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Lin J, Ran Y, Wu T, Wang Z, Zhao J, Tian Y. A New Method for Constructing Macrophage-Associated Predictors of Treatment Efficacy Based on Single-Cell Sequencing Analysis. J Immunother 2024; 47:33-48. [PMID: 37982646 DOI: 10.1097/cji.0000000000000497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 10/19/2023] [Indexed: 11/21/2023]
Abstract
Tumor-associated macrophages (TAMs) are highly infiltrated in the tumor microenvironment (TME) of colorectal cancer (CRC) and play a vital role in CRC's development as well as prognosis. The required data were obtained from the Gene Expression Omnibus database and The Cancer Genome Atlas. Univariate Cox regression and least absolute shrinkage operator analyses were executed for model construction. TME assessment and immune prediction were performed using the ESTIMATE software package and the single sample genome enrichment analysis algorithm. The results show patients with low a TAMs risk score (TRS) had a better prognosis in both The Cancer Genome Atlas and Gene Expression Omnibus cohorts. Patients with low TRS were more sensitive to 3 chemotherapeutic agents: oxaliplatin, paclitaxel, and cisplatin ( P <0.05). TME assessment showed that the low TRS group had less infiltration of M2 macrophages and regulatory T cells, but CD4 + T cells, NK cells, and dendritic cells occupy a greater proportion of TME. Low TRS group patients have a low StromalScore and ImmuneScore but have high TumorPurity. The immune checkpoint TIM-3 gene HAVCR2 expression was significantly higher in the high TRS group. Finally, we created a nomogram including TRS for forecasting survival, and TRS was significantly associated with the clinical stage of the patients. In conclusion, the TRS serves as a reliable prognostic indicator of CRC; it predicts patient outcomes to immunotherapy and chemotherapy and provides genomic evidence for the subsequent development of modulated TAMs for treating CRC.
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Affiliation(s)
- Jianxiu Lin
- Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yang Ran
- Department of Oncology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Tengfei Wu
- Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Zishan Wang
- Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Jinjin Zhao
- Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yun Tian
- Department of Oncology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
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2
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Millar DG, Yang SYC, Sayad A, Zhao Q, Nguyen LT, Warner K, Sangster AG, Nakatsugawa M, Murata K, Wang BX, Shaw P, Clarke B, Bernardini MQ, Pugh T, Thibault P, Hirano N, Perreault C, Ohashi PS. Identification of antigenic epitopes recognized by tumor infiltrating lymphocytes in high grade serous ovarian cancer by multi-omics profiling of the auto-antigen repertoire. Cancer Immunol Immunother 2023; 72:2375-2392. [PMID: 36943460 PMCID: PMC10264507 DOI: 10.1007/s00262-023-03413-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 02/16/2023] [Indexed: 03/23/2023]
Abstract
Immunotherapeutic strategies aimed at enhancing tumor cell killing by tumor-specific T cells hold great potential for reducing tumor burden and prolonging survival of cancer patients. Although many potential tumor antigens have been described, identifying relevant targets when designing anti-cancer vaccines or targeted cell therapies remains a challenge. To identify novel, potentially immunogenic candidate tumor antigens, we performed integrated tumor transcriptomic, seromic, and proteomic analyses of high grade serous ovarian cancer (HGSC) patient tumor samples. We identified tumor neo-antigens and over-expressed antigens using whole exome and RNA sequencing and examined these in relation to patient-matched auto-antibody repertoires. Focusing on MHC class I epitopes recognized by CD8+ T cells, HLA-binding epitopes were identified or predicted from the highly expressed, mutated, or auto-antibody target antigen, or MHC-associated peptides (MAPs). Recognition of candidate antigenic peptides was assessed within the tumor-infiltrating T lymphocyte (TIL) population expanded from each patient. Known tumor-associated antigens (TAA) and cancer/testis antigens (CTA) were commonly found in the auto-antibody and MAP repertoires and CD8+ TILs recognizing epitopes from these antigens were detected, although neither expression level nor the presence of auto-antibodies correlated with TIL recognition. Auto-antibodies against tumor-mutated antigens were found in most patients, however, no TIL recognition of the highest predicted affinity neo-epitopes was detected. Using high expression level, auto-antibody recognition, and epitope prediction algorithms, we identified epitopes in 5 novel antigens (MOB1A, SOCS3, TUBB, PRKAR1A, CCDC6) recognized by HGSC patient TILs. Furthermore, selection of epitopes from the MAP repertoire identified 5 additional targets commonly recognized by multiple patient TILs. We find that the repertoire of TIL specificities includes recognition of highly expressed and immunogenic self-antigens that are processed and presented by tumors. These results indicate an ongoing autoimmune response against a range of self-antigens targeted by HGSC TILs.
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Affiliation(s)
- Douglas G Millar
- Tumor Immunotherapy Program, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, M5G 2M9, Canada
| | - S Y Cindy Yang
- Tumor Immunotherapy Program, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, M5G 2M9, Canada
| | - Azin Sayad
- Tumor Immunotherapy Program, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, M5G 2M9, Canada
| | - Qingchuan Zhao
- Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec, Canada
| | - Linh T Nguyen
- Tumor Immunotherapy Program, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, M5G 2M9, Canada
| | - Kathrin Warner
- Tumor Immunotherapy Program, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, M5G 2M9, Canada
| | - Ami G Sangster
- Tumor Immunotherapy Program, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, M5G 2M9, Canada
| | - Munehide Nakatsugawa
- Tumor Immunotherapy Program, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, M5G 2M9, Canada
| | - Kenji Murata
- Tumor Immunotherapy Program, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, M5G 2M9, Canada
| | - Ben X Wang
- Tumor Immunotherapy Program, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, M5G 2M9, Canada
| | - Patricia Shaw
- Tumor Immunotherapy Program, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, M5G 2M9, Canada
| | - Blaise Clarke
- Tumor Immunotherapy Program, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, M5G 2M9, Canada
| | - Marcus Q Bernardini
- Division of Gynecologic Oncology, Cancer Clinical Research Unit (CCRU), Princess Margaret Cancer Centre, Toronto, ON, Canada
| | - Trevor Pugh
- Tumor Immunotherapy Program, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, M5G 2M9, Canada
| | - Pierre Thibault
- Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec, Canada
| | - Naoto Hirano
- Tumor Immunotherapy Program, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, M5G 2M9, Canada
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Claude Perreault
- Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec, Canada
| | - Pamela S Ohashi
- Tumor Immunotherapy Program, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, M5G 2M9, Canada.
- Department of Immunology, University of Toronto, Toronto, ON, Canada.
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3
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Tumor-reactive antibodies evolve from non-binding and autoreactive precursors. Cell 2022; 185:1208-1222.e21. [PMID: 35305314 DOI: 10.1016/j.cell.2022.02.012] [Citation(s) in RCA: 98] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 12/20/2021] [Accepted: 02/09/2022] [Indexed: 12/27/2022]
Abstract
The tumor microenvironment hosts antibody-secreting cells (ASCs) associated with a favorable prognosis in several types of cancer. Patient-derived antibodies have diagnostic and therapeutic potential; yet, it remains unclear how antibodies gain autoreactivity and target tumors. Here, we found that somatic hypermutations (SHMs) promote antibody antitumor reactivity against surface autoantigens in high-grade serous ovarian carcinoma (HGSOC). Patient-derived tumor cells were frequently coated with IgGs. Intratumoral ASCs in HGSOC were both mutated and clonally expanded and produced tumor-reactive antibodies that targeted MMP14, which is abundantly expressed on the tumor cell surface. The reversion of monoclonal antibodies to their germline configuration revealed two types of classes: one dependent on SHMs for tumor binding and a second with germline-encoded autoreactivity. Thus, tumor-reactive autoantibodies are either naturally occurring or evolve through an antigen-driven selection process. These findings highlight the origin and potential applicability of autoantibodies directed at surface antigens for tumor targeting in cancer patients.
