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Zhu S, Jin Y, Zhou M, Li L, Song X, Su X, Liu B, Shen J. KK-LC-1, a biomarker for prognosis of immunotherapy for primary liver cancer. BMC Cancer 2024; 24:811. [PMID: 38972967 PMCID: PMC11229184 DOI: 10.1186/s12885-024-12586-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 07/01/2024] [Indexed: 07/09/2024] Open
Abstract
PURPOSE There is mounting evidence that patients with liver cancer can benefit from Immune checkpoint inhibitors. However, due to the high cost and low efficacy, we aimed to explore new biomarkers for predicting the efficacy of immunotherapy. METHODS Specimens and medical records of liver cancer patients treated at Drum Tower Hospital of Nanjing University were collected, and the expression of Kita-Kyushu lung cancer antigen-1 (KK-LC-1) in tissues as well as the corresponding antibodies in serum were examined to find biomarkers related to the prognosis of immunotherapy and to explore its mechanism in the development of liver cancer. RESULTS KK-LC-1 expression was found to be 34.4% in histopathological specimens from 131 patients and was significantly correlated with Foxp3 expression (P = 0.0356). The expression of Foxp3 in the tissues of 24 patients who received immunotherapy was significantly correlated with overall survival (OS) (P = 0.0247), and there was also a tendency for prolonged OS in patients with high expression of KK-LC-1. In addition, the expression of KK-LC-1 antibody in the serum of patients who received immunotherapy with a first efficacy evaluation of stable disease (SD) was significantly higher than those with partial response (PR) (P = 0.0413). CONCLUSIONS Expression of KK-LC-1 in both tissues and serum has been shown to correlate with the prognosis of patients treated with immunotherapy, and KK-LC-1 is a potential therapeutic target for oncological immunotherapy.
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Affiliation(s)
- Sihui Zhu
- Comprehensive Cancer Centre, Department of Oncology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Comprehensive Cancer Centre of Nanjing international Hospital, Medical School of Nanjing University, Nanjing, China
- Clinical Cancer Institute of Nanjing University, Nanjing, China
| | - Yuncheng Jin
- Comprehensive Cancer Centre, Department of Oncology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Clinical Cancer Institute of Nanjing University, Nanjing, China
| | - Mingzhen Zhou
- Comprehensive Cancer Centre, Department of Oncology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Clinical Cancer Institute of Nanjing University, Nanjing, China
| | - Lin Li
- Comprehensive Cancer Centre, Department of Oncology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Clinical Cancer Institute of Nanjing University, Nanjing, China
- Department of Pathologyof Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Xueru Song
- Comprehensive Cancer Centre, Department of Oncology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Clinical Cancer Institute of Nanjing University, Nanjing, China
| | - Xinyu Su
- Comprehensive Cancer Centre, Department of Oncology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Clinical Cancer Institute of Nanjing University, Nanjing, China
| | - Baorui Liu
- Comprehensive Cancer Centre, Department of Oncology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
- Clinical Cancer Institute of Nanjing University, Nanjing, China.
| | - Jie Shen
- Comprehensive Cancer Centre, Department of Oncology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
- Clinical Cancer Institute of Nanjing University, Nanjing, China.
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Laisné M, Rodgers B, Benlamara S, Wicinski J, Nicolas A, Djerroudi L, Gupta N, Ferry L, Kirsh O, Daher D, Philippe C, Okada Y, Charafe-Jauffret E, Cristofari G, Meseure D, Vincent-Salomon A, Ginestier C, Defossez PA. A novel bioinformatic approach reveals cooperation between Cancer/Testis genes in basal-like breast tumors. Oncogene 2024; 43:1369-1385. [PMID: 38467851 PMCID: PMC11065691 DOI: 10.1038/s41388-024-03002-7] [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: 07/26/2023] [Revised: 02/22/2024] [Accepted: 03/01/2024] [Indexed: 03/13/2024]
Abstract
Breast cancer is the most prevalent type of cancer in women worldwide. Within breast tumors, the basal-like subtype has the worst prognosis, prompting the need for new tools to understand, detect, and treat these tumors. Certain germline-restricted genes show aberrant expression in tumors and are known as Cancer/Testis genes; their misexpression has diagnostic and therapeutic applications. Here we designed a new bioinformatic approach to examine Cancer/Testis gene misexpression in breast tumors. We identify several new markers in Luminal and HER-2 positive tumors, some of which predict response to chemotherapy. We then use machine learning to identify the two Cancer/Testis genes most associated with basal-like breast tumors: HORMAD1 and CT83. We show that these genes are expressed by tumor cells and not by the microenvironment, and that they are not expressed by normal breast progenitors; in other words, their activation occurs de novo. We find these genes are epigenetically repressed by DNA methylation, and that their activation upon DNA demethylation is irreversible, providing a memory of past epigenetic disturbances. Simultaneous expression of both genes in breast cells in vitro has a synergistic effect that increases stemness and activates a transcriptional profile also observed in double-positive tumors. Therefore, we reveal a functional cooperation between Cancer/Testis genes in basal breast tumors; these findings have consequences for the understanding, diagnosis, and therapy of the breast tumors with the worst outcomes.
