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Nagai H, Mukozu T, Matsui T, Mohri K, Nagumo H, Yoshimine N, Kobayashi K, Ogino Y, Daido Y, Wakui N, Momiyama K, Matsuda T, Igarashi Y, Higai K. Remaining Issues Related to Serum Cytokines in Patients with Unresectable Hepatocellular Carcinoma Treated by Atezolizumab plus Bevacizumab Combination Treatment. Oncology 2024; 102:828-840. [PMID: 38402871 DOI: 10.1159/000537965] [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: 01/06/2024] [Accepted: 02/15/2024] [Indexed: 02/27/2024]
Abstract
INTRODUCTION Atezolizumab plus bevacizumab (AteBev) combination treatment is widely used as first-line systemic therapy for unresectable hepatocellular carcinoma (uHCC). We aimed to clarify therapeutic issues regarding serum cytokines and the immune reaction in patients with uHCC treated with AteBev. METHODS We analyzed preserved serum from a previous prospective study on adult Japanese patients with chronic liver disease and uHCC who received AteBev treatment at our hospital. In that study, AteBev was administered intravenously every 3 weeks, and blood samples were collected before and after 3 weeks' treatment. Dynamic computed tomography was performed after 6 weeks of treatment to assess response. RESULTS In the prospective study, 21 of the 59 patients showed partial response (PR) and 19 patients showed stable disease, but 19 patients showed progressive disease (PD). We found that serum levels of tumor necrosis factor-alpha, interleukin (IL)-6, and soluble IL-2 receptor (IL-2R) increased significantly in the PR group, but only soluble IL-2R increased significantly in the PD group. Regulatory T cells decreased significantly in the PD group, but there was no significant change in Th1 or Th2 cells from before to after treatment in any group. As regards soluble MHC-class I, pre-treatment levels were significantly lower in the PD group than in the PR group, and serum levels increased significantly with treatment in the PD group. CONCLUSION These findings reveal a need to further improve T-cell priming and to further make T cells recognize tumor antigens in uHCC.
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Affiliation(s)
- Hidenari Nagai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Takanori Mukozu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Teppei Matsui
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Kunihide Mohri
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Hideki Nagumo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Naoyuki Yoshimine
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Kojiro Kobayashi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Yu Ogino
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Yasuko Daido
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Noritaka Wakui
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Koichi Momiyama
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Takahisa Matsuda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Yoshinori Igarashi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Koji Higai
- Department of Medical Biochemistry, Faculty of Pharmaceutical Sciences, Toho University, Chiba, Japan
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Burassakarn A, Phusingha P, Yugawa T, Noguchi K, Ekalaksananan T, Vatanasapt P, Kiyono T, Pientong C. Human Papillomavirus 16 E6 Suppresses Transporter Associated with Antigen-Processing Complex in Human Tongue Keratinocyte Cells by Activating Lymphotoxin Pathway. Cancers (Basel) 2022; 14:cancers14081944. [PMID: 35454851 PMCID: PMC9028769 DOI: 10.3390/cancers14081944] [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: 03/14/2022] [Revised: 04/10/2022] [Accepted: 04/10/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary There is still limited knowledge of the critical pathogenic processes by which HPV16 induces oral carcinogenesis. Therefore, we aimed to illuminate the oncogenic role of HPV16 in the context of oral squamous cell carcinomas (OSCCs). Using human tongue keratinocyte cells, we demonstrated that HPV16 E6 promotes LTα1β2 and LTβR expression, thus promoting the lymphotoxin signaling pathway and leading to suppression of the transporter associated with the antigen-processing complex (TAPs; TAP1 and TAP2). Additionally, in vitro, we also demonstrated regulation of the antigenic peptide-loaded machinery in HPV-infected OSCC tissues through analysis of the transcriptomic profiles of the head and neck squamous cell carcinoma (HNSCC) cohort from the TCGA database, which was validated using fresh biopsied specimens. Thus, our study enhances the proposed functional role of HPV16 E6-associated immune-evasive properties in oral epithelial cells, revealing a possible mechanism underlying the development of HPV-mediated OSCCs. Abstract Infection by high-risk human papillomaviruses (hrHPVs), including HPV type 16 (HPV16), is a major risk factor for oral squamous cell carcinomas (OSCCs). However, the pathogenic mechanism by which hrHPVs promote oral carcinogenesis remains to be elucidated. Here, we demonstrated that the suppression of a transporter associated with the antigen-processing complex (TAPs; TAP1 and TAP2), which is a key molecule in the transportation of viral antigenic peptides into MHC class-I cells, is affected by the E6 protein of HPV16. Mechanistically, HPV-mediated immune evasion is principally mediated via the signal-transduction network of a lymphotoxin (LT) pathway, in particular LTα1β2 and LTβR. Our analysis of transcriptomic data from an HNSCC cohort from the Cancer Genome Atlas (TCGA) indicated that expression of TAP genes, particularly TAP2, was downregulated in HPV-infected cases. We further demonstrated that LTα1β2 and LTβR were upregulated, which was negatively correlated with TAP1 and TAP2 expression in HPV-positive clinical OSCC samples. Taken together, our findings imply that HPV16 E6 regulates the machinery of the antigenic peptide-loading system and helps to clarify the role of oncogenic viruses in the context of oral carcinoma.
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Affiliation(s)
- Ati Burassakarn
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (A.B.); (T.E.)
- HPV & EBV and Carcinogenesis Research Group, Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand;
| | - Pensiri Phusingha
- Center of Excellence for Antibody Research (CEAR), Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand;
| | - Takashi Yugawa
- Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute, Tokyo 104-0045, Japan;
| | - Kazuma Noguchi
- Department of Oral and Maxillofacial Surgery, Hyogo Medical University, Mukogawa-Cho 1-1, Nishinomiya 663-8501, Japan;
| | - Tipaya Ekalaksananan
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (A.B.); (T.E.)
- HPV & EBV and Carcinogenesis Research Group, Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand;
| | - Patravoot Vatanasapt
- HPV & EBV and Carcinogenesis Research Group, Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand;
- Department of Otorhinolaryngology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Tohru Kiyono
- Project for Prevention of HPV-Related Cancer, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa 277-8577, Japan
- Correspondence: (T.K.); (C.P.); Tel./Fax: +66-4334-8385 (C.P.)
| | - Chamsai Pientong
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (A.B.); (T.E.)
- HPV & EBV and Carcinogenesis Research Group, Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand;
- Correspondence: (T.K.); (C.P.); Tel./Fax: +66-4334-8385 (C.P.)
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Dada S, Ellis SLS, Wood C, Nohara LL, Dreier C, Garcia NH, Saranchova I, Munro L, Pfeifer CG, Eyford BA, Kari S, Garrovillas E, Caspani G, Al Haddad E, Gray PW, Morova T, Lack NA, Andersen RJ, Tjoelker L, Jefferies WA. Specific cannabinoids revive adaptive immunity by reversing immune evasion mechanisms in metastatic tumours. Front Immunol 2022; 13:982082. [PMID: 36923728 PMCID: PMC10010394 DOI: 10.3389/fimmu.2022.982082] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 12/20/2022] [Indexed: 02/24/2023] Open
Abstract
Emerging cancers are sculpted by neo-Darwinian selection for superior growth and survival but minimal immunogenicity; consequently, metastatic cancers often evolve common genetic and epigenetic signatures to elude immune surveillance. Immune subversion by metastatic tumours can be achieved through several mechanisms; one of the most frequently observed involves the loss of expression or mutation of genes composing the MHC-I antigen presentation machinery (APM) that yields tumours invisible to Cytotoxic T lymphocytes, the key component of the adaptive cellular immune response. Fascinating ethnographic and experimental findings indicate that cannabinoids inhibit the growth and progression of several categories of cancer; however, the mechanisms underlying these observations remain clouded in uncertainty. Here, we screened a library of cannabinoid compounds and found molecular selectivity amongst specific cannabinoids, where related molecules such as Δ9-tetrahydrocannabinol, cannabidiol, and cannabigerol can reverse the metastatic immune escape phenotype in vitro by inducing MHC-I cell surface expression in a wide variety of metastatic tumours that subsequently sensitizing tumours to T lymphocyte recognition. Remarkably, H3K27Ac ChIPseq analysis established that cannabigerol and gamma interferon induce overlapping epigenetic signatures and key gene pathways in metastatic tumours related to cellular senescence, as well as APM genes involved in revealing metastatic tumours to the adaptive immune response. Overall, the data suggest that specific cannabinoids may have utility in cancer immunotherapy regimens by overcoming immune escape and augmenting cancer immune surveillance in metastatic disease. Finally, the fundamental discovery of the ability of cannabinoids to alter epigenetic programs may help elucidate many of the pleiotropic medicinal effects of cannabinoids on human physiology.
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Affiliation(s)
- Sarah Dada
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.,Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada.,Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.,The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada.,Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
| | - Samantha L S Ellis
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.,Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada.,Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.,The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada.,Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - Christi Wood
- Biotechnology - Biomedical Science and Technology (BST), University of Applied Sciences, Mannheim, Germany
| | - Lilian L Nohara
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.,Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.,The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada.,Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
| | - Carola Dreier
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.,Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.,The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada.,Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.,Biotechnology - Biomedical Science and Technology (BST), University of Applied Sciences, Mannheim, Germany
| | | | - Iryna Saranchova
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.,Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada.,Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.,The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
| | - Lonna Munro
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.,Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada.,Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.,The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
| | - Cheryl G Pfeifer
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.,Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada.,Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.,The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
| | - Brett A Eyford
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.,Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.,The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
| | - Suresh Kari
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.,Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada.,Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.,The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
| | - Emmanuel Garrovillas
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.,Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada.,Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.,The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada.,Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.,Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - Giorgia Caspani
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.,Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada.,Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.,The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada.,Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.,Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - Eliana Al Haddad
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.,Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada.,Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.,The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada.,Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.,Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | | | - Tunc Morova
- Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada
| | - Nathan A Lack
- Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada.,School of Medicine, Koç University, Istanbul, Türkiye
| | - Raymond J Andersen
- Department of Chemistry, University of British Columbia, Vancouver, BC, Canada
| | | | - Wilfred A Jefferies
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.,Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada.,Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.,The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada.,Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.,Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.,Department of Zoology, University of British Columbia, Vancouver, BC, Canada.,Department of Urological Science, University of British Columbia, Vancouver, BC, Canada
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Aflalo A, Boyle LH. Polymorphisms in MHC class I molecules influence their interactions with components of the antigen processing and presentation pathway. Int J Immunogenet 2021; 48:317-325. [PMID: 34176210 DOI: 10.1111/iji.12546] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 05/12/2021] [Accepted: 05/24/2021] [Indexed: 10/21/2022]
Abstract
MHC class I (MHC-I) molecules undergo an intricate folding process in order to pick up antigenic peptide to present to the immune system. In recent years, the discovery of a new peptide editor for MHC-I has added an extra level of complexity in our understanding of how peptide presentation is regulated. On top of this, the incredible diversity in MHC-I molecules leads to significant variation in the interaction between MHC-I and components of the antigen processing and presentation pathway. Here, we review our current understanding regarding how polymorphisms in human leukocyte antigen class I molecules influence their interactions with key components of the antigen processing and presentation pathway. A deeper understanding of this may offer new insights regarding how apparently subtle variation in MHC-I can have a significant impact on susceptibility to disease.