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Hagn M, Jahrsdörfer B. Why do human B cells secrete granzyme B? Insights into a novel B-cell differentiation pathway. Oncoimmunology 2021; 1:1368-1375. [PMID: 23243600 PMCID: PMC3518509 DOI: 10.4161/onci.22354] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
B cells are generally believed to operate as producers of high affinity antibodies to defend the body against microorganisms, whereas cellular cytotoxicity is considered as an exclusive prerogative of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). In conflict with this dogma, recent studies have demonstrated that the combination of interleukin-21 (IL-21) and B-cell receptor (BCR) stimulation enables B cells to produce and secrete the active form of the cytotoxic serine protease granzyme B (GrB). Although the production of GrB by B cells is not accompanied by that of perforin as in the case of many other GrB-secreting cells, recent findings suggest GrB secretion by B cells may play a significant role in early antiviral immune responses, in the regulation of autoimmune responses, and in cancer immunosurveillance. Here, we discuss in detail how GrB-secreting B cells may influence a variety of immune processes. A better understanding of the role that GrB-secreting B cells are playing in the immune system may allow for the development and improvement of novel immunotherapeutic approaches against infectious, autoimmune and malignant diseases.
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Affiliation(s)
- Magdalena Hagn
- Cancer Immunology Program; Peter MacCallum Cancer Centre; Melbourne, Australia
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Hetta HF, Elkady A, Yahia R, Meshall AK, Saad MM, Mekky MA, Al-Kadmy IMS. T follicular helper and T follicular regulatory cells in colorectal cancer: A complex interplay. J Immunol Methods 2020; 480:112753. [PMID: 32061875 DOI: 10.1016/j.jim.2020.112753] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Revised: 11/14/2019] [Accepted: 02/07/2020] [Indexed: 02/06/2023]
Abstract
Colorectal cancer is considered to be one of the major causes of morbidity and mortality all over the world. T Follicular helper (TFH) and T follicular regulatory (TFR) cells are specialized providers of T-cells to help B-cells and shaping germinal centers (GC) response. Recent researches reported a high percentage of TFH and TFR in different infectious diseases and certain malignancies. However, their functional role in human colorectal cancer (CRC) is relatively unknown. Furthermore, recent studies show that the interaction of both TFH cells and TFR cells are essential to promote several diseases. Under the control of specific cytokines and B-cell lymphoma 6 transcription factor (Bcl-6), the major transcription factor of TFH cells, TFH, can expand to the other distinct CD4 + T helper cells (TH1, TH2, and TH17) which exert a different role in the development of CRC. This review aims to discuss these suggested roles of the two-opposite subset of follicular T cells in colorectal cancer immune pathogenesis.
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Affiliation(s)
- Helal F Hetta
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | | | - Ramadan Yahia
- Department of Microbiology and Immunology, Faculty of Pharmacy, Deraya University, Minia, Egypt
| | - Ahmed Kh Meshall
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Assiut, Egypt
| | - Mahmoud M Saad
- Assiut University Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mohamed A Mekky
- Department of Tropical Medicine and Gastroenterology, Assiut University Hospital, Assiut, Egypt
| | - Israa M S Al-Kadmy
- Branch of Biotechnology, Department of Biology, College of Science, Mustansiriyah University, POX 10244, Baghdad, Iraq; Faculty of Science and Engineering, School of Engineering, University of Plymouth, Plymouth PL4 8AA, UK.
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6
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Hutchison S, Pritchard AL. Identifying neoantigens for use in immunotherapy. Mamm Genome 2018; 29:714-730. [PMID: 30167844 PMCID: PMC6267674 DOI: 10.1007/s00335-018-9771-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Accepted: 08/08/2018] [Indexed: 12/14/2022]
Abstract
This review focuses on the types of cancer antigens that can be recognised by the immune system and form due to alterations in the cancer genome, including cancer testis, overexpressed and neoantigens. Specifically, neoantigens can form when cancer cell-specific mutations occur that result in alterations of the protein from ‘self’. This type of antigen can result in an immune response sufficient to clear tumour cells when activated. Furthermore, studies have reported that the likelihood of successful immunotherapeutic targeting of cancer by many different methods was reliant on immune response to neoantigens. The recent resurgence of interest in the immune response to tumour cells, in conjunction with technological advances, has resulted in a large increase in the predicted, identified and functionally confirmed neoantigens. This growth in identified neoantigen sequences has increased the contents of training sets for algorithms, which in turn improves the prediction of which genetic mutations may form neoantigens. Additionally, algorithms predicting how proteins will be processed into peptide epitopes by the proteasome and which peptides bind to the transporter complex are also improving with this research. Now that large screens of all the tumour-specific protein altering mutations are possible, the emerging data from assessment of the immunogenicity of neoantigens suggest that only a minority of variants will form targetable epitopes. The potential for immunotherapeutic targeting of neoantigens will therefore be greater in cancers with a higher frequency of protein altering somatic variants. There is considerable potential in the use of neoantigens to treat patients, either alone or in combination with other immunotherapies and with continued advancements, these potentials will be realised.
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Affiliation(s)
- Sharon Hutchison
- Genetics and Immunology Research Group, University of the Highlands and Islands, An Lòchran, 10 Inverness Campus, Inverness, IV2 5NA, Scotland, UK
| | - Antonia L Pritchard
- Genetics and Immunology Research Group, University of the Highlands and Islands, An Lòchran, 10 Inverness Campus, Inverness, IV2 5NA, Scotland, UK.
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7
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Smazynski J, Webb JR. Resident Memory-Like Tumor-Infiltrating Lymphocytes (TIL RM): Latest Players in the Immuno-Oncology Repertoire. Front Immunol 2018; 9:1741. [PMID: 30093907 PMCID: PMC6070600 DOI: 10.3389/fimmu.2018.01741] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 07/13/2018] [Indexed: 12/12/2022] Open
Abstract
Resident memory T cells (TRM) are a recently identified subset of long-lived memory T cells that are characterized in terms of their unique surface phenotype combined with a non-recirculating pattern of localization to non-lymphoid, peripheral tissues. TRM have quickly become a key area of focus in understanding immune responses to microbial infection in so-called "barrier" tissues, and appear to be particularly critical for protection against repeat exposure at the same site. More recently, tumor-infiltrating T cells with canonical TRM features are being identified in human cancers, in particular cancers of epithelial origin, and their presence is broadly found to be associated with favorable long-term prognosis. Moreover, recent studies have shown that these "resident memory-like" tumor-infiltrating lymphocytes (referred to herein as TILRM) are uniquely activated in melanoma patients undergoing PD-1 directed checkpoint blockade therapy. Accordingly, there is much interest at present regarding the biology of these cells and their precise role in anti-cancer immunity. Herein, we review the current state of the literature regarding TILRM with a specific emphasis on their specificity, origins, and relationship to conventional pathogen-specific TRM and speculate upon the way(s) in which they might contribute to improved prognosis for cancer patients. We discuss the growing body of evidence that suggests TILRM may represent a population of bona-fide tumor-reactive T cells and the attractive possibility of leveraging this cell population for future immunotherapy.
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Affiliation(s)
- Julian Smazynski
- Deeley Research Centre, BC Cancer Agency, Victoria, BC, Canada
- Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada
| | - John R. Webb
- Deeley Research Centre, BC Cancer Agency, Victoria, BC, Canada
- Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada
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8
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Fortner RT, Damms-Machado A, Kaaks R. Systematic review: Tumor-associated antigen autoantibodies and ovarian cancer early detection. Gynecol Oncol 2017; 147:465-480. [PMID: 28800944 DOI: 10.1016/j.ygyno.2017.07.138] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 07/20/2017] [Accepted: 07/24/2017] [Indexed: 12/20/2022]
Abstract
OBJECTIVES Tumor-associated autoantibodies (AAbs), produced as an immune response to tumor-associated antigens (TAAs), are a novel pathway of early detection markers. METHODS We conducted a systematic review on AAbs and ovarian cancer to summarize the diagnostic performance of individual AAbs and AAb panels. A total of 29 studies including 85 AAbs were included; 27 of the studies were conducted in prevalent cases and cancer-free controls and 2 investigations included pre-diagnosis samples. The majority of studies were hypothesis-driven, evaluating AAbs to target TAAs; 10 studies used screening approaches such as serological expression cloning (SEREX) and nucleic acid-programmable protein arrays (NAPPA). RESULTS The highest sensitivities for individual AAbs were reported for RhoGDI-AAbs (89.5%) and TUBA1C-AAbs (89%); however, specificity levels were relatively low (80% and 75%, respectively). High sensitivities at high specificities were reported for HOXA7-AAbs for detection of moderately differentiated ovarian tumors (66.7% sensitivity at 100% specificity) and IL8-AAbs in stage I-II ovarian cancer (65.5% sensitivity at 98% specificity). A panel of 11 AAbs (ICAM3, CTAG2, p53, STYXL1, PVR, POMC, NUDT11, TRIM39, UHMK1, KSR1, and NXF3) provided 45% sensitivity at 98% specificity for serous ovarian cancer, when at least 2 AAbs were above a threshold of 95% specificity. Twelve of the AAbs identified in this review were investigated in more than one study. Data on diagnostic discrimination by tumor histology and stage at diagnosis are sparse. Limited data suggest select AAb markers improve diagnostic discrimination when combined with markers such as CA125 and HE4. CONCLUSIONS AAbs for ovarian cancer early detection is an emerging area, and large-scale, prospective investigations considering histology and stage are required for discovery and validation. However, data to date suggests panels of AAbs may eventually reach sufficient diagnostic discrimination to allow earlier detection of disease as a complement to existing markers and transvaginal ultrasound.