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Affiliation(s)
- Marthe Laisné
- Université Paris Cité, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France
| | - Brianna Rodgers
- Université Paris Cité, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France
| | - Sarah Benlamara
- Université Paris Cité, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France
| | - Julien Wicinski
- CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Laboratory, Equipe Labellisée LIGUE Contre le Cancer, Marseille, France
| | - André Nicolas
- Platform of Experimental Pathology, Department of Diagnostic and Theranostic Medicine, Institut Curie-Hospital, 75005, Paris, France
| | - Lounes Djerroudi
- Department of Pathology, Institut Curie, 26 Rue d'Ulm, 75005, Paris, France
| | - Nikhil Gupta
- Université Paris Cité, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France
| | - Laure Ferry
- Université Paris Cité, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France
| | - Olivier Kirsh
- Université Paris Cité, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France
| | - Diana Daher
- Université Paris Cité, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France
| | | | - Yuki Okada
- Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, Japan
| | - Emmanuelle Charafe-Jauffret
- CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Laboratory, Equipe Labellisée LIGUE Contre le Cancer, Marseille, France
| | | | - Didier Meseure
- Platform of Experimental Pathology, Department of Diagnostic and Theranostic Medicine, Institut Curie-Hospital, 75005, Paris, France
| | | | - Christophe Ginestier
- CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Laboratory, Equipe Labellisée LIGUE Contre le Cancer, Marseille, France
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Xiao J, Huang F, Li L, Zhang L, Xie L, Liu B. Expression of four cancer-testis antigens in TNBC indicating potential universal immunotherapeutic targets. J Cancer Res Clin Oncol 2023; 149:15003-15011. [PMID: 37610673 PMCID: PMC10602960 DOI: 10.1007/s00432-023-05274-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 08/10/2023] [Indexed: 08/24/2023]
Abstract
OBJECTIVE Immunotherapy is an attractive treatment for breast cancer. Cancer-testis antigens (CTAs) are potential targets for immunotherapy for their restricted expression. Here, we investigate the expression of CTAs in breast cancer and their value for prognosis. So as to hunt for a potential panel of CTAs for universal immunotherapeutic targets. MATERIAL AND METHODS A total of 137 breast cancer tissue specimens including 51 triple-negative breast cancer (TNBC) were assessed for MAGE-A4, MAGEA1, NY-ESO-1, KK-LC-1 and PRAME expression by immunohistochemistry. The expression of PD-L1 and TILs was also calculated and correlated with the five CTAs. Clinical data were collected to evaluate the CTA's value for prognosis. Data from the K-M plotter were used as a validation cohort. RESULTS The expression of MAGE-A4, NY-ESO-1 and KK-LC-1 in TNBC was significantly higher than in non-TNBC (P = 0.012, P = 0.005, P < 0.001 respectively). 76.47% of TNBC expressed at least one of the five CTAs. Patients with positive expression of either MAGE-A4 or PRAME had a significantly extended disease-free survival (DFS). Data from the Kaplan-Meier plotter confirm our findings. CONCLUSIONS MAGE-A4, NY-ESO-1, PRAME and KK-LC-1 are overexpressed in breast cancer, especially in TNBC. Positive expression of MAGE-A4 or PARME may be associated with prolonged DFS. A panel of CTAs is attractive universal targets for immunotherapy.
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Affiliation(s)
- Jie Xiao
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Fengli Huang
- Department of Oncology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, China
| | - Lin Li
- Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Lianru Zhang
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Li Xie
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
| | - Baorui Liu
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
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Imbimbo M, Wetterwald L, Friedlaender A, Parikh K, Addeo A. Cellular Therapy in NSCLC: Between Myth and Reality. Curr Oncol Rep 2023; 25:1161-1174. [PMID: 37646900 PMCID: PMC10556121 DOI: 10.1007/s11912-023-01443-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/26/2023] [Indexed: 09/01/2023]
Abstract
PURPOSE OF REVIEW In this paper, we review the current state and modalities of adoptive cell therapies (ACT) in non-small cell lung carcinoma (NSCLC). We also discuss the challenges hampering the use of ACT and the approaches to overcome these barriers. RECENT FINDINGS Several trials are ongoing investigating the three main modalities of T cell-based ACT: tumor-infiltrating lymphocytes (TILs), genetically engineered T-cell receptors (TCRs), and chimeric antigen receptor (CAR) T cells. The latter, in particular, has revolutionized the treatment of hematologic malignancies. However, the efficacy against solid tumor is still sparse. Major limitations include the following: severe toxicities, restricted infiltration and activation within the tumors, antigen escape and heterogeneity, and manufacturing issues. ACT is a promising tool to improve the outcome of metastatic NSCLC, but significant translational and clinical research is needed to improve its application and expand the use in NSCLC.