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Affiliation(s)
- Aure Aflalo
- Department of Pathology, University of Cambridge, Cambridge, UK
| | - Louise H Boyle
- Department of Pathology, University of Cambridge, Cambridge, UK
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5
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Maintenance of WT1 expression in tumor cells is associated with a good prognosis in malignant glioma patients treated with WT1 peptide vaccine immunotherapy. Cancer Immunol Immunother 2021; 71:189-201. [PMID: 34089373 DOI: 10.1007/s00262-021-02954-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 04/28/2021] [Indexed: 10/21/2022]
Abstract
We have previously revealed the overexpression of Wilms' tumor gene 1 (WT1) in malignant glioma and developed WT1 peptide vaccine cancer immunotherapy. A phase II clinical trial indicated the clinical efficacy of the WT1 peptide vaccine for recurrent malignant glioma. Here, we aimed to investigate the immunological microenvironment in glioma tissues before and after WT1 peptide vaccine treatment. Paired tissue samples were obtained from 20 malignant glioma patients who had received the WT1 peptide vaccine for > 3 months and experienced tumor progression, confirmed radiographically and/or clinically, during vaccination. We discovered that the expression of WT1 and HLA class I antigens in the tumor cells significantly decreased after vaccination. Maintenance of WT1 expression, which is the target molecule of immunotherapy, in tumor cells during the vaccination period was significantly associated with a longer progression-free and overall survival. A high expression of HLA class I antigens and low CD4+/CD8+ tumor-infiltrating lymphocytes (TIL) ratio in pre-vaccination specimens, were also associated with a good prognosis. No statistically significant difference existed in the number of infiltrating CD3+ or CD8+ T cells between the pre- and post-vaccination specimens, whereas the number of infiltrating CD4+ T cells significantly decreased in the post-vaccination specimens. This study provides insight into the mechanisms of intra-tumoral immune reaction/escape during WT1 peptide vaccine treatment and suggests potential clinical strategies for cancer immunotherapy.
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6
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Jin YJ, Byun S, Han S, Chamberlin J, Kim D, Kim MJ, Lee Y. Differential alternative splicing regulation among hepatocellular carcinoma with different risk factors. BMC Med Genomics 2019; 12:175. [PMID: 31856847 PMCID: PMC6923823 DOI: 10.1186/s12920-019-0635-z] [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: 11/14/2019] [Accepted: 11/25/2019] [Indexed: 12/11/2022] Open
Abstract
Background Hepatitis B virus (HBV), hepatitis C virus (HCV), and alcohol consumption are predominant causes of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying how differently these causes are implicated in HCC development are not fully understood. Therefore, we investigated differential alternative splicing (AS) regulation among HCC patients with these risk factors. Methods We conducted a genome-wide survey of AS events associated with HCCs among HBV (n = 95), HCV (n = 47), or alcohol (n = 76) using RNA-sequencing data obtained from The Cancer Genome Atlas. Results In three group comparisons of HBV vs. HCV, HBV vs. alcohol, and HCV vs. alcohol for RNA seq (ΔPSI> 0.05, FDR < 0.05), 133, 93, and 29 differential AS events (143 genes) were identified, respectively. Of 143 AS genes, eight and one gene were alternatively spliced specific to HBV and HCV, respectively. Through functional analysis over the canonical pathways and gene ontologies, we identified significantly enriched pathways in 143 AS genes including immune system, mRNA splicing-major pathway, and nonsense-mediated decay, which may be important to carcinogenesis in HCC risk factors. Among eight genes with HBV-specific splicing events, HLA-A, HLA-C, and IP6K2 exhibited more differential expression of AS events (ΔPSI> 0.1). Intron retention of HLA-A was observed more frequently in HBV-associated HCC than HCV- or alcohol-associated HCC, and intron retention of HLA-C showed vice versa. Exon 3 (based on ENST00000432678) of IP6K2 was less skipped in HBV-associated in HCC compared to HCV- or alcohol-associated HCC. Conclusion AS may play an important role in regulating transcription differences implicated in HBV-, HCV-, and alcohol-related HCC development.
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Affiliation(s)
- Young-Joo Jin
- Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT, USA.,Division of Gastroenterology, Department of Internal Medicine, Inha University School of Medicine, Incheon, South Korea
| | - Seyoun Byun
- Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Seonggyun Han
- Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - John Chamberlin
- Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Dongwook Kim
- Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Min Jung Kim
- Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT, USA.,Pharmacy program, Massachusetts College of Pharmacy and Health Sciences, Worcester, MA, USA
| | - Younghee Lee
- Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT, USA. .,Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
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7
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Banach M, Robert J. Evolutionary Underpinnings of Innate-Like T Cell Interactions with Cancer. Immunol Invest 2019; 48:737-758. [PMID: 31223047 DOI: 10.1080/08820139.2019.1631341] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Cancers impose a significant health and economic burden. By harnessing the immune system, current immunotherapies have revolutionized the treatment against human cancers and potentially offer a long-term cure. Among others, innate-like T (iT) cells, including natural killer T cells, are promising candidates for immunotherapies. Unlike conventional T cells, iT cells regulate multiple immune processes and express an invariant T cell receptor that is shared among different individuals. However, the conditions that activate the pro- and antitumor functions of iT cells are partially understood. These gaps in knowledge hamper the use of iT cell in clinics. It might be beneficial to examine the roles of iT cells in an alternative animal model - the amphibian Xenopus whose immune system shares many similarities to that of mammals. Here, we review the iT cell biology in the context of mammalian cancers and discuss the challenges currently found in the field. Next, we introduce the advantages of Xenopus as a model to investigate the role of iT cells and interacting major histocompatibility complex (MHC) class I-like molecules in tumor immunity. In Xenopus, 2 specific iT cell subsets, Vα6 and Vα22 iT cells, recognize and fight tumor cells. Furthermore, our recent data reveal the complex functions of the Xenopus MHC class I-like (XNC) gene XNC10 in tumor immune responses. By utilizing reverse genetics, transgenesis, and MHC tetramers, we have a unique opportunity to uncover the relevance of XNC genes and iT cell in Xenopus tumor immunity.
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Affiliation(s)
- Maureen Banach
- Department of Immunology & Microbiology, University of Colorado School of Medicine , Aurora , CO , USA.,Department of Microbiology & Immunology, University of Rochester Medical Center , Rochester , NY , USA
| | - Jacques Robert
- Department of Microbiology & Immunology, University of Rochester Medical Center , Rochester , NY , USA
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8
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Zhang ML, Kem M, Mooradian MJ, Eliane JP, Huynh TG, Iafrate AJ, Gainor JF, Mino-Kenudson M. Differential expression of PD-L1 and IDO1 in association with the immune microenvironment in resected lung adenocarcinomas. Mod Pathol 2019; 32:511-523. [PMID: 30367104 DOI: 10.1038/s41379-018-0160-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 09/18/2018] [Accepted: 09/19/2018] [Indexed: 11/09/2022]
Abstract
Like programmed cell death ligand 1 (PD-L1), indoleamine 2,3-dioxygenase 1 (IDO1) is known to exert immunosuppressive effects and be variably expressed in human lung cancer. However, IDO1 expression has not been well studied in lung adenocarcinoma. PD-L1 and IDO1 expression was evaluated in 261 resected lung adenocarcinomas using tissue microarrays and H-scores (cutoff: 5). We compared IDO1 and PD-L1 expression with clinical features, tumor-infiltrating lymphocytes, HLA class I molecule expression, molecular alterations, and patient outcomes. There was expression of PD-L1 in 89 (34%) and IDO1 in 74 (29%) cases, with co-expression in 49 (19%). Both PD-L1 and IDO1 were significantly associated with smoking, aggressive pathologic features, and abundant CD8+ and T-bet+ (Th1 marker) tumor-infiltrating lymphocytes. PD-L1 expression was also associated with preserved HLA class I molecule expression (p = 0.002). Compared to PD-L1+/IDO1+ and PD-L1+ only cases, significantly fewer IDO1+ only cases had abundant CD8+ and T-bet+ tumor-infiltrating lymphocytes (p < 0.001, respectively). PD-L1 expression was significantly associated with EGFR wild-type (p < 0.001) and KRAS mutants (p = 0.021), whereas isolated IDO1 expression was significantly associated with EGFR mutations (p = 0.007). As for survival, PD-L1 was a significant predictor of decreased progression-free and overall survival by univariate but not multivariate analysis, while IDO1 was not associated with progression-free or overall survival. Interestingly, there was a significant difference in the 5-year progression-free and overall survival (p = 0.004 and 0.038, respectively), where cases without PD-L1 or IDO1 expression had the longest survival, and those with PD-L1 alone had the shortest survival. While PD-L1+/-IDO1 expression is observed in association with HLA class I expression, cytotoxic T lymphocyte/Th1 microenvironments, EGFR wild-type, and KRAS mutations, isolated IDO1 expression does not demonstrate these associations, suggesting that IDO1 may serve a distinct immunosuppressive role in lung adenocarcinomas. Thus, further investigation of IDO1 may demonstrate its role as a potential biomarker for patients who undergo anti-PD-1/PD-L1 therapy.
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Affiliation(s)
- M Lisa Zhang
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Marina Kem
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Meghan J Mooradian
- Cancer Center, Massachusetts General Hospital, Boston, MA, USA.,Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Jean-Pierre Eliane
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Tiffany G Huynh
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - A John Iafrate
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.,Cancer Center, Massachusetts General Hospital, Boston, MA, USA.,Department of Pathology, Harvard Medical School, Boston, MA, USA
| | - Justin F Gainor
- Cancer Center, Massachusetts General Hospital, Boston, MA, USA.,Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Mari Mino-Kenudson
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. .,Cancer Center, Massachusetts General Hospital, Boston, MA, USA. .,Department of Pathology, Harvard Medical School, Boston, MA, USA.
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9
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Yu F, Gong L, Mo Z, Wang W, Wu M, Yang J, Zhang Q, Li L, Yao J, Dong J. Programmed death ligand-1, tumor infiltrating lymphocytes and HLA expression in Chinese extrahepatic cholangiocarcinoma patients: Possible immunotherapy implications. Biosci Trends 2019; 13:58-69. [PMID: 30773525 DOI: 10.5582/bst.2019.01003] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Immunotherapy might be an effective treatment in extrahepatic cholangiocarcinoma (eCCA), a tumor with extremely limited therapeutic options. Our study is to characterize the programmed death ligand-1 (PD-L1) protein expression and cancer microenvironment profiles in surgically resected eCCA samples. PD-L1 positivity was observed on tumor cells (32.3%) as well as on tumor-associated macrophages (74.2%). PD-L1 expression by eCCA correlated significantly with immune parameters such as intra-tumoral CD3+ tumor infiltrating lymphocytes (TILs) density (P = 0.002), intra-tumoral CD8+ TILs density (P < 0.001), and the expression pattern of human leukocyte antigen (HLA) class I (P < 0.001). Immunofluorescence showed that PD-L1 positive tumor cells were adjacent to PD-1 positive cells and the stroma covered with interferon-γ. Correlation with clinicopathological parameters and survival analyses revealed that PD-L1 positivity in eCCA was related to the absence of venous invasion (P = 0.030), improved overall survival (P = 0.020) and progressionfree survival (P = 0.011). HLA class I molecules defect, which is an important mechanism of immune evasion, was frequently observed in eCCA (50.0%) and was associated with a decreased number of intra-tumoral CD8+ TIL density (P = 0.028). Additionally, the presence of unusually high numbers of tumor-associated macrophages (TAMs) subsets M2 in most of eCCA (74.2%) was noted. Our study indicated that PD-L1 expression in association with intra-tumoral TILs infiltration and HLA class I expression in 32.3% of the eCCA reflects an active immune microenvironment potentially responsive to PD-1/PD-L1 inhibitors. In addition, the combination of macrophage-targeting agents may provide therapeutic synergy for future immunotherapy.