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Affiliation(s)
| | - Antje Damms-Machado
- Division of Cancer Epidemiology, German Cancer Research Center (DFKZ), Heidelberg, Germany
| | - Rudolf Kaaks
- Division of Cancer Epidemiology, German Cancer Research Center (DFKZ), Heidelberg, Germany.
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Taherian-Esfahani Z, Abedin-Do A, Nikpayam E, Tasharofi B, Ghahghaei Nezamabadi A, Ghafouri-Fard S. Cancer-Testis Antigens: A Novel Group of Tumor Biomarkers in Ovarian Cancers. IRANIAN JOURNAL OF CANCER PREVENTION 2016. [DOI: 10.17795/ijcp-4993] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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10
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Oncogenic cancer/testis antigens: prime candidates for immunotherapy. Oncotarget 2016; 6:15772-87. [PMID: 26158218 PMCID: PMC4599236 DOI: 10.18632/oncotarget.4694] [Citation(s) in RCA: 247] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Accepted: 06/21/2015] [Indexed: 12/15/2022] Open
Abstract
Recent developments have set the stage for immunotherapy as a supplement to conventional cancer treatment. Consequently, a significant effort is required to further improve efficacy and specificity, particularly the identification of optimal therapeutic targets for clinical testing. Cancer/testis antigens are immunogenic, highly cancer-specific, and frequently expressed in various types of cancer, which make them promising candidate targets for cancer immunotherapy, including cancer vaccination and adoptive T-cell transfer with chimeric T-cell receptors. Our current understanding of tumor immunology and immune escape suggests that targeting oncogenic antigens may be beneficial, meaning that identification of cancer/testis antigens with oncogenic properties is of high priority. Recent work from our lab and others provide evidence that many cancer/testis antigens, in fact, have oncogenic functions, including support of growth, survival and metastasis. This novel insight into the function of cancer/testis antigens has the potential to deliver more effective cancer vaccines. Moreover, immune targeting of oncogenic cancer/testis antigens in combination with conventional cytotoxic therapies or novel immunotherapies such as checkpoint blockade or adoptive transfer, represents a highly synergistic approach with the potential to improve patient survival.
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11
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Esfandiary A, Ghafouri-Fard S. New York esophageal squamous cell carcinoma-1 and cancer immunotherapy. Immunotherapy 2016; 7:411-39. [PMID: 25917631 DOI: 10.2217/imt.15.3] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
New York esophageal squamous cell carcinoma 1 (NY-ESO-1) is a known cancer testis gene with exceptional immunogenicity and prevalent expression in many cancer types. These characteristics have made it an appropriate vaccine candidate with the potential application against various malignancies. This article reviews recent knowledge about the NY-ESO-1 biology, function, immunogenicity and expression in cancers as well as and the results of clinical trials with this antigen.
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Affiliation(s)
- Ali Esfandiary
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran 19857-17443, Iran
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12
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Liao JB, Ovenell KJ, Curtis EEM, Cecil DL, Koehnlein MR, Rastetter LR, Gad EA, Disis ML. Preservation of tumor-host immune interactions with luciferase-tagged imaging in a murine model of ovarian cancer. J Immunother Cancer 2015; 3:16. [PMID: 25992288 PMCID: PMC4437454 DOI: 10.1186/s40425-015-0060-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2014] [Accepted: 03/24/2015] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Ovarian cancer is immunogenic and residual tumor volume after surgery is known to be prognostic. Ovarian cancer often follows a recurring-remitting course and microscopic disease states may present ideal opportunities for immune therapies. We sought to establish the immune profile of a murine model of ovarian cancer that allows in vivo tumor imaging and the quantitation of microscopic disease. RESULTS AND DISCUSSION Baseline imaging and weight measurements were taken within 1 and 2 weeks after intraperitoneal tumor injection, respectively. Significantly higher photons per second from baseline imaging were first observed 5 weeks after tumor cell injection (p < 0.05) and continued to be significant through 8 weeks after injection (p < 0.01), whereas a significant increase in weight above baseline was not observed until day 56 (p < 0.0001). Expression of luc2 in ID8 cells did not alter the cellular immune microenvironment of the tumor. FOXP3+ T cells were more likely to be detected in the intraepithelial compartment and CD4+ T cells in the stroma as compared to CD3+ T cells, which were found equally in stroma and intraepithelial compartments. CONCLUSIONS Use of an intraperitoneal tumor expressing a codon-optimized firefly luciferase in an immunocompetent mouse model allows tumor quantitation in vivo and detection of microscopic tumor burdens. Expression of this foreign protein does not significantly effect tumor engraftment or the immune microenvironment of the ID8 cells in vivo and may allow novel immunotherapies to be assessed in a murine model for their translational potential to ovarian cancers in remission or minimal disease after primary cytoreductive surgery or chemotherapy. METHODS Mouse ovarian surface epithelial cells from C57BL6 mice transformed after serial passage in vitro were transduced with a lentiviral vector expressing a codon optimized firefly luciferase (luc2). Cell lines were selected and luc2 expression functionally confirmed in vitro. Cell lines were intraperitoneally (IP) implanted in albino C57BL/6/BrdCrHsd-Tyrc mice and albino B6(Cg)-Tyrc-2 J/J mice for serial imaging. D-luciferin substrate was injected IP and tumors were serially imaged in vivo using a Xenogen IVIS. Tumor take, weights, and luminescent intensities were measured. Immunohistochemistry was performed on tumors and assessed for immune infiltrates in stromal and intraepithelial compartments.
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Affiliation(s)
- John B Liao
- />Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, 1959 NE Pacific St., Seattle, WA 98195 USA
- />Tumor Vaccine Group, Center for Translational Medicine in Women’s Health, University of Washington, 850 Republican St., Seattle, WA 98109 USA
| | - Kelsie J Ovenell
- />Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, 1959 NE Pacific St., Seattle, WA 98195 USA
- />Tumor Vaccine Group, Center for Translational Medicine in Women’s Health, University of Washington, 850 Republican St., Seattle, WA 98109 USA
| | - Erin E M Curtis
- />Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, 1959 NE Pacific St., Seattle, WA 98195 USA
- />Tumor Vaccine Group, Center for Translational Medicine in Women’s Health, University of Washington, 850 Republican St., Seattle, WA 98109 USA
- />Swarthmore College, 500 College Ave, Swarthmore, PA 19081 USA
| | - Denise L Cecil
- />Tumor Vaccine Group, Center for Translational Medicine in Women’s Health, University of Washington, 850 Republican St., Seattle, WA 98109 USA
| | - Marlese R Koehnlein
- />Tumor Vaccine Group, Center for Translational Medicine in Women’s Health, University of Washington, 850 Republican St., Seattle, WA 98109 USA
| | - Lauren R Rastetter
- />Tumor Vaccine Group, Center for Translational Medicine in Women’s Health, University of Washington, 850 Republican St., Seattle, WA 98109 USA
| | - Ekram A Gad
- />Tumor Vaccine Group, Center for Translational Medicine in Women’s Health, University of Washington, 850 Republican St., Seattle, WA 98109 USA
| | - Mary L Disis
- />Tumor Vaccine Group, Center for Translational Medicine in Women’s Health, University of Washington, 850 Republican St., Seattle, WA 98109 USA
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13
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Webb JR, Milne K, Nelson BH. PD-1 and CD103 Are Widely Coexpressed on Prognostically Favorable Intraepithelial CD8 T Cells in Human Ovarian Cancer. Cancer Immunol Res 2015; 3:926-35. [DOI: 10.1158/2326-6066.cir-14-0239] [Citation(s) in RCA: 159] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 05/04/2015] [Indexed: 11/16/2022]
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Abstract
The accumulation of tumor infiltrating lymphocytes (TILs) in ovarian cancer is prognostic for increased survival while increases in immunosuppressive regulatory T-cells (Tregs) are associated with poor outcomes. Approaches that bolster tumor-reactive TILs may limit tumor progression. However, identifying tumor-reactive TILs in ovarian cancer has been challenging, though adoptive TIL therapy in patients has been encouraging. Other forms of TIL immunomodulation remain under investigation including Treg depletion, antibody-based checkpoint modification, activation and amplification using dendritic cells, antigen presenting cells or IL-2 cytokine culture, adjuvant cytokine injections, and gene-engineered T-cells. Many approaches to TIL manipulation inhibit ovarian cancer progression in preclinical or clinical studies as monotherapy. Here, we review the impact of TILs in ovarian cancer and attempts to mobilize TILs to halt tumor progression. We conclude that effective TIL therapy for ovarian cancer is at the brink of translation and optimal TIL activity may require combined methodologies to deliver clinically-relevant treatment.
