancer. To date, these treatments have shown impressive results of efficacy and tolerability in early clinical trials, leading to testing in several large, randomized Phase III trials. As these results will be confirmed, these drugs will be available in the near future, offering new exciting therapeutic options for lung cancer treatment.
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Affiliation(s)
- Christian Rolfo
- Oncology Department, Phase I - Early Clinical Trials Unit, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium
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Tomioka Y, Morimatsu M, Nishijima KI, Usui T, Yamamoto S, Suyama H, Ozaki K, Ito T, Ono E. A soluble form of Siglec-9 provides an antitumor benefit against mammary tumor cells expressing MUC1 in transgenic mice. Biochem Biophys Res Commun 2014; 450:532-7. [DOI: 10.1016/j.bbrc.2014.06.009] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2014] [Accepted: 06/02/2014] [Indexed: 11/28/2022]
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Xu F, Liu J, Liu D, Liu B, Wang M, Hu Z, Du X, Tang L, He F. LSECtin Expressed on Melanoma Cells Promotes Tumor Progression by Inhibiting Antitumor T-cell Responses. Cancer Res 2014; 74:3418-28. [DOI: 10.1158/0008-5472.can-13-2690] [Citation(s) in RCA: 195] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Armon-Omer A, Hadary A, Hilu G, Tayar BE, Keren T, Sharabi-Nov A, Bickel A, Klein O. Detection of breast cancer from blood through analysis of lymphocyte fluorescent intensity using MUC1 antigen. Breast Cancer 2014; 22:626-33. [PMID: 24696421 DOI: 10.1007/s12282-014-0529-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Accepted: 03/17/2014] [Indexed: 12/01/2022]
Abstract
BACKGROUND Sensitive and reliable early diagnostic markers for breast cancer (BC) are still unavailable today. In this work, we proposed a new complementary method for detection of BC. This method is based on an observation that lymphocytes re-exposed in vitro to antigenic stimulation express cytoplasmic changes. METHODS In the new protocol, we recorded changes in the fluorescence intensity of light emitted from lymphocytes obtained from females with and without BC after stimulation with MUC1 antigen utilized flow cytometry. RESULTS Out of 55 BC patients tested, 46 were correctly diagnosed. Of 73 controls, 55 were correctly identified as healthy subjects. The sensitivity of the test was 84 %; the specificity was 75 %. CONCLUSION These results suggest a potentially valuable method for detection of BC. The clinical importance of this procedure relies on the ability to screen populations for BC with widely available flow cytometry by a relatively fast, accurate, and economical procedure. Another potential benefit would be identification of candidates for vaccination as a primary or secondary preventive measure.
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Affiliation(s)
| | - Amram Hadary
- Surgery Department, Ziv Medical Center, Safed, Israel
- Faculty of Medicine, Bar-Ilan University, 14302, Safed, Israel
| | | | - Bat-El Tayar
- Research Department, Ziv Medical Center, Safed, Israel
| | - Tali Keren
- Research Department, Ziv Medical Center, Safed, Israel
| | | | - Amitai Bickel
- Surgery Department, Western Galilee Hospital, Nahariya, Israel
- Faculty of Medicine, Bar-Ilan University, 14302, Safed, Israel
| | - Ofer Klein
- Research Department, Ziv Medical Center, Safed, Israel
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Kidiyoor A, Schettini J, Besmer DM, Rego SL, Nath S, Curry JM, Roy LD, Dréau D, Mukherjee P. Pancreatic Cancer Cells Isolated from Muc1-Null Tumors Favor the Generation of a Mature Less Suppressive MDSC Population. Front Immunol 2014; 5:67. [PMID: 24605110 PMCID: PMC3932420 DOI: 10.3389/fimmu.2014.00067] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2013] [Accepted: 02/07/2014] [Indexed: 01/07/2023] Open
Abstract
Mucin 1 (MUC1) is a transmembrane mucin glycoprotein that is over-expressed and aberrantly glycosylated in >80% of human pancreatic ductal adenocarcinoma (PDA) and is associated with poor prognosis. To understand the role of MUC1 in PDA, we have recently developed two mouse models of spontaneous PDA, one that expresses full-length human MUC1 transgene (KCM mice) and one that is null for MUC1 (KCKO mice). We have previously reported that KCM mice express high levels of myeloid derived suppressor cells (MDSCs) in their tumors and develop highly aggressive PDA. To further understand the underlying mechanism for high MDSC levels in KCM-tumors, we generated primary cell lines from KCM and KCKO-tumors. In this study, we report that MDSCs derived using KCM cells express significantly higher levels of arginase 1 and inducible nitric oxide synthase (markers associated with immune suppression) and lower levels of CD115 (a marker associated with maturation of myeloid cells) as compared to KCKO-derived MDSCs. Functionally, KCM-derived MDSCs secrete significantly higher levels of urea and nitric oxide (NO) when co-cultured with normal splenic cells as compared to KCKO-derived MDSCs. Data indicates that KCM-derived MDSCs remain immature and are more suppressive as compared to KCKO-derived MDSCs. This was further corroborated in vivo where MDSCs isolated from KCM-tumor-bearing mice retained their immature state and were highly suppressive as compared to MDSCs derived from KCKO-tumor-bearing mice. Finally, we show that KCM cells secrete significantly higher levels of prostaglandin E2 (PGE2), a COX-2 metabolite and a known driver of suppressive MDSCs as compared to KCKO cells. Thus, inhibiting PGE2 with a specific COX-2 inhibitor reverses the immunosuppressive and immature phenotype of KCM-derived MDSCs. This is the first report that clearly suggests a functional role of pancreatic tumor-associated MUC1 in the development of functional MDSCs.