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Affiliation(s)
- Fei Yu
- School of Clinical Medicine, Tsinghua University
| | - Lei Gong
- Department of Hepatopancreatobiliary Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University
| | - Zheng Mo
- Department of Hematology and Oncology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University
| | - Wenran Wang
- School of Clinical Medicine, Tsinghua University.,Department of Hepatopancreatobiliary Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University
| | - Meilong Wu
- School of Clinical Medicine, Tsinghua University.,Department of Hepatopancreatobiliary Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University
| | - Jianghui Yang
- Department of Pathology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University
| | | | - Li Li
- Department of Pathology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University
| | - Jingjing Yao
- Department of Pathology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University
| | - Jiahong Dong
- School of Clinical Medicine, Tsinghua University
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Grizzi F, Borroni EM, Qehajaj D, Stifter S, Chiriva-Internati M, Cananzi FCM. The Complex Nature of Soft Tissue Sarcomas, Including Retroperitoneal Sarcomas. Updates Surg 2019:21-32. [DOI: 10.1007/978-88-470-3980-3_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/28/2023]
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11
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Uppendahl LD, Dahl CM, Miller JS, Felices M, Geller MA. Natural Killer Cell-Based Immunotherapy in Gynecologic Malignancy: A Review. Front Immunol 2018; 8:1825. [PMID: 29354116 PMCID: PMC5760535 DOI: 10.3389/fimmu.2017.01825] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Accepted: 12/04/2017] [Indexed: 12/20/2022] Open
Abstract
Harnessing the immune system has proven an effective therapy in treating malignancies. Since the discovery of natural killer (NK) cells, strategies aimed to manipulate and augment their effector function against cancer have been the subject of intense research. Recent progress in the immunobiology of NK cells has led to the development of promising therapeutic approaches. In this review, we will focus on the recent advances in NK cell immunobiology and the clinical application of NK cell immunotherapy in ovarian, cervical, and uterine cancer.
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Affiliation(s)
- Locke D Uppendahl
- Department of Obstetrics, Gynecology and Women's Health, Division of Gynecologic Oncology, University of Minnesota School of Medicine, Minneapolis, MN, United States
| | - Carly M Dahl
- University of Minnesota School of Medicine, Minneapolis, MN, United States
| | - Jeffrey S Miller
- Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota School of Medicine, Minneapolis, MN, United States
| | - Martin Felices
- Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota School of Medicine, Minneapolis, MN, United States
| | - Melissa A Geller
- Department of Obstetrics, Gynecology and Women's Health, Division of Gynecologic Oncology, University of Minnesota School of Medicine, Minneapolis, MN, United States
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12
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Non Melanoma Skin Cancer Pathogenesis Overview. Biomedicines 2018; 6:biomedicines6010006. [PMID: 29301290 PMCID: PMC5874663 DOI: 10.3390/biomedicines6010006] [Citation(s) in RCA: 152] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Revised: 12/07/2017] [Accepted: 12/20/2017] [Indexed: 12/12/2022] Open
Abstract
(1) Background: Non-melanoma skin cancer is the most frequently diagnosed cancer in humans. The process of skin carcinogenesis is still not fully understood. However, several studies have been conducted to better explain the mechanisms that lead to malignancy; (2) Methods: We reviewed the more recent literature about the pathogenesis of non-melanoma skin cancer focusing on basal cell carcinomas, squamous cell carcinoma and actinic keratosis; (3) Results: Several papers reported genetic and molecular alterations leading to non-melanoma skin cancer. Plenty of risk factors are involved in non-melanoma skin cancer pathogenesis, including genetic and molecular alterations, immunosuppression, and ultraviolet radiation; (4) Conclusion: Although skin carcinogenesis is still not fully understood, several papers demonstrated that genetic and molecular alterations are involved in this process. In addition, plenty of non-melanoma skin cancer risk factors are now known, allowing for an effective prevention of non-melanoma skin cancer development. Compared to other papers on the same topic, our review focused on molecular and genetic factors and analyzed in detail several factors involved in non-melanoma skin cancer.
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13
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Hirai A, Yoneda K, Shimajiri S, Kuroda K, Hanagiri T, Fujino Y, Tanaka F. Prognostic impact of programmed death-ligand 1 expression in correlation with human leukocyte antigen class I expression status in stage I adenocarcinoma of the lung. J Thorac Cardiovasc Surg 2017; 155:382-392.e1. [PMID: 28711324 DOI: 10.1016/j.jtcvs.2017.05.106] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Revised: 05/24/2017] [Accepted: 05/31/2017] [Indexed: 12/24/2022]
Abstract
OBJECTIVE The study objective was to investigate the prognostic impact of programmed death-ligand 1 expression in correlation with human leukocyte antigen class I expression on tumor cells in early-stage adenocarcinoma of the lung, because both programmed death-ligand 1 and human leukocyte antigen class I molecules play important roles in cancer immunity. METHODS Ninety-four patients with completely resected pathologic stage I lung adenocarcinoma were retrospectively reviewed. Programmed death-ligand 1 expression on tumor cells was evaluated with immunohistochemistry in correlation with several clinicopathologic and molecular features, including human leukocyte antigen class I expression on tumor cells. RESULTS Fifteen patients (16.0%) had tumor with positive programmed death-ligand 1 expression (percentage of tumor cells expressing programmed death-ligand 1, ≥5%), and the incidence was significantly higher in poorly differentiated tumors. There was no significant correlation between human leukocyte antigen class I expression and programmed death-ligand 1 expression. Programmed death-ligand 1 positivity was a significant factor to predict a poor survival (5-year survival, 66.7% vs 85.9%; P = .049), which was enhanced in tumors with normal human leukocyte antigen class I expression (P = .029) but was not evident in tumors with reduced human leukocyte antigen class I expression (P = .552). CONCLUSIONS The prognostic impact of programmed death-ligand 1 expression on tumor cells in early-stage lung adenocarcinoma may be distinct according to concurrent human leukocyte antigen class I expression.
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Affiliation(s)
- Ayako Hirai
- Second Department of Surgery (Chest Surgery), University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Kazue Yoneda
- Second Department of Surgery (Chest Surgery), University of Occupational and Environmental Health, Kitakyushu, Japan.
| | - Shohei Shimajiri
- Second Department of Pathology and Cell Biology, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Koji Kuroda
- Second Department of Surgery (Chest Surgery), University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Takeshi Hanagiri
- Department of Thoracic Surgery, Shin-Kokura Hospital, Kitakyushu, Japan
| | - Yoshihisa Fujino
- Department of Preventive Medicine and Community Health, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Fumihiro Tanaka
- Second Department of Surgery (Chest Surgery), University of Occupational and Environmental Health, Kitakyushu, Japan
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Yesantharao P, Wang W, Ioannidis NM, Demehri S, Whittemore AS, Asgari MM. Cutaneous squamous cell cancer (cSCC) risk and the human leukocyte antigen (HLA) system. Hum Immunol 2017; 78:327-335. [PMID: 28185865 DOI: 10.1016/j.humimm.2017.02.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Revised: 02/03/2017] [Accepted: 02/03/2017] [Indexed: 01/20/2023]
Abstract
Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer among Caucasians in the United States, with rising incidence over the past decade. Treatment for non-melanoma skin cancer, including cSCC, in the United States was estimated to cost $4.8 billion in 2014. Thus, an understanding of cSCC pathogenesis could have important public health implications. Immune function impacts cSCC risk, given that cSCC incidence rates are substantially higher in patients with compromised immune systems. We report a systematic review of published associations between cSCC risk and the human leukocyte antigen (HLA) system. This review includes studies that analyze germline class I and class II HLA allelic variation as well as HLA cell-surface protein expression levels associated with cSCC risk. We propose biological mechanisms for these HLA-cSCC associations based on known mechanisms of HLA involvement in other diseases. The review suggests that immunity regulates the development of cSCC and that HLA-cSCC associations differ between immunocompetent and immunosuppressed patients. This difference may reflect the presence of viral co-factors that affect tumorigenesis in immunosuppressed patients. Finally, we highlight limitations in the literature on HLA-cSCC associations, and suggest directions for future research aimed at understanding, preventing and treating cSCC.
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Affiliation(s)
- Pooja Yesantharao
- Epidemiology Division, Department of Health Research & Policy, Stanford University, Stanford, CA 94305, USA
| | - Wei Wang
- Epidemiology Division, Department of Health Research & Policy, Stanford University, Stanford, CA 94305, USA
| | - Nilah M Ioannidis
- Epidemiology Division, Department of Health Research & Policy, Stanford University, Stanford, CA 94305, USA
| | - Shadmehr Demehri
- Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Alice S Whittemore
- Epidemiology Division, Department of Health Research & Policy, Stanford University, Stanford, CA 94305, USA.
| | - Maryam M Asgari
- Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
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15
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Banach M, Robert J. Tumor immunology viewed from alternative animal models-the Xenopus story. CURRENT PATHOBIOLOGY REPORTS 2017; 5:49-56. [PMID: 28944105 DOI: 10.1007/s40139-017-0125-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
A PURPOSE OF REVIEW Nonmammalian comparative animal models are important not only to gain fundamental evolutionary understanding of the complex interactions of tumors with the immune system, but also to better predict the applicability of novel immunotherapeutic approaches to humans. After reviewing recent advances in developing alternative models, we focus on the amphibian Xenopus laevis and its usefulness in deciphering the perplexing roles of MHC class I-like molecules and innate (i)T cells in tumor immunity. B RECENT FINDINGS Experiments using MHC-defined inbred and cloned animals, tumor cell lines, effective reagents, sequenced genomes, and adapted gene editing techniques in Xenopus, have revealed that the critical involvement of class I-like molecules and iT cells in tumor immunity has been conserved during evolution. C SUMMARY Comparative studies with the X. laevis tumor immunity model can contribute to the development of better and more efficient cancer immunotherapies.