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Affiliation(s)
- Phillip P Santoiemma
- a Ovarian Cancer Research Center ; Department of Obstetrics and Gynecology ; Perelman School of Medicine; University of Pennsylvania ; Philadelphia , PA USA
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Santoiemma PP, Powell DJ. Tumor infiltrating lymphocytes in ovarian cancer. Cancer Biol Ther 2015. [PMID: 25894333 DOI: 10.1080/15384047.2015.1040960]+[] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/30/2022] Open
Abstract
The accumulation of tumor infiltrating lymphocytes (TILs) in ovarian cancer is prognostic for increased survival while increases in immunosuppressive regulatory T-cells (Tregs) are associated with poor outcomes. Approaches that bolster tumor-reactive TILs may limit tumor progression. However, identifying tumor-reactive TILs in ovarian cancer has been challenging, though adoptive TIL therapy in patients has been encouraging. Other forms of TIL immunomodulation remain under investigation including Treg depletion, antibody-based checkpoint modification, activation and amplification using dendritic cells, antigen presenting cells or IL-2 cytokine culture, adjuvant cytokine injections, and gene-engineered T-cells. Many approaches to TIL manipulation inhibit ovarian cancer progression in preclinical or clinical studies as monotherapy. Here, we review the impact of TILs in ovarian cancer and attempts to mobilize TILs to halt tumor progression. We conclude that effective TIL therapy for ovarian cancer is at the brink of translation and optimal TIL activity may require combined methodologies to deliver clinically-relevant treatment.
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Affiliation(s)
- Phillip P Santoiemma
- a Ovarian Cancer Research Center ; Department of Obstetrics and Gynecology ; Perelman School of Medicine; University of Pennsylvania ; Philadelphia , PA USA
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Abstract
The accumulation of tumor infiltrating lymphocytes (TILs) in ovarian cancer is prognostic for increased survival while increases in immunosuppressive regulatory T-cells (Tregs) are associated with poor outcomes. Approaches that bolster tumor-reactive TILs may limit tumor progression. However, identifying tumor-reactive TILs in ovarian cancer has been challenging, though adoptive TIL therapy in patients has been encouraging. Other forms of TIL immunomodulation remain under investigation including Treg depletion, antibody-based checkpoint modification, activation and amplification using dendritic cells, antigen presenting cells or IL-2 cytokine culture, adjuvant cytokine injections, and gene-engineered T-cells. Many approaches to TIL manipulation inhibit ovarian cancer progression in preclinical or clinical studies as monotherapy. Here, we review the impact of TILs in ovarian cancer and attempts to mobilize TILs to halt tumor progression. We conclude that effective TIL therapy for ovarian cancer is at the brink of translation and optimal TIL activity may require combined methodologies to deliver clinically-relevant treatment.
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Affiliation(s)
- Phillip P Santoiemma
- a Ovarian Cancer Research Center ; Department of Obstetrics and Gynecology ; Perelman School of Medicine; University of Pennsylvania ; Philadelphia , PA USA
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Wick DA, Webb JR, Nielsen JS, Martin SD, Kroeger DR, Milne K, Castellarin M, Twumasi-Boateng K, Watson PH, Holt RA, Nelson BH. Surveillance of the tumor mutanome by T cells during progression from primary to recurrent ovarian cancer. Clin Cancer Res 2013; 20:1125-34. [PMID: 24323902 DOI: 10.1158/1078-0432.ccr-13-2147] [Citation(s) in RCA: 136] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Cancers accumulate mutations over time, each of which brings the potential for recognition by the immune system. We evaluated T-cell recognition of the tumor mutanome in patients with ovarian cancer undergoing standard treatment. EXPERIMENTAL DESIGN Tumor-associated T cells from 3 patients with ovarian cancer were assessed by ELISPOT for recognition of nonsynonymous mutations identified by whole exome sequencing of autologous tumor. The relative levels of mutations and responding T cells were monitored in serial tumor samples collected at primary surgery and first and second recurrence. RESULTS The vast majority of mutations (78/79) were not recognized by tumor-associated T cells; however, a highly specific CD8(+) T-cell response to the mutation hydroxysteroid dehydrogenase-like protein 1 (HSDL1)(L25V) was detected in one patient. In the primary tumor, the HSDL1(L25V) mutation had low prevalence and expression, and a corresponding T-cell response was undetectable. At first recurrence, there was a striking increase in the abundance of the mutation and corresponding MHC class I epitope, and this was accompanied by the emergence of the HSDL1(L25V)-specific CD8(+) T-cell response. At second recurrence, the HSDL1(L25V) mutation and epitope continued to be expressed; however, the corresponding T-cell response was no longer detectable. CONCLUSION The immune system can respond to the evolving ovarian cancer genome. However, the T-cell response detected here was rare, was transient, and ultimately failed to prevent disease progression. These findings reveal the limitations of spontaneous tumor immunity in the setting of standard treatments and suggest a high degree of ignorance of tumor mutations that could potentially be reversed by immunotherapy.
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Affiliation(s)
- Darin A Wick
- Authors' Affiliations: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency; Department of Biochemistry and Microbiology, University of Victoria, Victoria; Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver; Departments of Medical Genetics and Pathology and Laboratory Medicine, University of British Columbia, Vancouver; and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada
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Webb JR, Milne K, Watson P, Deleeuw RJ, Nelson BH. Tumor-infiltrating lymphocytes expressing the tissue resident memory marker CD103 are associated with increased survival in high-grade serous ovarian cancer. Clin Cancer Res 2013; 20:434-44. [PMID: 24190978 DOI: 10.1158/1078-0432.ccr-13-1877] [Citation(s) in RCA: 348] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND The presence of CD8(+) tumor-infiltrating lymphocytes (TIL) is associated with prolonged survival in high-grade serous ovarian cancer (HGSC) and other epithelial cancers. Survival is most strongly associated with intraepithelial versus intrastromal CD8(+) TILs; however, the mechanisms that promote the intraepithelial localization of TILs remain poorly understood. We hypothesized that intraepithelial CD8(+) TILs, like normal mucosal intraepithelial lymphocytes, might express CD103, a subunit of αE/β7 integrin, which binds E-cadherin on epithelial cells. METHODS A large collection of primary ovarian tumors (HGSC, endometrioid, mucinous, and clear cell) was analyzed by immunohistochemistry for the presence of TIL-expressing CD103. The activation and differentiation status of CD103(+) TILs were assessed by flow cytometry. The prognostic significance of TIL subsets was evaluated by Kaplan-Meier analysis. RESULTS CD103(+) TILs were present in all major ovarian cancer subtypes and were most abundant in HGSC. CD103(+) TILs were preferentially localized to epithelial regions of tumors and were comprised predominantly of CD8(+) T cells expressing activation (HLA-DR, Ki-67, PD-1) and cytolytic (TIA-1) markers, as well as CD56(+) NK cells. Tumor infiltration by CD103(+) TILs was strongly associated with patient survival in HGSC. Tumors containing CD8(+) TILs that were CD103(-) showed poor prognosis equivalent to tumors lacking CD8(+) TILs altogether. CONCLUSIONS CD103(+) TILs comprise intraepithelial, activated CD8(+) T cells, and NK cells and are strongly associated with patient survival in HGSC. CD103 may serve as a useful marker for enriching the most beneficial subsets of TILs for immunotherapy.