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Affiliation(s)
- Amritha Kidiyoor
- Department of Biology, University of North Carolina at Charlotte , Charlotte, NC , USA
| | - Jorge Schettini
- Department of Biology, University of North Carolina at Charlotte , Charlotte, NC , USA
| | - Dahlia Marie Besmer
- Department of Biology, University of North Carolina at Charlotte , Charlotte, NC , USA
| | - Stephen Lee Rego
- Department of Biology, University of North Carolina at Charlotte , Charlotte, NC , USA
| | - Sritama Nath
- Department of Biology, University of North Carolina at Charlotte , Charlotte, NC , USA
| | - Jennifer Marie Curry
- Department of Biology, University of North Carolina at Charlotte , Charlotte, NC , USA
| | - Lopamudra Das Roy
- Department of Biology, University of North Carolina at Charlotte , Charlotte, NC , USA
| | - Didier Dréau
- Department of Biology, University of North Carolina at Charlotte , Charlotte, NC , USA
| | - Pinku Mukherjee
- Department of Biology, University of North Carolina at Charlotte , Charlotte, NC , USA
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Syed A, Garcia MA, Lyu SC, Bucayu R, Kohli A, Ishida S, Berglund JP, Tsai M, Maecker H, O'Riordan G, Galli SJ, Nadeau KC. Peanut oral immunotherapy results in increased antigen-induced regulatory T-cell function and hypomethylation of forkhead box protein 3 (FOXP3). J Allergy Clin Immunol 2014; 133:500-10. [PMID: 24636474 PMCID: PMC4121175 DOI: 10.1016/j.jaci.2013.12.1037] [Citation(s) in RCA: 360] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2013] [Revised: 12/10/2013] [Accepted: 12/16/2013] [Indexed: 12/15/2022]
Abstract
BACKGROUND The mechanisms contributing to clinical immune tolerance remain incompletely understood. This study provides evidence for specific immune mechanisms that are associated with a model of operationally defined clinical tolerance. OBJECTIVE Our overall objective was to study laboratory changes associated with clinical immune tolerance in antigen-induced T cells, basophils, and antibodies in subjects undergoing oral immunotherapy (OIT) for peanut allergy. METHODS In a phase 1 single-site study, we studied participants (n = 23) undergoing peanut OIT and compared them with age-matched allergic control subjects (n = 20) undergoing standard of care (abstaining from peanut) for 24 months. Participants were operationally defined as clinically immune tolerant (IT) if they had no detectable allergic reactions to a peanut oral food challenge after 3 months of therapy withdrawal (IT, n = 7), whereas those who had an allergic reaction were categorized as nontolerant (NT; n = 13). RESULTS Antibody and basophil activation measurements did not statistically differentiate between NT versus IT participants. However, T-cell function and demethylation of forkhead box protein 3 (FOXP3) CpG sites in antigen-induced regulatory T cells were significantly different between IT versus NT participants. When IT participants were withdrawn from peanut therapy for an additional 3 months (total of 6 months), only 3 participants remained classified as IT participants, and 4 participants regained sensitivity along with increased methylation of FOXP3 CpG sites in antigen-induced regulatory T cells. CONCLUSION In summary, modifications at the DNA level of antigen-induced T-cell subsets might be predictive of a state of operationally defined clinical immune tolerance during peanut OIT.
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Affiliation(s)
- Aleena Syed
- Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif
| | - Marco A Garcia
- Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif
| | - Shu-Chen Lyu
- Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif
| | - Robert Bucayu
- Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif
| | - Arunima Kohli
- Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif
| | - Satoru Ishida
- Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif
| | - Jelena P Berglund
- Duke Translational Medicine Institute, Regulatory Affairs, Durham, NC
| | - Mindy Tsai
- Department of Pathology, Stanford University School of Medicine, Stanford, Calif
| | - Holden Maecker
- Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, Calif
| | - Gerri O'Riordan
- Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif
| | - Stephen J Galli
- Department of Pathology, Stanford University School of Medicine, Stanford, Calif; Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, Calif
| | - Kari C Nadeau
- Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif.
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Massarelli E, Papadimitrakopoulou V, Welsh J, Tang C, Tsao AS. Immunotherapy in lung cancer. Transl Lung Cancer Res 2014; 3:53-63. [PMID: 25806281 PMCID: PMC4367607 DOI: 10.3978/j.issn.2218-6751.2014.01.01] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2013] [Accepted: 01/17/2014] [Indexed: 12/13/2022]
Abstract
Survival rates for metastatic lung cancer including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are poor with 5-year survival of less than 5%. The use of molecular targeted therapies has improved median overall survival (OS) in a limited group of NSCLC patients whose tumors harbor specific genetic alterations. However for a large group of NSCLC and SCLC molecular alterations are not available to lead to direct targeted therapies. Recent favorable results of newer trials of therapeutic vaccines and checkpoint inhibitors have proven against the common belief that lung cancer is nonimmunogenic. In particular, the checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed death-1 (PD-1) pathway have shown durable clinical responses with manageable toxicity. Several phase II and III clinical trials testing the association of different schedule of chemotherapy and immunotherapy or immunotherapy alone are ongoing in lung cancer and important results are expected in the near future. However, more studies are needed to understand the optimal combination of immunotherapeutic agents with chemotherapy and radiation therapy for the treatment of NSCLC and SCLC.
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Perez CA, Santos ES, Raez LE. Active immunotherapy for non-small-cell lung cancer: moving toward a reality. Expert Rev Anticancer Ther 2014; 11:1599-605. [DOI: 10.1586/era.11.155] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
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