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Affiliation(s)
- Maureen Banach
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, USA
| | - Jacques Robert
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, USA
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16
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Voutsas IF, Anastasopoulou EA, Tzonis P, Papamichail M, Perez SA, Baxevanis CN. Unraveling the role of preexisting immunity in prostate cancer patients vaccinated with a HER-2/neu hybrid peptide. J Immunother Cancer 2016; 4:75. [PMID: 27891225 PMCID: PMC5109671 DOI: 10.1186/s40425-016-0183-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 10/27/2016] [Indexed: 01/09/2023] Open
Abstract
Background Cancer vaccines aim at eliciting not only an immune response against specific tumor antigens, but also at enhancing a preexisting immunity against the tumor. In this context, we recently reported on the levels of preexisting immunity in prostate cancer patients vaccinated with the HER-2 hybrid peptide (AE37), during a phase I clinical trial. The purpose of the current study was to correlate between preexisting immunity to the native HER-2 peptide, AE36, and expression of HLA-A2 and -A24 molecules with the clinical outcome. Additionally, we investigated the ability of the AE37 vaccine to induce an antitumor immune response against other tumor associated antigens, not integrated in the vaccine formulation, with respect to the clinical response. Methods We analyzed prostate cancer patients who were vaccinated with the AE37 vaccine [Ii-Key-HER-2/neu(776–790) hybrid peptide vaccine (AE37), which is a MHC class II long peptide vaccine encompassing MHC class I epitopes, during a phase I clinical trial. Preexisting immunity to the native HER-2/neu(776–790) (AE36) peptide was assessed by IFNγ response or dermal reaction at the inoculation site. Antigen specificity against other tumor antigens was defined using multimer analysis. Progression free survival (PFS) was considered as the patients’ clinical outcome. Two-tailed Wilcoxon signed rank test at 95 % confidence interval was used for statistical evaluation at different time points and Kaplan–Meier curves with log-rank (Mantel-Cox) test were used for the evaluation of PFS. Results Preexisting immunity to AE36, irrespectively of HLA expression, was correlated with longer PFS. Specific CD8+ T cell immunity against E75 and PSA146–151 (HLA-A2 restricted), as well as, PSA153–161 (HLA-A24 restricted) was detected at relatively high frequencies which were further enhanced during vaccinations. Specific immunity against PSA153–161 correlated with longer PFS in HLA-A24+ patients. However, HLA-A2+ patients with high preexisting or vaccine-induced immunity to E75, showed a trend for shorter PFS. Conclusions Our data cast doubt on whether preexisting immunity or epitope spreading specific for HLA-class I-restricted peptides can actually predict a favorable clinical outcome. They also impose that preexisting immunity to long vaccine peptides, encompassing both HLA class II and I epitopes should be considered as an important prerequisite for the improvement of future immunotherapeutic protocols. Protocol ID Code: Generex-06-07 National Organization for Medicines (EOF) ID Code: IS-107-01-06 NEC Study Code: EED107/1/06 EudraCT Number: 2006-003299-37 Date of registration: 07/06/2006 Date of enrolment of the first participant to the trial: Nov 1st, 2007 Electronic supplementary material The online version of this article (doi:10.1186/s40425-016-0183-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ioannis F Voutsas
- Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, Athens, Greece
| | | | - Panagiotis Tzonis
- Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, Athens, Greece
| | - Michael Papamichail
- Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, Athens, Greece
| | - Sonia A Perez
- Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, Athens, Greece
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17
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Haynes-Gilmore N, Banach M, Edholm ES, Lord E, Robert J. A critical role of non-classical MHC in tumor immune evasion in the amphibian Xenopus model. Carcinogenesis 2014; 35:1807-13. [PMID: 24776220 DOI: 10.1093/carcin/bgu100] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Non-classical class Ib (class Ib) genes are found in all jawed vertebrates, including the amphibian Xenopus, which possesses at least 20 distinct Xenopus non-classical class Ib genes (XNCs). As an immune evasion strategy, tumors often downregulate surface expression of classical major histocompatibility complex class Ia molecules. In contrast, cancers commonly express class Ib molecules, presenting an alternative for tumor immune recognition. We characterized a novel XNC, XNC10, functionally similar to CD1d from a class Ia-deficient thymic lymphoid tumor (15/0), which grows aggressively in Xenopus LG-15 cloned animals. To investigate the roles of XNC10 in antitumor immunity, we generated stable 15/0-transfectants with silenced XNC10 mRNA and protein expression. Notably, XNC10 silencing resulted in acute tumor rejection by naturally class Ia-deficient syngeneic tadpoles, with greater potency of rejection in tumors with more efficient XNC10 knockdown. In vivo killing assays shows that the rejection of XNC10-deficient tumors is due to a cell-mediated cytotoxic immune response elicited by the tadpole host. Importantly, priming enhances XNC10-deficient tumor rejection. Flow cytometry reveals that XNC10-deficient tumor rejection is associated with an accumulation of XNC10-restricted invariant T cells and conventional CD8 T cells as well as other leukocytes. Similarly, semisolid tumor grafts in tadpoles also exhibit leukocytes infiltration. These findings suggest that XNC10 allows the 15/0-tumor to escape immune recognition and class Ia-independent cytotoxicity, thus emphasizing the critical roles of class Ibs in tumor immunity.
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Affiliation(s)
- Nikesha Haynes-Gilmore
- Department of Microbiology and Immunology and Department of Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA
| | | | | | - Edith Lord
- Department of Microbiology and Immunology and
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Atreya I, Neurath MF. Immune cells in colorectal cancer: prognostic relevance and therapeutic strategies. Expert Rev Anticancer Ther 2014; 8:561-72. [DOI: 10.1586/14737140.8.4.561] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Nicolay HJM, Sigalotti L, Fonsatti E, Covre A, Parisi G, Fratta E, Coral S, Maio M. Epigenetically regulated tumor-associated antigens in melanoma. ACTA ACUST UNITED AC 2014. [DOI: 10.1586/edm.09.6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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20
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Koringa PG, Jakhesara SJ, Bhatt VD, Meshram CP, Patel AK, Fefar DT, Joshi CG. Comprehensive transcriptome profiling of squamous cell carcinoma of horn in Bos indicus. Vet Comp Oncol 2013; 14:122-36. [PMID: 24314272 DOI: 10.1111/vco.12079] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2012] [Revised: 09/25/2013] [Accepted: 10/31/2013] [Indexed: 01/05/2023]
Abstract
Squamous cell carcinoma (SCC) of horn is frequently observed in Bos indicus affecting 1% of cattle population and accounting 83.34% of total tumours found. The transcriptome profile of horn cancer (HC) tissue and the matched normal (HN) tissue were analysed by RNA-seq using Roche 454 sequencing. A total of 1 504 900 reads comprising of 612 MB data were used to identify differentially expressed genes using CLC Genomic Workbench. These include up-regulation of KRT6A, KRT6B, KRT6C, KRT14, SFN, KRT84, PI3, COL17A1, ANLN, SERPINB5 and down-regulation of BOLA, SCGB1A1, CXCL17, KRT19, BPIFB1, NR4A1 and TFF3 in HC, which are involved in regulation of gene transcription, cell proliferation, apoptosis, cell survival and metabolic pathways. The qPCR analysis of several targets suggested concordance of gene expression profile with RNA-seq analysis. The present findings would provide basis for further screening of genes and identification of markers for early diagnosis and therapeutic intervention of HC.
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Affiliation(s)
- P G Koringa
- Department of Animal Biotechnology, College of Veterinary Science and Animal Husbandry, Anand Agricultural University, Anand, 388001, Gujarat, India
| | - S J Jakhesara
- Department of Animal Biotechnology, College of Veterinary Science and Animal Husbandry, Anand Agricultural University, Anand, 388001, Gujarat, India
| | - V D Bhatt
- Department of Animal Biotechnology, College of Veterinary Science and Animal Husbandry, Anand Agricultural University, Anand, 388001, Gujarat, India
| | - C P Meshram
- Department of Animal Biotechnology, College of Veterinary Science and Animal Husbandry, Anand Agricultural University, Anand, 388001, Gujarat, India
| | - A K Patel
- Department of Animal Biotechnology, College of Veterinary Science and Animal Husbandry, Anand Agricultural University, Anand, 388001, Gujarat, India
| | - D T Fefar
- Department of Animal Biotechnology, College of Veterinary Science and Animal Husbandry, Anand Agricultural University, Anand, 388001, Gujarat, India
| | - C G Joshi
- Department of Animal Biotechnology, College of Veterinary Science and Animal Husbandry, Anand Agricultural University, Anand, 388001, Gujarat, India
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Tanaka T, Shimada T, Akiyoshi H, Shimizu J, Zheng C, Yijyun L, Mie K, Hayashi A, Kuwamura M, Hoshi F, Ohashi F. Relationship between major histocompatibility complex class I expression and prognosis in canine mammary gland tumors. J Vet Med Sci 2013; 75:1393-8. [PMID: 23728200 PMCID: PMC3942927 DOI: 10.1292/jvms.13-0080] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The aim of this study was to evaluate MHC class I expression and prognosis using tumor
tissues surgically removed from 9 dogs with mammary gland carcinomas and from 13 dogs with
complex carcinomas. We assessed MHC class I expression and its correlation with tumor
size, B2M expression, infiltration of lymphocytes, histological grade and prognosis.
Hematoxylin and eosin-stained sections were histologically graded using the Elston and
Ellis grading method. MHC class I expression on tumor cells was evaluated using the
avidin-biotin peroxidase complex method. Loss of MHC class I expression from canine
mammary gland carcinomas was significantly correlated with poor prognosis
(P<0.05). Loss of MHC class I expression showed no association with
poor prognosis in canine mammary gland complex carcinomas, because the data were not
balanced. Only 1 of 13 (7.6%) canine mammary gland complex carcinomas showed loss of MHC
class I expression. All 13 of these dogs showed good prognosis. Thus, the low frequency of
MHC class I expression loss from canine mammary gland complex carcinomas may be associated
with good prognosis. Taken together, these results suggest that loss of MHC class I
expression may be associated with poor prognosis in canine mammary gland carcinomas.
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Affiliation(s)
- Toshiyuki Tanaka
- Laboratory of Veterinary Surgery, Department of Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-58 Rinku-Oraikita, Izumisano, Osaka 598-8531, Japan
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Tanaka T, Shimada T, Akiyoshi H, Zheng C, Mie K, Yijyun L, Hayashi A, Ohashi F. Germline polymorphism at the β2-microglobulin exon 1/intron 1 splice site in canine mammary gland simple and complex carcinomas. Vet Rec 2013; 172:529. [PMID: 23584472 DOI: 10.1136/vr.101238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
- T Tanaka
- Veterinary Medical Center, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-58 Rinku-oraikita, Izumisano-shi, Osaka 598-8531, Japan
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Domingues PH, Teodósio C, Ortiz J, Sousa P, Otero A, Maillo A, Bárcena P, García-Macias MC, Lopes MC, de Oliveira C, Orfao A, Tabernero MD. Immunophenotypic identification and characterization of tumor cells and infiltrating cell populations in meningiomas. THE AMERICAN JOURNAL OF PATHOLOGY 2012; 181:1749-61. [PMID: 22982440 DOI: 10.1016/j.ajpath.2012.07.033] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2012] [Revised: 06/12/2012] [Accepted: 07/06/2012] [Indexed: 11/27/2022]
Abstract
Meningiomas are primary tumors of the central nervous system composed of both neoplastic and other infiltrating cells. We determined the cellular composition of 51 meningioma samples by multiparameter flow cytometric (MFC) immunophenotyping and investigated the potential relationship between mRNA and protein expression levels of neoplastic cells. For immunophenotypic, morphologic, and cytogenetic characterization of individual cell populations, a large panel of markers was used together with phagocytic/endocytic functional assays and MFC sorting. Overall, our results revealed coexistence of CD45(-) neoplastic cells and CD45(+) immune infiltrating cells in all meningiomas. Infiltrating cells included tissue macrophages, with an HLA-DR(+)CD14(+)CD45(+)CD68(+)CD16(-/+)CD33(-/+) phenotype and high phagocytic/endocytic activity, and a small proportion of cytotoxic lymphocytes (mostly T CD8(+) and natural killer cells). Tumor cells expressed multiple cell adhesion proteins, tetraspanins, HLA-I/HLA-DR molecules, complement regulatory proteins, cell surface ectoenzymes, and growth factor receptors. Noteworthy, the relationship between mRNA and protein levels was variable, depending on the proteins evaluated and the level of infiltration by immune cells. In summary, our results indicate that MFC immunophenotyping provides a reliable tool for the characterization of the patterns of protein expression of different cell populations coexisting in meningioma samples, with a more accurate measure of gene expression profiles of tumor cells at the functional/protein level than conventional mRNA microarray, independently of the degree of infiltration of the tumor by immune cells.