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Affiliation(s)
- John R Webb
- Authors' Affiliations: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency; Department of Biochemistry and Microbiology, University of Victoria; Departments of Pathology and Laboratory Medicine and Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
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Di J, Duiveman-de Boer T, Figdor CG, Torensma R. Aiming to immune elimination of ovarian cancer stem cells. World J Stem Cells 2013; 5:149-162. [PMID: 24179603 PMCID: PMC3812519 DOI: 10.4252/wjsc.v5.i4.149] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2013] [Revised: 03/15/2013] [Accepted: 07/19/2013] [Indexed: 02/06/2023] Open
Abstract
Ovarian cancer accounts for only 3% of all cancers in women, but it causes more deaths than any other gynecologic cancer. Treatment with chemotherapy and cytoreductive surgery shows a good response to the therapy. However, in a large proportion of the patients the tumor grows back within a few years. Cancer stem cells, that are less responsive to these treatments, are blamed for this recurrence of disease. Immune therapy either cellular or humoral is a novel concept to treat cancer. It is based on the notice that immune cells invade the tumor. However, the tumor invest heavily to escape from immune elimination by recruiting several immune suppressive mechanisms. These processes are normally in place to limit excessive immune activation and prevent autoimmune phenomena. Here, we discuss current knowledge about the immune (suppressive) status in ovarian cancer. Moreover, we discuss the immunological targets of ovarian cancer stem cells.
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Chen Y, Huang A, Gao M, Yan Y, Zhang W. Potential therapeutic value of dendritic cells loaded with NY‑ESO‑1 protein for the immunotherapy of advanced hepatocellular carcinoma. Int J Mol Med 2013; 32:1366-72. [PMID: 24085111 DOI: 10.3892/ijmm.2013.1510] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2013] [Accepted: 09/17/2013] [Indexed: 12/25/2022] Open
Abstract
NY‑ESO‑1 is one of the most immunogenic cancer-testis (CT) antigens. Cancer vaccine trials based on NY‑ESO‑1 are currently ongoing. Dendritic cells (DCs) are the most potent antigen-presenting cells. The immune functions of DCs in a number of tumors have been identified; however, the potential therapeutic value of DCs pulsed with NY‑ESO‑1 in hepatocellular carcinoma (HCC) has not been extensively investigated. The objectives of the present study were to evaluate T cell response following stimulation with DCs pulsed with the recombinant NY‑ESO‑1 protein (rESO) and to establish a correlation between NY‑ESO‑1 expression and clinicopathological features in HCC patients. DCs were generated with granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL‑4) from human peripheral blood mononuclear cells. A mixed T cell reaction with DCs loaded with recombinant NY‑ESO‑1 protein (rESO-DCs) was evaluated by MTT assay. T cell responses against HCC cell lines were analyzed by measuring lactate dehydrogenase (LDH) activity. The protein levels of NY‑ESO‑1 were detected by immunohistochemistry (IHC) in a tissue microarray (TMA) containing 190 HCC samples. NY‑ESO‑1 transcript abundance was determined by reverse transcriptase-polymerase chain reaction (RT-PCR) in 54 out of the 190 HCC samples. The results revealed that mature DCs were induced and that rESO‑DCs significantly stimulated T cell proliferation. The specific lysis of T cells stimulated with rESO‑DCs was significantly higher in the NY‑ESO‑1-positive HCC cells compared with the NY‑ESO‑1-negative cells and the other controls (p<0.01). NY‑ESO‑1 was expressed in 15.8% (30/190)of the HCC samples, as shown by IHC and in 24.1% (13/54) of the samples, as shown by RT-PCR. The frequency of NY‑ESO‑1 expression was significantly higher in HCC patients with portal vein tumor thrombosis (24.6%) compared with those without thrombosis (11.2%, p=0.013). Our data suggest that DCs loaded with NY‑ESO‑1 protein stimulate antigen-specific T cell responses against HCC cells in vitro. NY‑ESO‑1 may thus be used as a potential target for immunotherapy in advanced HCC.
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Affiliation(s)
- Yuqing Chen
- Department of Pathology, Fujian Medical University, Fuzhou, Fujian 350004 P.R. China
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21
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Hou T, Liang D, Xu L, Huang X, Huang Y, Zhang Y. Atypical chemokine receptors predict lymph node metastasis and prognosis in patients with cervical squamous cell cancer. Gynecol Oncol 2013; 130:181-7. [PMID: 23603371 DOI: 10.1016/j.ygyno.2013.04.015] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2012] [Revised: 04/05/2013] [Accepted: 04/07/2013] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Atypical chemokine receptors (ACRs), including CCX-CKR, DARC, and D6, have been reported to be involved in cancer invasion and metastasis. The objective of this study was to investigate the prognostic importance of ACRs in patients with cervical squamous cell carcinoma (CSCC). METHODS The expression of three ACRs was investigated by immunohistochemical (IHC) examination in a total of 317 cervical specimens including 40 normal cervical tissues, 50 cases of carcinoma in situ of cervix (CIS), and 227 cases of CSCC by immunohistochemistry. RESULTS The expression rate of DARC and CCX-CKR in CSCC, CIS, and normal cervix increased gradually (p<0.01). D6 expression is decreased in CSCC compared to either in CIS or in normal cervix (p<0.05). In addition, the expression of CCL2 and CCL19 was inversely associated with ACR expression (p<0.05), while that of LCA was positively correlated with ACR expression (p<0.05). Moreover, DARC expression, CCX-CKR expression, and ACR coexpression were negatively correlated with lymph node metastasis (P<0.01). D6 expression and ACR coexpression were negatively related to tumor size (p=0.018) and recurrence (p=0.028). In multivariate Cox regression analysis, CCX-CKR expression was a positive indicator for overall survival (p=0.008), and D6 expression was an independent predictor of both overall and recurrence-free survival (p=0.041) in CSCC. CONCLUSIONS Our results suggest that the loss of ACRs may play important roles in the tumorigenesis and migration of cervical cancer. ACR expression may be considered as prognostic markers in patients with CSCC.
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Affiliation(s)
- Teng Hou
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, GD 510060, China
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22
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Dai N, Cao XJ, Li MX, Qing Y, Liao L, Lu XF, Zhang SH, Li Z, Yang YX, Wang D. Serum APE1 autoantibodies: a novel potential tumor marker and predictor of chemotherapeutic efficacy in non-small cell lung cancer. PLoS One 2013; 8:e58001. [PMID: 23472128 PMCID: PMC3589448 DOI: 10.1371/journal.pone.0058001] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2012] [Accepted: 01/29/2013] [Indexed: 12/31/2022] Open
Abstract
Apurinic/apyrimidinic endonuclease 1 (APE1), which has the dual functions of both DNA repair and redox activity, has been reported to be highly expressed in non-small cell lung cancer (NSCLC), and this appears to be a characteristic related to chemotherapy resistance. In this study, we identified serum APE1 autoantibodies (APE1-AAbs) in NSCLC patients and healthy controls by immunoblotting and investigated the expression of APE1-AAbs by indirect ELISA from the serum of 292 NSCLC patients and 300 healthy controls. In addition, serum APE1-AAbs level alterations of 91 patients were monitored before and after chemotherapy. Our results showed that serum APE1-AAbs can be detected in both NSCLC patients and healthy controls. Serum APE1-AAbs were significantly higher than those of healthy controls and closely related to APE1 antigen levels both in tumor tissues and the peripheral blood. Moreover, the change in levels of serum APE1-AAbs in NSCLC is closely associated with the response to chemotherapy. These results suggest that APE1-AAbs is a potential tumor marker and predictor of therapeutic efficacy in NSCLC.
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Affiliation(s)
- Nan Dai
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, China
| | - Xiao-Jing Cao
- Department of Pathology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Meng-Xia Li
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, China
| | - Yi Qing
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, China
| | - Ling Liao
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, China
| | - Xian-Feng Lu
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, China
| | - Shi-Heng Zhang
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, China
| | - Zheng Li
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, China
| | - Yu-Xin Yang
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, China
| | - Dong Wang
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, China
- * E-mail:
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Linnebacher M. Tumor-infiltrating B cells come into vogue. World J Gastroenterol 2013; 19:8-11. [PMID: 23326156 PMCID: PMC3542760 DOI: 10.3748/wjg.v19.i1.8] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2012] [Revised: 11/08/2012] [Accepted: 11/14/2012] [Indexed: 02/06/2023] Open
Abstract
Lymphocyte infiltration into solid tumors has been recognized as a main determinator of positive prognosis. For the most part this is attributed to cytotoxic T cells capable of directly destroying malignant cells. However, when considering the complex composition of the human immune system, recent findings of Nielsen et al on a potentially central role of tumor-infiltrating B cells is not really surprising. In this commentary article, I want to highlight the enormous potential impact of this observation for basic and translational research, prognostic procedures and ultimately for the development of future therapeutic concepts.
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Stiff PJ, Potkul RK, Venkataraman G, Sojitra P, Drakes ML. Immune Surveillance Tissue Antigen Profiling in Advanced Ovarian Cancer. ACTA ACUST UNITED AC 2012. [DOI: 10.1016/j.cogc.2012.09.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Nielsen JS, Sahota RA, Milne K, Kost SE, Nesslinger NJ, Watson PH, Nelson BH. CD20+ tumor-infiltrating lymphocytes have an atypical CD27- memory phenotype and together with CD8+ T cells promote favorable prognosis in ovarian cancer. Clin Cancer Res 2012; 18:3281-92. [PMID: 22553348 DOI: 10.1158/1078-0432.ccr-12-0234] [Citation(s) in RCA: 427] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE Tumor-infiltrating lymphocytes (TIL), in particular CD8(+) T cells and CD20(+) B cells, are strongly associated with survival in ovarian cancer and other carcinomas. Although CD8(+) TIL can mediate direct cytolytic activity against tumors, the role of CD20(+) TIL is poorly understood. Here, we investigate the possible contributions of CD20(+) TIL to humoral and cellular tumor immunity. EXPERIMENTAL DESIGN Tumor and serum specimens were obtained from patients with high-grade serous ovarian cancer. CD8(+) and CD20(+) TIL were analyzed by immunohistochemistry and flow cytometry. Immunoglobulin molecules were evaluated by DNA sequencing. Serum autoantibody responses to the tumor antigens p53 and NY-ESO-1 were measured by ELISA. RESULTS The vast majority of CD20(+) TIL were antigen experienced, as evidenced by class-switching, somatic hypermutation, and oligoclonality, yet they failed to express the canonical memory marker CD27. CD20(+) TIL showed no correlation with serum autoantibodies to p53 or NY-ESO-1. Instead, they colocalized with activated CD8(+) TIL and expressed markers of antigen presentation, including MHC class I, MHC class II, CD40, CD80, and CD86. The presence of both CD20(+) and CD8(+) TIL correlated with increased patient survival compared with CD8(+) TIL alone. CONCLUSIONS In high-grade serous ovarian tumors, CD20(+) TIL have an antigen-experienced but atypical CD27(-) memory B-cell phenotype. They are uncoupled from serum autoantibodies, express markers of antigen-presenting cells, and colocalize with CD8(+) T cells. We propose that the association between CD20(+) TIL and patient survival may reflect a supportive role in cytolytic immune responses.
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Affiliation(s)
- Julie S Nielsen
- Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada.
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Absolute lymphocyte count is associated with survival in ovarian cancer independent of tumor-infiltrating lymphocytes. J Transl Med 2012; 10:33. [PMID: 22369276 PMCID: PMC3310776 DOI: 10.1186/1479-5876-10-33] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2011] [Accepted: 02/27/2012] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND The immune system strongly influences outcome in patients with ovarian cancer. In particular, the absolute lymphocyte count in peripheral blood (ALC) and the presence of tumor-infiltrating lymphocytes (TIL) have each been associated with favourable prognosis. However, the mechanistic relationships between ALC, TIL and prognosis are poorly understood. We hypothesized that high ALC values might be associated with stronger tumor immunity as manifested by increased TIL, decreased tumor burden and longer survival. METHODS ALC values were collected from patient records ≥ 2 years before, during or after primary treatment for high-grade serous ovarian cancer (HGSC). Lymphocyte subsets were assessed in peripheral blood by flow cytometry. CD8+ and CD20+ TIL were assessed by immunohistochemistry. RESULTS Overall, patients had normal ALC values two or more years prior to diagnosis of HGSC. These values were not predictive of disease severity or survival upon subsequent development of HGSC. Rather, ALC declined upon development of HGSC in proportion to disease burden. This decline involved all lymphocyte subsets. ALC increased following surgery, remained stable during chemotherapy, but rarely recovered to pre-diagnostic levels. ALC values recorded at diagnosis did not correlate with CD8+ or CD20+ TIL but were associated with progression-free survival. CONCLUSIONS Patients with high intrinsic ALC values show no clinical or survival advantage upon subsequent development of HGSC. ALC values at diagnosis are prognostic due to an association with disease burden rather than TIL. Therapeutic enhancement of ALC may be necessary but not sufficient to improve survival in HGSC.
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West NR, Milne K, Truong PT, Macpherson N, Nelson BH, Watson PH. Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer. Breast Cancer Res 2011; 13:R126. [PMID: 22151962 PMCID: PMC3326568 DOI: 10.1186/bcr3072] [Citation(s) in RCA: 291] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2011] [Revised: 09/06/2011] [Accepted: 12/08/2011] [Indexed: 12/22/2022] Open
Abstract
Introduction Infiltration of breast tumors by tumor-infiltrating lymphocytes (TIL) has been associated with sensitivity to anthracycline-based chemotherapy. However, it is unclear whether this is true within the estrogen receptor-alpha (ER)-negative subset of breast tumors that frequently manifest high TIL levels. Methods The association of TIL with short-term and long-term clinical response to anthracycline-based therapy was assessed in two independent ER-negative breast cancer cohorts in which patients were categorized as TIL-high or TIL-low. We defined an eight-gene lymphocyte mRNA expression signature (including CD19, CD3D, CD48, GZMB, LCK, MS4A1, PRF1, and SELL) and used unsupervised hierarchical clustering to examine the association between TIL and short-term response to neoadjuvant chemotherapy in a previously published cohort of ER-negative tumors (n = 113). We also examined the association between TIL and long-term chemotherapeutic efficacy in a second cohort of ER-negative tumors (n = 255) with longer than 6 years of median follow-up by using tissue microarrays and immunohistochemistry (IHC) for detection of CD3, CD8, CD4, CD20, and TIA-1. Results In patients with ER-negative tumors treated with neoadjuvant anthracycline-based chemotherapy, pathologic complete responses (pCRs) were achieved by 23 (74%) of 31 TIL-high patients and 25 (31%) of 80 TIL-low patients (odds ratio (OR), 6.33; 95% confidence interval (CI), 2.49 to 16.08; P < 0.0001). Multivariate logistic regression with standard clinicopathologic features demonstrated that only tumor size (P = 0.037) and TIL status (P = 0.001) were independent predictors of anthracycline response. In the second cohort, adjuvant anthracycline-based therapy was associated with increased disease-free survival (DFS) only in patients with high levels of intraepithelial CD3+ TIL (P = 0.0023). In contrast, outcomes after CMF treatment (cyclophosphamide, methotrexate, and fluorouracil) showed no association with CD3 status. In both cohorts, cytotoxic T-cells were the primary TIL subtype associated with anthracycline sensitivity. Finally, TIL significantly predicted anthracycline sensitivity for both the Her2-positive and triple-negative tumor phenotypes. Conclusions ER-negative breast cancers with high levels of TIL have heightened sensitivity to anthracycline-based chemotherapy, as assessed by the immediate response to neoadjuvant therapy and long-term outcome following adjuvant therapy. Investigations of TIL-based predictive tests to identify patients likely to benefit from anthracycline-based treatments are warranted.