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Affiliation(s)
- Patrícia H Domingues
- Centre for Neurosciences and Cell Biology, Faculty of Pharmacy, University of Coimbra, Portugal
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Amedei A, Della Bella C, Silvestri E, Prisco D, D'Elios MM. T cells in gastric cancer: friends or foes. Clin Dev Immunol 2012; 2012:690571. [PMID: 22693525 PMCID: PMC3369415 DOI: 10.1155/2012/690571] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2012] [Revised: 03/15/2012] [Accepted: 03/27/2012] [Indexed: 12/13/2022]
Abstract
Gastric cancer is the second cause of cancer-related deaths worldwide. Helicobacter pylori is the major risk factor for gastric cancer. As for any type of cancer, T cells are crucial for recognition and elimination of gastric tumor cells. Unfortunately T cells, instead of protecting from the onset of cancer, can contribute to oncogenesis. Herein we review the different types, "friend or foe", of T-cell response in gastric cancer.
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Affiliation(s)
- Amedeo Amedei
- Patologia Medica, Dipartimento de Biomedicina, Azienda Ospedaliera Universitaria Careggi, Largo Brambilla 3, 50134 Firenze, Italy
- Department of Internal Medicine, University of Florence, Florence 50134, Italy
| | - Chiara Della Bella
- Patologia Medica, Dipartimento de Biomedicina, Azienda Ospedaliera Universitaria Careggi, Largo Brambilla 3, 50134 Firenze, Italy
- Department of Internal Medicine, University of Florence, Florence 50134, Italy
| | - Elena Silvestri
- Patologia Medica, Dipartimento de Biomedicina, Azienda Ospedaliera Universitaria Careggi, Largo Brambilla 3, 50134 Firenze, Italy
- Department of Medical and Surgical Critical Care, University of Florence, Florence 50134, Italy
| | - Domenico Prisco
- Patologia Medica, Dipartimento de Biomedicina, Azienda Ospedaliera Universitaria Careggi, Largo Brambilla 3, 50134 Firenze, Italy
- Department of Medical and Surgical Critical Care, University of Florence, Florence 50134, Italy
| | - Mario M. D'Elios
- Patologia Medica, Dipartimento de Biomedicina, Azienda Ospedaliera Universitaria Careggi, Largo Brambilla 3, 50134 Firenze, Italy
- Department of Internal Medicine, University of Florence, Florence 50134, Italy
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25
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Tudor CS, Dawson CW, Eckhardt J, Niedobitek G, Büttner AC, Seliger B, Hartmann A, Buettner M. c-Myc and EBV-LMP1: two opposing regulators of the HLA class I antigen presentation machinery in epithelial cells. Br J Cancer 2012; 106:1980-8. [PMID: 22588558 PMCID: PMC3388564 DOI: 10.1038/bjc.2012.197] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Background: Epstein–Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) up-regulates the human leukocyte antigen (HLA) class I antigen presentation machinery (APM). This appears counterintuitive with immune evasion in EBV-associated tumours like nasopharyngeal carcinoma (NPC). Methods: Latent membrane protein 1-transfected epithelial cell lines were used as a model system to study the impact of LMP1 and c-Myc on HLA class I components. The expression of components of the HLA class I APM, c-Myc and Ki-67 was analysed in LMP1+ and LMP1− NPC by immunohistochemistry. Results: In epithelial cells, LMP1 up-regulated HLA class I APM. This effect could be counteracted by c-Myc, which itself was up-regulated by LMP1 apparently through IL6 induction and Jak3/STAT3 activation. Studies of NPC biopsies revealed down-regulation of HLA class I APM expression. No difference was observed between LMP1+ and LMP1− NPC. However, expression of Ki-67 and c-Myc were up-regulated in LMP1+ tumours. Conclusion: These findings raise the possibility that c-Myc activation in NPC might antagonise the effect of LMP1 on HLA class I expression thus contributing to immune escape of tumour cells.
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Affiliation(s)
- C S Tudor
- Institute of Pathology, Department of Nephropathology, Friedrich-Alexander-University, Erlangen-Nuremberg, Germany.
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26
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A novel category of antigens enabling CTL immunity to tumor escape variants: Cinderella antigens. Cancer Immunol Immunother 2011; 61:119-25. [PMID: 22116347 PMCID: PMC3249164 DOI: 10.1007/s00262-011-1160-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2011] [Accepted: 11/10/2011] [Indexed: 12/11/2022]
Abstract
Deficiencies in MHC class I antigen presentation are a common feature of tumors and allows escape from cytotoxic T lymphocyte (CTL)-mediated killing. It is crucial to take this capacity of tumors into account for the development of T-cell-based immunotherapy, as it may strongly impair their effectiveness. A variety of escape mechanisms has been described thus far, but progress in counteracting them is poor. Here we review a novel strategy to target malignancies with defects in the antigenic processing machinery (APM). The concept is based on a unique category of CD8+ T-cell epitopes that is associated with impaired peptide processing, which we named TEIPP. We characterized this alternative peptide repertoire emerging in MHC-I on tumors lacking classical antigen processing due to defects in the peptide transporter TAP (transporter associated with peptide processing). These TEIPPs exemplify interesting parallels with the folktale figure Cinderella: they are oppressed and neglected by a stepmother (like functional TAP prevents TEIPP presentation), until the suppression is released and Cinderella/TEIPP achieves unexpected recognition. TEIPP-specific CTLs and their cognate peptide-epitopes provide a new strategy to counteract immune evasion by APM defects and bear potential to targeting escape variants observed in a wide range of cancers.
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27
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Oliveira CC, Querido B, Sluijter M, Derbinski J, van der Burg SH, van Hall T. Peptide transporter TAP mediates between competing antigen sources generating distinct surface MHC class I peptide repertoires. Eur J Immunol 2011; 41:3114-24. [PMID: 21898382 DOI: 10.1002/eji.201141836] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2011] [Revised: 08/10/2011] [Accepted: 08/30/2011] [Indexed: 01/28/2023]
Abstract
We recently described a category of TAP-independent peptide-epitopes that are selectively presented by cells with processing defects in the classical MHC class I (MHC-I) pathway. Here, we studied the ER-resident ceramide synthase Trh4 as a prototypic example of these neo-antigens and found that moderate inhibition of TAP permits cell surface presentation of the Trh4 peptide. The absence of this peptide from WT cells was not related to the binding or stability of the Trh4/D(b) complexes, or to the availability of MHC-I heavy chains, but rather to the limited expression of the antigen. Strongly elevated antigen levels were needed to reach comparable peptide display on WT as on TAP-deficient cells. Our data suggest that the normal influx of TAP-transported peptides in the ER during routine processing creates an efficient barrier for peptides from alternative processing routes. Impairment of TAP function, as commonly found in cancers and virus-infected cells, lowers this resistance allowing for MHC-I presentation of other peptide sources.
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Affiliation(s)
- Cláudia C Oliveira
- Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands
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28
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Nieto-Sampedro M, Valle-Argos B, Gómez-Nicola D, Fernández-Mayoralas A, Nieto-Díaz M. Inhibitors of Glioma Growth that Reveal the Tumour to the Immune System. Clin Med Insights Oncol 2011; 5:265-314. [PMID: 22084619 PMCID: PMC3201112 DOI: 10.4137/cmo.s7685] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Treated glioblastoma patients survive from 6 to 14 months. In the first part of this review, we describe glioma origins, cancer stem cells and the genomic alterations that generate dysregulated cell division, with enhanced proliferation and diverse response to radiation and chemotherapy. We review the pathways that mediate tumour cell proliferation, neo-angiogenesis, tumor cell invasion, as well as necrotic and apoptotic cell death. Then, we examine the ability of gliomas to evade and suppress the host immune system, exhibited at the levels of antigen recognition and immune activation, limiting the effective signaling between glioma and host immune cells.The second part of the review presents current therapies and their drawbacks. This is followed by a summary of the work of our laboratory during the past 20 years, on oligosaccharide and glycosphingolipid inhibitors of astroblast and astrocytoma division. Neurostatins, the O-acetylated forms of gangliosides GD1b and GT1b naturally present in mammalian brain, are cytostatic for normal astroblasts, but cytotoxic for rat C6 glioma cells and human astrocytoma grades III and IV, with ID50 values ranging from 200 to 450 nM. The inhibitors do not affect neurons or fibroblasts up to concentrations of 4 μM or higher.At least four different neurostatin-activated, cell-mediated antitumoral processes, lead to tumor destruction: (i) inhibition of tumor neovascularization; (ii) activation of microglia; (iii) activation of natural killer (NK) cells; (iv) activation of cytotoxic lymphocytes (CTL). The enhanced antigenicity of neurostatin-treated glioma cells, could be related to their increased expression of connexin 43. Because neurostatins and their analogues show specific activity and no toxicity for normal cells, a clinical trial would be the logical next step.
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Affiliation(s)
- Manuel Nieto-Sampedro
- Instituto Cajal de Neurobiología, CSIC, 28002 Madrid, Spain
- Hospital Nacional de Parapléjicos, SESCAM, 45071 Toledo, Spain
| | - Beatriz Valle-Argos
- Instituto Cajal de Neurobiología, CSIC, 28002 Madrid, Spain
- Hospital Nacional de Parapléjicos, SESCAM, 45071 Toledo, Spain
| | - Diego Gómez-Nicola
- Instituto Cajal de Neurobiología, CSIC, 28002 Madrid, Spain
- Hospital Nacional de Parapléjicos, SESCAM, 45071 Toledo, Spain
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29
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Kim DH, Kim EM, Lee EH, Ji KY, Yi J, Park M, Kim KD, Cho YY, Kang HS. Human papillomavirus 16E6 suppresses major histocompatibility complex class I by upregulating lymphotoxin expression in human cervical cancer cells. Biochem Biophys Res Commun 2011; 409:792-8. [DOI: 10.1016/j.bbrc.2011.05.090] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2011] [Accepted: 05/16/2011] [Indexed: 12/20/2022]
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30
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Lampen MH, Verweij MC, Querido B, van der Burg SH, Wiertz EJHJ, van Hall T. CD8+ T cell responses against TAP-inhibited cells are readily detected in the human population. THE JOURNAL OF IMMUNOLOGY 2010; 185:6508-17. [PMID: 20980626 DOI: 10.4049/jimmunol.1001774] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Target cell recognition by CTLs depends on the presentation of peptides by HLA class I molecules. Tumors and herpes viruses have adopted strategies to greatly hamper this peptide presentation at the important bottleneck, the peptide transporter TAP. Previously, we described the existence of a CD8(+) CTL subpopulation that selectively recognizes such TAP-deficient cells in mouse models. In this study, we show that the human counterpart of this CTL subset is readily detectable in healthy subjects. Autologous PBMC cultures were initiated with dendritic cells rendered TAP-impaired by gene transfer of the viral evasion molecule UL49.5. Strikingly, specific reactivity to B-LCLs expressing one of the other viral TAP-inhibitors (US6, ICP47, or BNLF2a) was already observed after three rounds of stimulation. These short-term T cell cultures and isolated CD8(+) CTL clones derived thereof did not recognize the normal B-LCL, indicating that the cognate peptide-epitopes emerge at the cell surface upon an inhibition in the MHC class I processing pathway. A diverse set of TCRs was used by the clones, and the cellular reactivity was TCR-dependent and HLA class I-restricted, implying the involvement of a broad antigenic peptide repertoire. Our data indicate that the human CD8(+) T cell pool comprises a diverse reactivity to target cells with impairments in the intracellular processing pathway, and these might be exploited for cancers that are associated with such defects and for infections with immune-evading herpes viruses.