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Affiliation(s)
- Nathan R West
- Trev & Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia, V8R 6V5, Canada
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Hwang WT, Adams SF, Tahirovic E, Hagemann IS, Coukos G. Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-analysis. Gynecol Oncol 2011; 124:192-8. [PMID: 22040834 DOI: 10.1016/j.ygyno.2011.09.039] [Citation(s) in RCA: 532] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2011] [Revised: 09/28/2011] [Accepted: 09/28/2011] [Indexed: 11/19/2022]
Abstract
OBJECTIVE The presence of T cells within the epithelial component of tumors, as histologic evidence of anti-tumor immunity, has been associated with a survival advantage in multiple studies across diverse patient cohorts. We performed a meta-analysis of studies evaluating the prognostic value of tumor-infiltrating lymphocytes (TIL) on survival among women with ovarian cancer and to investigate factors associated with variations in this effect, including patient characteristics, surgical outcomes, tumor histology, and study protocols. METHOD Published studies that evaluated the association between TIL and patient survival were identified. Descriptive statistics, outcome data, and study quality were extracted from studies that met inclusion criteria. Hazard ratios and 95% confidence intervals were pooled across studies using the random-effects model. Publication bias was investigated using a funnel plot and heterogeneity was assessed with subgroup analysis and I(2) statistics. RESULTS Ten suitable studies comprising 1815 patients with ovarian cancer were analyzed. Our results demonstrate that a lack of intraepithelial TILs is significantly associated with a worse survival among patients (pooled HR: 2.24, 95% CI; 1.71-2.91). Variations in the prognostic value of TIL status based on debulking status, scoring method, and geographic regions were identified. CONCLUSIONS Intraepithelial TILs are a robust predictor of outcome in ovarian cancer and define a specific class of patients, whose distinct tumor biology should be taken into account in devising appropriate therapeutic strategies.
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Affiliation(s)
- Wei-Ting Hwang
- Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, PA 19104, USA
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Potential target antigens for a universal vaccine in epithelial ovarian cancer. Clin Dev Immunol 2010; 2010. [PMID: 20885926 PMCID: PMC2946591 DOI: 10.1155/2010/891505] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2010] [Accepted: 07/16/2010] [Indexed: 01/08/2023]
Abstract
The prognosis of epithelial ovarian cancer (EOC), the primary cause of death from gynaecological malignancies, has only modestly improved over the last decades. Immunotherapeutic treatment using a cocktail of antigens has been proposed as a "universal" vaccine strategy. We determined the expression of tumor antigens in the context of MHC class I expression in 270 primary tumor samples using tissue microarray. Expression of tumor antigens p53, SP17, survivin, WT1, and NY-ESO-1 was observed in 120 (48.0%), 173 (68.9%), 208 (90.0%), 129 (56.3%), and 27 (11.0%) of 270 tumor specimens, respectively. In 93.2% of EOC, at least one of the investigated tumor antigens was (over)expressed. Expression of MHC class I was observed in 78.1% of EOC. In 3 out 4 primary tumors, (over)expression of a tumor antigen combined with MHC class I was observed. These results indicate that a multiepitope vaccine, comprising these antigens, could serve as a universal therapeutic vaccine for the vast majority of ovarian cancer patients.
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Gjerstorff MF, Burns J, Ditzel HJ. Cancer-germline antigen vaccines and epigenetic enhancers: future strategies for cancer treatment. Expert Opin Biol Ther 2010; 10:1061-75. [PMID: 20420535 DOI: 10.1517/14712598.2010.485188] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
IMPORTANCE OF THE FIELD Immunotherapy holds great potential for disseminated cancer, and cancer-germline (CG) antigens are among the most promising tumor targets. They are widely expressed in different cancer types and are essentially tumor-specific, since their expression in normal tissues is largely restricted to immune-privileged sites. Although the therapeutic potential of these antigens may be compromised by their highly heterogeneous expression in many tumors and low frequency in some cancers, recent developments suggest that tumor-cell-selective enhancement of CG antigen gene expression can be achieved using epigenetic modifiers. AREAS COVERED IN THIS REVIEW We provide an overview of the potential of CG antigens as targets for cancer immunotherapy, including advantages and disadvantages. We also discuss the current state of development of CG antigen vaccines, and the potential synergistic effect of combining CG antigen immunotherapeutic strategies with epigenetic modifiers. WHAT THE READER WILL GAIN The reader will gain an overview of the past, present and future role of CG antigens in cancer immunotherapy. TAKE HOME MESSAGE Chemoimmunotherapy using epigenetic drugs and CG antigen vaccines may be a useful approach for treating cancer.
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Webb JR, Wick DA, Nielsen JS, Tran E, Milne K, McMurtrie E, Nelson BH. Profound elevation of CD8+ T cells expressing the intraepithelial lymphocyte marker CD103 (αE/β7 Integrin) in high-grade serous ovarian cancer. Gynecol Oncol 2010; 118:228-36. [PMID: 20541243 DOI: 10.1016/j.ygyno.2010.05.016] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2010] [Revised: 05/13/2010] [Accepted: 05/14/2010] [Indexed: 11/25/2022]
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Bay JO, Cabrespine-Faugeras A, Tabrizi R, Blaise D, Viens P, Ehninger G, Bornhauser M, Slavin S, Rosti G, Peccatori J, Demirer T, Bregni M. Allogeneic hematopoietic stem cell transplantation in ovarian cancer-the EBMT experience. Int J Cancer 2010; 127:1446-52. [PMID: 20049839 DOI: 10.1002/ijc.25149] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Although preliminary results suggest that allogeneic hematopoietic stem cell transplantation (allo HCT) for ovarian cancer (OC) is a feasible procedure, the low patient number in previous studies had limited ability to evaluate the true benefit of allo HCT in OC. This retrospective multicenter study included 30 patients with OC allografted between 1995 and 2005 to determine the outcome of patients with OC treated with allo HCT. Prior to allo HCT, patients were in complete response (n = 1), partial response (n = 7), stable disease (n = 11) or had progressive disease (n = 13). An objective response (OR) was observed in 50% (95% CI, 33-67) of patients. Three patients of responding patients had an objective response following the development of acute graft-versus-host disease (aGvHD). The cumulative incidence of chronic GvHD (cGVHD) was 34% (95% CI, 18-50). Transplant relative mortality rates were 7 and 20% on day 100 and 1 year, respectively. With a median follow-up of 74.5 months (range 16-148), median progression free survival (PFS) was 6 months and median overall survival (OS) was 10.4 months. Patients who developed cGvHD following allo HCT had a significant OS improvement compared to those who did not (17.6 months vs. 6.5 months, p = 0.042). However, PFS was not similarly significantly improved in patients who developed cGvHD (12 months versus 3.7 months, p = 0.81). Allo HCT in OC may lead to graft-versus-OC effects. Their clinical relevance remains to be shown.
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Affiliation(s)
- Jacques-Olivier Bay
- Cellular Therapy and Clinic Hematology Unit, Hôtel-Dieu, Clermont-Ferrand, France.
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Kobold S, Lütkens T, Cao Y, Bokemeyer C, Atanackovic D. Autoantibodies against tumor-related antigens: Incidence and biologic significance. Hum Immunol 2010; 71:643-51. [DOI: 10.1016/j.humimm.2010.03.015] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2009] [Revised: 03/22/2010] [Accepted: 03/25/2010] [Indexed: 01/05/2023]
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Hughes SE, Barnes RO, Watson PH. Biospecimen Use in Cancer Research Over Two Decades. Biopreserv Biobank 2010; 8:89-97. [DOI: 10.1089/bio.2010.0005] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Affiliation(s)
- Shevaun E. Hughes
- Tumour Tissue Repository, Trev and Joyce Deeley Research Centre, BC Cancer Agency, 2410 Lee Ave, Victoria, BC, Canada
| | - Rebecca O Barnes
- Tumour Tissue Repository, Trev and Joyce Deeley Research Centre, BC Cancer Agency, 2410 Lee Ave, Victoria, BC, Canada
| | - Peter H Watson
- Tumour Tissue Repository, Trev and Joyce Deeley Research Centre, BC Cancer Agency, 2410 Lee Ave, Victoria, BC, Canada
- Department of Pathology and Laboratory Medicine, BC Cancer Agency and UBC, Vancouver, BC, Canada
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Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci U S A 2010; 107:7875-80. [PMID: 20385810 DOI: 10.1073/pnas.1003345107] [Citation(s) in RCA: 712] [Impact Index Per Article: 47.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
NY-ESO-1 is a "cancer-testis" antigen frequently expressed in epithelial ovarian cancer (EOC) and is among the most immunogenic tumor antigens defined to date. In an effort to understand in vivo tolerance mechanisms, we assessed the phenotype and function of NY-ESO-1-specific CD8(+) T cells derived from peripheral blood lymphocytes (PBLs), tumor-infiltrating lymphocytes (TILs), and tumor-associated lymphocytes (TALs) of EOC patients with NY-ESO-1-expressing tumors, with or without humoral immunity to NY-ESO-1. Whereas NY-ESO-1-specific CD8(+) T cells were readily detectable ex vivo with tetramers in TILs and TALs of seropositive patients, they were only detectable in PBLs following in vitro stimulation. Compared with PBLs, tumor-derived NY-ESO-1-specific CD8(+) T cells demonstrated impaired effector function, preferential usage of dominant T-cell receptor, and enriched coexpression of inhibitory molecules LAG-3 and PD-1. Expression of LAG-3 and PD-1 on CD8(+) T cells was up-regulated by IL-10, IL-6 (cytokines found in tumor ascites), and tumor-derived antigen-presenting cells. Functionally, CD8(+)LAG-3(+)PD-1(+) T cells were more impaired in IFN-gamma/TNF-alpha production compared with LAG-3(+)PD-1(-) or LAG-3(-)PD-1(-) subsets. Dual blockade of LAG-3 and PD-1 during T-cell priming efficiently augmented proliferation and cytokine production by NY-ESO-1-specific CD8(+) T cells, indicating that antitumor function of NY-ESO-1-specific CD8(+) T cells could potentially be improved by therapeutic targeting of these inhibitory receptors.
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Lai B, Zhu PQ, Zhu SC, Luo HL. Clinical implications of expression of MAGE-1 and NY-ESO-1 mRNAs in gastrointestinal stromal tumors. Shijie Huaren Xiaohua Zazhi 2010; 18:355-360. [DOI: 10.11569/wcjd.v18.i4.355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the possibility of using melanoma antigen-1 (MAGE-1) and New York-esophageal-1 (NY-ESO-1) antigens as specific targets for immunotherapy of gastrointestinal stromal tumors (GISTs) and using MAGE-1 and NY-ESO-1 mRNA levels as auxiliary parameters for risk classification of GISTs.
METHODS: The expression of MAGE-1 and NY-ESO-1 mRNAs was detected by reverse transcription-polymerase chain reaction (RT-PCR) in 30 GIST tissue specimens. The correlation of MAGE-1 and NY-ESO-1 mRNA expression with pathological parameters was analyzed in GISTs.
RESULTS: The positive rates of MAGE-1 and NY-ESO-1 mRNA expression in GIST specimens were 30% and 47%, respectively. At least one of these two cancer-testis antigens (CTAs) was detected in 18 GIST tissue specimens. The expression of MAGE-1 and NY-ESO-1 mRNAs was not correlated with age, sex or pathologic type (P > 0.05), but correlated with tumor site, tumor diameter and risk grade (all P < 0.05). The expression levels of MAGE-1 and NY-ESO-1 mRNAs in GISTs of high risk grade were significantly higher than those in GISTs of low risk grade (P < 0.05). No negative correlation was noted between the expression of MAGE-1 and NY-ESO-1 mRNAs in GISTs (r = 0.018, P > 0.05).
CONCLUSION: MAGE-1 and NY-ESO-1 mRNAs are expressed specifically in GIST tissue and may be potentially promising targets for antigen-specific immunotherapy of GISTs. The expression of MAGE-1 and NY-ESO-1 mRNAs is correlated with the risk grade of GISTs. MAGE-1 and NY-ESO-1 mRNA levels are promising auxiliary parameters for risk classification of GISTs.
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Yang T, Martin ML, Nielsen JS, Milne K, Wall EM, Lin W, Watson PH, Nelson BH. Mammary tumors with diverse immunological phenotypes show differing sensitivity to adoptively transferred CD8+ T cells lacking the Cbl-b gene. Cancer Immunol Immunother 2009; 58:1865-75. [PMID: 19350239 PMCID: PMC11030869 DOI: 10.1007/s00262-009-0698-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2008] [Accepted: 03/12/2009] [Indexed: 12/14/2022]
Abstract
We tested the efficacy of CD8+ T cells lacking the Cbl-b gene against a panel of mammary tumor lines with different intrinsic sensitivities to T cells. Mice bearing established tumors expressing an ovalbumin-tagged version of HER-2/neu underwent adoptive transfer with Cbl-b-replete or -null CD8+ T cells from OT-I T cell receptor transgenic donor mice. In general, Cbl-b-null OT-I cells showed enhanced expansion, persistence, and capacity for tumor infiltration. This resulted in markedly enhanced efficacy against two tumor lines that normally demonstrate complete (NOP21) or partial (NOP23) regression. Moreover, a third tumor line (NOP6) that normally demonstrates progressive disease underwent complete regression in response to Cbl-b-null OT-I cells. However, a fourth tumor line (NOP18) was resistant to Cbl-b-null OT-I cells owing to a profound barrier to lymphocyte infiltration. Thus, Cbl-b-null CD8+ T cells are generally more efficacious but are nonetheless unable to mediate curative responses against all tumor phenotypes.
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Affiliation(s)
- Taimei Yang
- Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, 2410 Lee Avenue, Victoria, BC V8R 6V5, Canada
| | - Michele L. Martin
- Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, 2410 Lee Avenue, Victoria, BC V8R 6V5, Canada
- Department of Biology, University of Victoria, Victoria, BC Canada
| | - Julie S. Nielsen
- Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, 2410 Lee Avenue, Victoria, BC V8R 6V5, Canada
| | - Katy Milne
- Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, 2410 Lee Avenue, Victoria, BC V8R 6V5, Canada
| | - Erika M. Wall
- Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, 2410 Lee Avenue, Victoria, BC V8R 6V5, Canada
- Department of Biochemistry/Microbiology, University of Victoria, Victoria, BC Canada
| | - Wendy Lin
- Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, 2410 Lee Avenue, Victoria, BC V8R 6V5, Canada
| | - Peter H. Watson
- Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, 2410 Lee Avenue, Victoria, BC V8R 6V5, Canada
- Department of Biochemistry/Microbiology, University of Victoria, Victoria, BC Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC Canada
| | - Brad H. Nelson
- Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, 2410 Lee Avenue, Victoria, BC V8R 6V5, Canada
- Department of Biology, University of Victoria, Victoria, BC Canada
- Department of Biochemistry/Microbiology, University of Victoria, Victoria, BC Canada
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Intraepithelial CD8-positive T lymphocytes predict survival for patients with serous stage III ovarian carcinomas: relevance of clonal selection of T lymphocytes. Br J Cancer 2009; 101:1513-21. [PMID: 19861998 PMCID: PMC2778517 DOI: 10.1038/sj.bjc.6605274] [Citation(s) in RCA: 98] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background: The aim of this study was to investigate the prognostic effect of tumour-infiltrating lymphocytes (TILs) in serous stage III ovarian carcinoma to determine TIL clonality and to correlate this to Her2/neu expression. Methods: Formalin-fixed and paraffin-embedded ovarian carcinomas were examined for CD20-, CD3-, CD4- and CD8-positive lymphocytes (n=100), and for Her2/neu-positive tumour cells (n=55/100) by immunohistochemistry. Clonality analysis was carried out by T-cell receptor γ (TCRγ) gene rearrangements (n=93/100). Statistical analyses included experimental and clinico-pathological variables, as well as disease-free (DFS) and overall (OS) survival. Results: CD20-positive B lymphocytes were present in 57.7% (stromal)/33.0% (intraepithelial) and CD3-positive T lymphocytes in 99.0% (stromal)/90.2% (intraepithelial) of ovarian carcinomas. Intraepithelial CD3-positive T lymphocytes were correlated with improved DFS in optimally debulked patients (P=0.0402). Intraepithelial CD8-positive T lymphocytes were correlated with improved OS in all optimally debulked patients (P=0.0201) and in those undergoing paclitaxel/carboplatin therapy (P=0.0092). Finally, rarified and clonal TCRγ gene rearrangements were detected in 37 out of 93 (39.8%) and 15 out of 93 (16.1%) cases, respectively. This was marginally associated with improved DFS (P=0.0873). Despite a significant correlation of HER2/neu status and intraepithelial CD8-positive lymphocytes (P=0.0264), this was non-directional (R=−0.257; P=0.0626). Conclusion: Improved survival of ovarian cancer patients is related to the infiltration, clonal selection and intraepithelial persistence of T lymphocytes.
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