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Affiliation(s)
- Margit H Lampen
- Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands
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31
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Kloor M, Michel S, von Knebel Doeberitz M. Immune evasion of microsatellite unstable colorectal cancers. Int J Cancer 2010; 127:1001-10. [PMID: 20198617 DOI: 10.1002/ijc.25283] [Citation(s) in RCA: 116] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Colorectal cancers (CRC) develop through 2 major pathways of genetic instability. In contrast to the majority of CRCs, which are characterized by chromosomal instability, high-level microsatellite unstable (MSI-H) CRCs arise as a consequence of the loss of DNA mismatch repair (MMR) functions and show accumulation of insertion and deletion mutations particularly in microsatellite sequences. MSI-H occurs in about 15% of CRCs, and virtually all CRCs occurring in the context of the hereditary cancer-predisposing Lynch syndrome. These tumors are characterized by a comparably good prognosis and a low frequency of distant metastases. Because of the expression of a defined set of tumor-specific antigens, MSI-H CRCs elicit a strong local and systemic antitumoral immune response of the host and therefore use different strategies to evade the control of the immune system. In this review, we will summarize novel molecular mechanisms that at the same time drive pathogenesis, immunogenicity and immune evasion during the development and progression of MSI-H CRCs. We will focus on the current knowledge about alterations in human leukocyte antigen (HLA) antigen presentation and discuss how immune evasion-while offering protection against local antitumoral immune responses-paradoxically might interfere with the ability of the tumor to form distant organ metastases.
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Affiliation(s)
- Matthias Kloor
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany
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32
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Abstract
Even though the central nervous system (CNS) was conventionally defined as "immunologically privileged", new discoveries have demonstrated the role of the immune system in neurologic disease and illness, including gliomas. Brain tumor immunotherapy is an exciting and revived area of research, in which neurosurgeons have taken a major position. Despite the ability to induce a tumor-specific systemic immune response, the challenge to effectively eradicate intracranial gliomas remains mainly because of tumor-induced immunoresistance. This article gives an overview of the immunologic responses that occur in the CNS and their potential role in brain tumors. The main cellular and molecular mechanisms that mediate tumor escape from natural immune surveillance are also covered in this article. Glioma cells have been shown to diminish the expression of danger signals necessary for immune activation and to increase the concentration of immunosuppressive factors in the tumor microenvironment, which results in T-cell anergy or apoptosis. Finally, the authors discuss most of the over-expressed oncogenic signaling pathways that cause tumor tolerance.
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Affiliation(s)
- Emilia Albesiano
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
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33
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Seliger B. Different regulation of MHC class I antigen processing components in human tumors. J Immunotoxicol 2009; 5:361-7. [PMID: 19404870 DOI: 10.1080/15476910802482870] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
In recent years, progress has been made in understanding how peptides presented by MHC Class I molecules were generated, in particular which proteases are involved in this process and how intracellular pathways influence antigen presentation in professional antigen-presenting cells and various types of tumor cells. This review will give an overview of MHC Class I abnormalities in malignancies and their underlying molecular mechanisms. Dependent on the tumor types structural alterations in particular of the MHC Class I heavy chain, beta(2)-m and the TAP1 subunit have been found at a low frequency, whereas dysregulation of MHC Class I antigen processing components appears to be the major mechanism of MHC Class I down-regulation in tumors of distinct origin. This could occur at the epigenetic, transcriptional and/or post-transcriptional level. The lack or suppression of MHC Class I surface expression due to antigen-processing deficiencies are accompanied by reduced recognition and lysis by antigen-specific cytotoxic T-lymphocytes, which is further often associated with disease progression.
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Affiliation(s)
- Barbara Seliger
- Martin-Luther-Universitat Halle-Wittenberg, Institute of Medical Immunology, Halle (Saale), Germany.
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34
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Shen Y, Xia M, Zhang J, Xu L, Yang J, Chen A, Miao F, Ferrone S, Xie W. IRF-1 and p65 mediate upregulation of constitutive HLA-A antigen expression by hepatocellular carcinoma cells. Mol Immunol 2009; 46:2045-53. [PMID: 19428110 DOI: 10.1016/j.molimm.2009.03.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2008] [Revised: 01/28/2009] [Accepted: 03/01/2009] [Indexed: 10/20/2022]
Abstract
Malignant transformation of hepatocytes is frequently associated with upregulation of HLA-A expression. Currently there is no information available regarding the mechanisms underlying this phenotypic change. We investigated HLA-A expression in 165 paraffin embedded tissues and 21 fresh tissues from liver cancer patients. Utilizing truncated HLA-A promoter-reporter constructs and gel-shift assay we had identified the regulatory elements and transcription factors required for HLA-A upregulation. 54% of the paraffin embedded tissues showed increased HLA-A expression in their cancerous part. 43% of the fresh liver cancer tissues had increased HLA-A complex expression with the HLA-A heavy chain gene demonstrating the highest level of upregulation (62%). Enhanced HLA-A expression in the liver cell lines QGY7701 and BEL7402 was found to be mediated by binding of interferon regulatory factor 1 (IRF-1) to interferon stimulated response element, and of nuclear transcription factor p65 binding to enhancer A element in the HLA-A promoter of these cell lines. The in vivo relevance of these findings was indicated by the association of the enhanced expression of IRF-1 and accumulation of nuclear p65 with HLA-A upregulation in 8 of the 21 liver cancer lesions investigated. Our results indicated that HLA-A upregulation in liver cancer was mediated by both increased nuclear aggregation of transcription factor p65 and upregulation of transcription factor IRF-1.
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Affiliation(s)
- Yuqing Shen
- The Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Department of Genetics and Developmental Biology, Southeast University Medical School, Nanjing, Jiangsu 210009, China
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35
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Frecuencias de las pérdidas de heterocigocidad en la región que codifica para HLA en biopsias de pacientes con cáncer de cuello uterino. ACTA ACUST UNITED AC 2009. [DOI: 10.1016/s0123-9015(09)70118-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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36
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Kimura S, Kozakai Y, Kawaguchi S, Tsukahara T, Ida K, Murase M, Matsumura T, Kaya M, Torigoe T, Wada T, Sato N, Yamashita T. Clonal T-cell response against autologous pleomorphic malignant fibrous histiocytoma antigen presented by retrieved HLA-A*0206. J Orthop Res 2008; 26:271-8. [PMID: 17853492 DOI: 10.1002/jor.20497] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Towards the goal of identifying tumor-rejection antigens on eradicated tumors in bone and soft tissue sarcomas, we evaluated the immune response against antigens presented by lost HLA class I molecules. Tumor specimens and peripheral blood samples were obtained from a 70-year-old woman with pleomorphic malignant fibrous histiocytoma. Over 1-year culture, a tumor cell line (MFH2004) was established. A B-cell line infected with Epstein-Barr virus (B2004-EBV) was developed from the blood samples. HLA genotypes of B2004-EBVcells were A*0206/2402, B*4006/4601, and C*0102/0801, whereas MFH2004 cells were defective for A*0206, B*4006, and C*0102. Loss of HLA-A2 expression was also proved immunohistochemically in the primary tumor tissues. Lost HLA-A2 in MFH2004 cells was retrieved by transfection of HLA-A*0206 cDNA to develop MFH2004-A2. Attempts to induce CTLs by mixed culture with autologous T cells and MFH2004 cells resulted in failure. In contrast, those with MFH2004-A2 induced CTL clones CTL2004-c6 and CTL2004-c17. These CTL clones specifically killed MFH2004-A2 but not MFH2004 or B2004-EBV in an HLA-A2-restricted manner. These findings suggest that CTL2004-c6 and CTL2004-c17 recognize autologous tumor-rejection antigens presented by HLA-A*0206, which may have been expressed by tumor cells that had been eradicated by the host's immunosurveillance system.
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Affiliation(s)
- Shigeharu Kimura
- Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, Sapporo, 060-8543, Japan
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37
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Wang Z, Zhang L, Qiao A, Watson K, Zhang J, Fan GH. Activation of CXCR4 triggers ubiquitination and down-regulation of major histocompatibility complex class I (MHC-I) on epithelioid carcinoma HeLa cells. J Biol Chem 2007; 283:3951-9. [PMID: 18083706 DOI: 10.1074/jbc.m706848200] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Many cancer cells display down-regulated major histocompatibility complex (MHC) class I antigen (MHC-I), which seems to enable them to evade immune surveillance, whereas the underlying mechanisms remain incompletely understood. Here, we demonstrate that ligand (CXCL12) stimulation of CXCR4, a major chemokine receptor expressed in many malignant cancer cells, induced MHC-I heavy chain down-regulation from the cell surface of the human epithelioid carcinoma HeLa cells, the human U251 and U87 glioblastoma cells, the human MDA-MD 231 breast cancer cells, and the human SK-N-BE (2) neuroblastoma cells. Activation of CXCR4 also induced MHC-I down-regulation in human peripheral blood mononuclear cells. The internalized MHC-I heavy chain molecules were partially co-localized with Rab7, a later endosomal marker. Activation of CXCR4 induced ubiquitination of MHC-I heavy chain, and mutation of the C-terminal two lysine residues (Lys-332, Lys-337) on one of the MHC-I alleles, HLA.B7, blocked CXCR4-evoked ubiquitination and down-regulation of HLA.B7. Moreover, purified GST-conjugated CXCR4 C terminus directly associated with the purified His-tagged beta2-microglobulin (beta2M), and MHC-I heavy chain was co-immunoprecipitated with CXCR4 in a beta2M-dependent manner. This interaction appears to be critical for CXCR4-evoked down-regulation of MHC-I heavy chain as evidenced by the data that MHC-I heavy chain down-regulation was inhibited by either truncation of the CXCR4 C terminus or knockdown of beta2M. All together, these findings shed new light on the role of CXCR4 in tumor evasion of immune surveillance via inducing MHC-I down-regulation from the cell surface.
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Affiliation(s)
- Ziqing Wang
- Institute of Health Sciences, Shanghai Institutes for Biological Sciences Chinese Academy of Sciences, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
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38
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Optimizing engagement of the immune system by anti-tumor antibodies: an engineer's perspective. Drug Discov Today 2007; 12:898-910. [DOI: 10.1016/j.drudis.2007.08.009] [Citation(s) in RCA: 95] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2007] [Revised: 08/03/2007] [Accepted: 08/21/2007] [Indexed: 11/23/2022]
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39
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Baba T, Hanagiri T, Ichiki Y, Kuroda K, Shigematsu Y, Mizukami M, Sugaya M, Takenoyama M, Sugio K, Yasumoto K. Lack and restoration of sensitivity of lung cancer cells to cellular attack with special reference to expression of human leukocyte antigen class I and/or major histocompatibility complex class I chain related molecules A/B. Cancer Sci 2007; 98:1795-802. [PMID: 17725806 PMCID: PMC11159108 DOI: 10.1111/j.1349-7006.2007.00586.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2007] [Revised: 07/03/2007] [Accepted: 07/06/2007] [Indexed: 11/28/2022] Open
Abstract
Both cytotoxic T lymphocytes (CTL) and natural killer (NK) cells may play major roles in the host defense against cancer. However, their relationship against the same tumor remains to be elucidated. Among 26 human lung cancer cell lines established in our laboratory, 10 (38%) exhibited human leukocyte antigen (HLA)-class I haplotype loss and three (12%) lost HLA-class I expression totally by flow cytometry analysis. The two cell lines (E522L and C831L) that lost their expression of HLA-class I in vitro and in vivo were applied for further evaluations. Genetic abnormalities of beta2-microglobulin gene were observed in both E522L (loss of mRNA) and C831L (point mutation). Transduction of the wild-type beta2-microglobulin gene rendered them positive for HLA-class I expression. The CTL were induced from autologous peripheral blood mononuclear cells or regional lymph node lymphocytes by stimulation with wild-type beta2-microglobulin transduced-E522L or -C831L, and they showed tumor-specific cytotoxicity against wild-type beta2-microglobulin-transductant, but not parental cells. In NK cell cytotoxicity, E522L showed high sensitivity to NK cells; however, C831L showed resistance despite loss of HLA-class I expression. E522L expressed MHC class I chain related molecules A/B, but C831L did not. The transduction of the MHC class I chain related molecule A gene from E522L rendered C831L positive for expression and sensitive to NK cell cytotoxicity. Reconstruction of HLA-class I and MHC class I chain related molecules A expression could abrogate evasion from cellular attack by CTL and NK cells, and it may lead to a breakthrough in the development of cancer immunotherapy.
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Affiliation(s)
- Tetsuro Baba
- Department of Surgery II, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan
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40
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He Q, Cheng R, Chen Z, Xiao X, Xiao Z, Li C, Li B, Zhang P, Zheng H, Feng D. Cell transformation and proteome alteration in QSG7701 cells transfected with hepatitis C virus non-structural protein 3. Acta Biochim Biophys Sin (Shanghai) 2007; 39:751-62. [PMID: 17928924 DOI: 10.1111/j.1745-7270.2007.00344.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Persistent hepatitis C virus (HCV) infection can cause liver cirrhosis and hepatocellular carcinoma. Non-structural protein 3 (NS3), an important part of HCV, has been implicated in the life cycle of the virus and interacts with host cellular proteins. In this study, we investigated the effect of NS3 protein on cell tranformation and related protein alteration in human hepatocyte QSG7701 cells. The results indicated that stable expression of the NS3 protein in QSG7701 cells induced transformed characters with reduced population doubling time, anchorage-independent growth and tumor development. Fifteen differentially-expressed proteins were separated and identified using 2-D electrophoresis and matrix-assisted laser desorption ionization-time of flight mass spectrometry. Western blot analysis confirmed that the increase of phospho-p44/42 and phospho-p38 proteins was associated with transformed cells. These results supported the view that HCV NS3 protein plays a transforming role and provided some clues to elucidate the carcinogenesis mechanism of HCV-related hepatocellular carcinoma.
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Affiliation(s)
- Qiongqiong He
- Department of Pathology, Basic Medical College, Central South University, Changsha 410078, China
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41
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Wessendorf S, Barth TFE, Viardot A, Mueller A, Kestler HA, Kohlhammer H, Lichter P, Bentz M, Döhner H, Möller P, Schwaenen C. Further delineation of chromosomal consensus regions in primary mediastinal B-cell lymphomas: an analysis of 37 tumor samples using high-resolution genomic profiling (array-CGH). Leukemia 2007; 21:2463-9. [PMID: 17728785 DOI: 10.1038/sj.leu.2404919] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Primary mediastinal B-cell lymphoma (PMBL) is an aggressive extranodal B-cell non-Hodgkin's lymphoma with specific clinical, histopathological and genomic features. To characterize further the genotype of PMBL, we analyzed 37 tumor samples and PMBL cell lines Med-B1 and Karpas1106P using array-based comparative genomic hybridization (matrix- or array-CGH) to a 2.8k genomic microarray. Due to a higher genomic resolution, we identified altered chromosomal regions in much higher frequencies compared with standard CGH: for example, +9p24 (68%), +2p15 (51%), +7q22 (32%), +9q34 (32%), +11q23 (18%), +12q (30%) and +18q21 (24%). Moreover, previously unknown small interstitial chromosomal low copy number alterations (for example, -6p21, -11q13.3) and a total of 19 DNA amplifications were identified by array-CGH. For 17 chromosomal localizations (10 gains and 7 losses), which were altered in more than 10% of the analyzed cases, we delineated minimal consensus regions based on genomic base pair positions. These regions and selected immunohistochemistries point to candidate genes that are discussed in the context of NF-kappaB transcription activation, human leukocyte antigen class I/II defects, impaired apoptosis and Janus kinase/signal transducer and activator of transcription (JAK/STAT) activation. Our data confirm the genomic uniqueness of this tumor and provide physically mapped genomic regions of interest for focused candidate gene analysis.
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Affiliation(s)
- S Wessendorf
- Klinik für Innere Medizin III, Zentrum für Innere Medizin der Universität Ulm, Ulm, Germany.
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42
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Niens M, Jarrett RF, Hepkema B, Nolte IM, Diepstra A, Platteel M, Kouprie N, Delury CP, Gallagher A, Visser L, Poppema S, te Meerman GJ, van den Berg A. HLA-A*02 is associated with a reduced risk and HLA-A*01 with an increased risk of developing EBV+ Hodgkin lymphoma. Blood 2007; 110:3310-5. [PMID: 17630352 DOI: 10.1182/blood-2007-05-086934] [Citation(s) in RCA: 106] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Previous studies showed that the HLA class I region is associated with Epstein-Barr virus (EBV)-positive Hodgkin lymphoma (HL) and that HLA-A is the most likely candidate gene in this region. This suggests that antigenic presentation of EBV-derived peptides in the context of HLA-A is involved in the pathogenesis of EBV+ HL by precluding efficient immune responses. We genotyped exons 2 and 3, encoding the peptide-binding groove of HLA-A, for 32 single nucleotide polymorphisms in 70 patients with EBV+ HL, 31 patients with EBV- HL, and 59 control participants. HLA-A*01 was significantly overrepresented and HLA-A*02 was significantly underrepresented in patients with EBV+ HL versus controls and patients with EBV- HL. In addition, HLA-A*02 status was determined by immunohistochemistry or HLA-A*02-specific polymerase chain reaction (PCR) on 152 patients with EBV+ HL and 322 patients with EBV- HL. The percentage of HLA-A*02+ patients in the EBV+ HL group (35.5%) was significantly lower than in 6107 general control participants (53.0%) and the EBV- HL group (50.9%). Our results indicate that individuals carrying the HLA-A*02 allele have a reduced risk of developing EBV+ HL, while individuals carrying the HLA-A*01 allele have an increased risk. It is known that HLA-A*02 can present EBV-derived peptides and can evoke an effective immune response, which may explain the protective phenotype.
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Affiliation(s)
- Marijke Niens
- Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands
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43
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Shen YQ, Zhang JQ, Xia M, Miao FQ, Shan XN, Xie W. Low-molecular-weight protein (LMP)2/LMP7 abnormality underlies the downregulation of human leukocyte antigen class I antigen in a hepatocellular carcinoma cell line. J Gastroenterol Hepatol 2007; 22:1155-61. [PMID: 17608862 DOI: 10.1111/j.1440-1746.2006.04421.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND Tumor cells may alter the expression of numerous components involved in antigen-processing machinery to decrease human leukocyte antigen (HLA) class I expression, allowing the tumor cells to escape immune surveillance. The purpose of the present study was to investigate the involvement of these components in the downregulation of HLA class I expression in human hepatocellular carcinoma cell line BEL7,404. METHODS Expression of HLA-I and antigen presentation-related genes were analyzed by flow cytometry and polymerase chain reaction. The HLA class I-deficient BEL7,404 cell was transfected with the low-molecular-weight protein (LMP) 2 and LMP7 gene and were analyzed by flow cytometry for restoration of surface HLA class I expression. RESULTS The BEL7,404 cells downregulated the expression of HLA class I antigen and lacked expression of LMP2 and LMP7. Interferon (IFN)-gamma treatment increased the expression of LMP2 but not LMP7. The LMP2-transfected BEL7,404 cells or LMP2 and LMP7-cotransfected cells restored surface HLA class I expression while LMP7-transfected cells did not. However, in IFN-gamma-treated BEL7,404 cells, transfection with the LMP7 gene induced more HLA class I expression than mock transfection. CONCLUSIONS The LMP2 gene was required for the expression of HLA class I molecules in BEL7,404. The LMP7 was not the major reason for loss of HLA class I in BEL7,404 cells, although the supply of exogenous LMP7 could increase surface expression of HLA class I antigen.
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Affiliation(s)
- Yu-Qing Shen
- State Education Ministry Laboratory of Developmental Genes and Human Diseases, Jiangsu Provincial Key Laboratory of Gene Diagnosis and Therapy, Genetics Research Center, Southeast University Medical School, Nanjing, Jiangsu Province, China
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44
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Aptsiauri N, Cabrera T, Garcia-Lora A, Lopez-Nevot MA, Ruiz-Cabello F, Garrido F. MHC Class I Antigens and Immune Surveillance in Transformed Cells. INTERNATIONAL REVIEW OF CYTOLOGY 2007; 256:139-89. [PMID: 17241907 DOI: 10.1016/s0074-7696(07)56005-5] [Citation(s) in RCA: 111] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
MHC class I antigens play a crucial role in the interaction of tumor cells with the host immune system, in particular, in the presentation of peptides as tumor-associated antigens to cytotoxic lymphocytes (CTLs) and in the regulation of cytolytic activity of natural killer (NK) cells. In this review we discuss the role of MHC class I antigens in the recognition and elimination of transformed cells and in the generation of tumor immune escape routes when MHC class I losses occur in tumors. The different altered MHC class I phenotypes and their distribution in different human tumors are the main topic of this review. In addition, molecular defects that underlie MHC alterations in transformed cells are also described in detail. Future research directions in this field are also discussed, including the laboratory analysis of tumor MHC class I-negative variants and the possible restoration of MHC class I expression.
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Affiliation(s)
- Natalia Aptsiauri
- Servicio de Análisis Clínicos, Hospital Universitario Virgen de las Nieves, Granada, Spain
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45
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Tsukahara T, Kawaguchi S, Torigoe T, Asanuma H, Nakazawa E, Shimozawa K, Nabeta Y, Kimura S, Kaya M, Nagoya S, Wada T, Yamashita T, Sato N. Prognostic significance of HLA class I expression in osteosarcoma defined by anti-pan HLA class I monoclonal antibody, EMR8-5. Cancer Sci 2006; 97:1374-80. [PMID: 16995877 PMCID: PMC11158095 DOI: 10.1111/j.1349-7006.2006.00317.x] [Citation(s) in RCA: 117] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
With the goal of establishing efficacious peptide-based immunotherapy for patients with bone and soft tissue sarcomas, we previously identified the cytotoxic T lymphocyte-defined osteosarcoma antigenic gene Papillomavirus binding factor. The present study was designed to determine the status of HLA class I expression in osteosarcoma and other bone and soft tissue sarcomas. Seventy-four formalin-fixed paraffin-embedded specimens of various bone and soft tissue sarcomas, including 33 osteosarcomas, were stained with the anti-HLA class I monoclonal antibody EMR8-5, which we recently generated. The expression of HLA class I was lost or downregulated in 46 of these specimens (62%). With respect to osteosarcoma, loss or downregulation of HLA class I expression was seen in 13 (52%) of 25 primary tumors and seven (88%) of eight metastatic tumors. In six of 11 HLA class I-negative osteosarcoma specimens, the expression of beta-2 microglobulin was also lost. Subsequently the prognostic significance of HLA class I expression was analyzed in 21 patients with osteosarcoma who had completed multidrug neoadjuvant chemotherapy and undergone adequate surgery. Patients with osteosarcoma highly expressing HLA class I showed significantly better overall and event-free survival than those with HLA class I-negative osteosarcoma. In contrast, such prognostic significance of HLA class I expression was not found in 15 patients with malignant fibrous histiocytoma of soft tissue. These findings suggest that the class I-restricted cytotoxic T lymphocyte pathway plays a major role in immune surveillance of patients with osteosarcoma.
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MESH Headings
- Adolescent
- Adult
- Antibodies, Monoclonal/immunology
- Bone Neoplasms/immunology
- Bone Neoplasms/metabolism
- Bone Neoplasms/secondary
- Child
- Female
- Histiocytoma, Malignant Fibrous/immunology
- Histiocytoma, Malignant Fibrous/pathology
- Histiocytoma, Malignant Fibrous/secondary
- Histocompatibility Antigens Class I/genetics
- Histocompatibility Antigens Class I/immunology
- Histocompatibility Antigens Class I/metabolism
- Humans
- Immunoenzyme Techniques
- Lymphocytes, Tumor-Infiltrating/immunology
- Male
- Middle Aged
- Osteosarcoma/diagnosis
- Osteosarcoma/immunology
- Osteosarcoma/metabolism
- Prognosis
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- RNA, Neoplasm/genetics
- RNA, Neoplasm/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Sarcoma/immunology
- Sarcoma/metabolism
- Sarcoma/secondary
- Soft Tissue Neoplasms/immunology
- Soft Tissue Neoplasms/metabolism
- Soft Tissue Neoplasms/pathology
- Survival Rate
- T-Lymphocytes, Cytotoxic/immunology
- beta 2-Microglobulin/genetics
- beta 2-Microglobulin/immunology
- beta 2-Microglobulin/metabolism
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Affiliation(s)
- Tomohide Tsukahara
- Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo 060-8543, Japan
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Abstract
BACKGROUND Advances in immunology and molecular biology have shown that colorectal cancer is potentially immunogenic and that host immune responses influence survival. However, immune surveillance and activation is frequently ineffective in preventing and/or controlling tumour growth. AIM To discuss potential ways in which colorectal cancer induces immune suppression, its effect upon prognosis and avenues for therapeutic development. METHOD A literature review was undertaken for evidence of colorectal cancer-induced immune suppression using PubMed and Medline searches. Further studies were identified from the reference lists of identified papers. RESULTS Immune suppression occurs at a molecular and cellular level and can result in a shift from cellular to humoral immunity. Several mechanisms for immune suppression have been described affecting innate and adaptive immunity with suppression linked to poorer clinical outcome. CONCLUSIONS Colorectal cancer causes direct inhibition of the host's immune response with a detrimental effect upon prognosis. Immunotherapy offers a therapeutic strategy to counteract these effects with promising results seen particularly in precancerous conditions and early tumours. This review strongly suggests that immunotherapy should be incorporated into adjuvant therapeutic trials for stage 2 tumours and be considered as adjuvant treatment in conjunction with standard chemotherapy regimes for advanced disease.
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Affiliation(s)
- C Evans
- Institution Colorectal Surgery Unit & Division of Oncology, St George's Hospital, Blackshaw Road, London, UK
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Leys CM, Nomura S, LaFleur BJ, Ferrone S, Kaminishi M, Montgomery E, Goldenring JR. Expression and prognostic significance of prothymosin-alpha and ERp57 in human gastric cancer. Surgery 2006; 141:41-50. [PMID: 17188166 DOI: 10.1016/j.surg.2006.05.009] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2005] [Revised: 05/18/2006] [Accepted: 05/22/2006] [Indexed: 11/23/2022]
Abstract
PURPOSE Prothymosin-alpha and ERp57 were previously identified as markers for gastric metaplasia in a mouse model of Helicobacter-induced gastric metaplasia and neoplasia. In this paper we assess whether the expression of these putative biomarkers in humans is correlated with gastric metaplasia and adenocarcinoma and clinical outcomes. METHODS Eight tissue microarrays, containing 749 paraffin-embedded tissue cores from 164 gastric cancer patients, were stained for prothymosin-alpha and ERp57 by horseradish peroxidase immunohistochemical techniques. The proportion of stained cells per core was quantitated using the Ariol SL-50 automated image analysis system. RESULTS Prothymosin-alpha stained a significantly higher percentage of nuclei in cancer and metastases compared with normal gastric mucosa. ERp57 staining was significantly decreased in cancer and metastases compared with both normal gastric mucosa and metaplasias. ERp57 expression also correlated with greater depth of tumor invasion and advanced stage of disease. Kaplan-Meier survival analysis determined that tumors with the highest quartile of ERp57 expression were statistically associated with longer postoperative survival. A Cox proportional hazard analysis showed that maintenance of ERp57 expression was associated with longer postoperative survival. CONCLUSIONS These results suggest that although prothymosin-alpha is overexpressed in gastric adenocarcinoma, it is not associated with alterations in survival. In contrast, loss of ERp57 expression correlated with more aggressive disease and could provide useful prognostic information for gastric cancer patients.
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Affiliation(s)
- Charles M Leys
- Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN 37232-2733, USA
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48
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Koene G, Mulder A, van der Ven K, Eijsink C, Franke M, Slootweg P, Claas F, Tilanus M. Human monoclonal antibodies as a tool for the detection of HLA class I allele-specific expression loss in head-and-neck squamous cell carcinoma and corresponding lymph node metastases. Hum Immunol 2006; 67:692-9. [PMID: 17002899 DOI: 10.1016/j.humimm.2006.06.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2006] [Accepted: 06/06/2006] [Indexed: 01/10/2023]
Abstract
Human leukocyte antigen (HLA) expression is important for the elimination of tumor cells by the immune system and immunotherapy. Activated T cells directed against tumor-associated antigens are fully capable of recognizing and eradicating neoplastic cells. Therefore, HLA expression loss is considered to be a main factor in tumor development. We report for the first time HLA-A and HLA-B allele-specific expression analysis by immunohistochemical staining of fresh tumor tissue and 9 lymph node metastases of 15 patients with head-and-neck squamous cell carcinoma. Heterogeneous HLA expression and HLA expression loss was detected in 13 tumor patients. Approximately 50% of the tumors had allele-specific expression loss, which would have remained undetected using HLA monomorphic and locus-specific antibodies. In the majority of the patients with head-and-neck squamous cell carcinoma, HLA allele-specific expression loss differed between primary lesions and metastases. This is important for the efficacy of immunotherapy in these patients. It can be concluded that it is crucial to study HLA expression at the allele-specific level of primary lesions and metastases. It increases and refines our knowledge of HLA expression loss in tumorgenesis, which will improve the development of specific immunotherapy.
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Affiliation(s)
- Geert Koene
- Department of Pathology, University Medical Centre, Utrecht, the Netherlands
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49
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Norell H, Carlsten M, Ohlum T, Malmberg KJ, Masucci G, Schedvins K, Altermann W, Handke D, Atkins D, Seliger B, Kiessling R. Frequent Loss of HLA-A2 Expression in Metastasizing Ovarian Carcinomas Associated with Genomic Haplotype Loss and HLA-A2-Restricted HER-2/neu-Specific Immunity. Cancer Res 2006; 66:6387-94. [PMID: 16778217 DOI: 10.1158/0008-5472.can-06-0029] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Defective expression of HLA class I molecules is common in tumor cells and may allow escape from CTL-mediated immunity. We here investigate alterations in expression of HLA class I and their underlying molecular mechanisms in ovarian cancer patients. The HLA class I and HLA-A2 expression levels on noncultured tumor cells of 12 patients diagnosed with ovarian carcinoma were investigated by flow cytometry. Molecular analyses of antigen-processing machinery (APM) components were done in metastatic cancer cells, and the HLA genotype was determined in both these and the primary tumor. HER-2/neu-specific immunity was evaluated by enzyme-linked immunospot assays. The metastatic tumor cells from all patients expressed low levels of HLA class I surface antigens. In six of nine HLA-A2+ patients, HLA-A2 expression was heterogeneous with a subpopulation of tumor cells exhibiting decreased or absent HLA-A2 expression. One patient-derived tumor cell line completely lacked HLA-A2 but exhibited constitutive expression of APM components and high HLA class I expression that was further inducible by IFN-gamma treatment. Genotyping showed a haplotype loss in the metastatic tumor cells, whereas tumor tissue microdissected from the primary tumor exhibited an intact HLA gene complex. Interestingly, HLA-A2-restricted HER-2/neu-specific T-cell responses were evident among the lymphocytes of this patient. Abnormalities in HLA class I antigen expression are common features during the progression of ovarian cancer, and haplotype loss was, for the first time, described as an underlying mechanism.
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Affiliation(s)
- Håkan Norell
- Department of Oncology and Pathology, Immune and Gene Therapy Laboratory, Cancer Center Karolinska, Karolinska Institutet, Karolinska University Hospital, Sweden.
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50
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Knutson KL, Wagner W, Disis ML. Adoptive T cell therapy of solid cancers. Cancer Immunol Immunother 2006; 55:96-103. [PMID: 15891880 PMCID: PMC11030201 DOI: 10.1007/s00262-005-0706-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2005] [Accepted: 03/24/2005] [Indexed: 11/28/2022]
Abstract
The development of immune-based approaches for the treatment of cancer has been actively investigated for many years. One strategy that has emerged as a potentially effective strategy for the treatment of aggressive established malignancies is adoptive T cell therapy. The power of this approach has been repeatedly observed in preclinical animal models. However, moving from homogeneous animal models to the heterogeneous human clinical setting has been very difficult. It is only in recent times that we have been able to pinpoint the problems of the clinical translation of adoptive T cell therapy. Some of the major problems are sources of tumor-specific T cells, ex vivo expansion, persistence, and anti-tumor activity. This review overviews the nature of these problems and some of the emerging solutions.
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Affiliation(s)
- Keith L. Knutson
- Mayo Clinic College of Medicine, 342D Guggenheim, 200 First St SW, Mayo Clinic, Rochester, MN 55905 USA
- Department of Immunology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905 USA
| | - Wolfgang Wagner
- Department of Oncology, University of Washington, Tumor Vaccine Group, 1959 NE Pacific Street, 356527, Seattle, WA 98195 USA
| | - Mary L. Disis
- Department of Oncology, University of Washington, Tumor Vaccine Group, 1959 NE Pacific Street, 356527, Seattle, WA 98195 USA
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