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Affiliation(s)
- Martina Imbimbo
- Oncology Department, Centre Hospitalier Universitaire Vaudois (CHUV), Rue du Bugnon 46, Lausanne University Hospital, Lausanne, Switzerland.
| | - Laureline Wetterwald
- Oncology Department, Centre Hospitalier Universitaire Vaudois (CHUV), Rue du Bugnon 46, Lausanne University Hospital, Lausanne, Switzerland
| | - Alex Friedlaender
- Oncology Department, University Hospital Geneva (HUG), 1205, Geneva, Switzerland
- Oncology Department, Clinique Générale Beaulieu, 1206, Geneva, Switzerland
| | - Kaushal Parikh
- Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA
| | - Alfredo Addeo
- Oncology Department, University Hospital Geneva (HUG), 1205, Geneva, Switzerland
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Komuro H, Shinohara S, Fukushima Y, Demachi-Okamura A, Muraoka D, Masago K, Matsui T, Sugita Y, Takahashi Y, Nishida R, Takashima C, Ohki T, Shigematsu Y, Watanabe F, Adachi K, Fukuyama T, Hamana H, Kishi H, Miura D, Tanaka Y, Onoue K, Onoguchi K, Yamashita Y, Stratford R, Clancy T, Yamaguchi R, Kuroda H, Doi K, Iwata H, Matsushita H. Single-cell sequencing on CD8 + TILs revealed the nature of exhausted T cells recognizing neoantigen and cancer/testis antigen in non-small cell lung cancer. J Immunother Cancer 2023; 11:e007180. [PMID: 37544663 PMCID: PMC10407349 DOI: 10.1136/jitc-2023-007180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/10/2023] [Indexed: 08/08/2023] Open
Abstract
BACKGROUND CD8+tumor infiltrating lymphocytes (TILs) are often observed in non-small cell lung cancers (NSCLC). However, the characteristics of CD8+ TILs, especially T-cell populations specific for tumor antigens, remain poorly understood. METHODS High throughput single-cell RNA sequencing and single-cell T-cell receptor (TCR) sequencing were performed on CD8+ TILs from three surgically-resected lung cancer specimens. Dimensional reduction for clustering was performed using Uniform Manifold Approximation and Projection. CD8+ TIL TCR specific for the cancer/testis antigen KK-LC-1 and for predicted neoantigens were investigated. Differentially-expressed gene analysis, Gene Set Enrichment Analysis (GSEA) and single sample GSEA was performed to characterize antigen-specific T cells. RESULTS A total of 6998 CD8+ T cells was analyzed, divided into 10 clusters according to their gene expression profile. An exhausted T-cell (exhausted T (Tex)) cluster characterized by the expression of ENTPD1 (CD39), TOX, PDCD1 (PD1), HAVCR2 (TIM3) and other genes, and by T-cell oligoclonality, was identified. The Tex TCR repertoire (Tex-TCRs) contained nine different TCR clonotypes recognizing five tumor antigens including a KK-LC-1 antigen and four neoantigens. By re-clustering the tumor antigen-specific T cells (n=140), it could be seen that the individual T-cell clonotypes were present on cells at different stages of differentiation and functional states even within the same Tex cluster. Stimulating these T cells with predicted cognate peptide indicated that TCR signal strength and subsequent T-cell proliferation and cytokine production was variable but always higher for neoantigens than KK-LC-1. CONCLUSIONS Our approach focusing on T cells with an exhausted phenotype among CD8+ TILs may facilitate the identification of tumor antigens and clarify the nature of the antigen-specific T cells to specify the promising immunotherapeutic targets in patients with NSCLC.
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Affiliation(s)
- Hiroyasu Komuro
- Division of Translational Oncoimmunology, Aichi Cancer Center Research Institute, Nagoya, Japan
- Department of General Thoracic Surgery, Gifu University School of Medicine Graduate School of Medicine, Gifu, Japan
| | - Shuichi Shinohara
- Division of Translational Oncoimmunology, Aichi Cancer Center Research Institute, Nagoya, Japan
- Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Yasunori Fukushima
- Division of Translational Oncoimmunology, Aichi Cancer Center Research Institute, Nagoya, Japan
- Department of General Thoracic Surgery, Gifu University School of Medicine Graduate School of Medicine, Gifu, Japan
| | - Ayako Demachi-Okamura
- Division of Translational Oncoimmunology, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Daisuke Muraoka
- Division of Translational Oncoimmunology, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Katsuhiro Masago
- Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Takuya Matsui
- Division of Translational Oncoimmunology, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Yusuke Sugita
- Division of Translational Oncoimmunology, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Yusuke Takahashi
- Division of Translational Oncoimmunology, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Reina Nishida
- Division of Translational Oncoimmunology, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Chieko Takashima
- Division of Translational Oncoimmunology, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Takashi Ohki
- Department of Respiratory Surgery, Ichinomiya Nishi Hospital, Ichinomiya, Japan
| | - Yoshiki Shigematsu
- Department of Respiratory Surgery, Ichinomiya Nishi Hospital, Ichinomiya, Japan
| | - Fumiaki Watanabe
- Department of Thoracic Surgery, Mie Chuo Medical Center, Tsu, Japan
| | | | - Takashi Fukuyama
- Division of Biomedical Research, Kitasato University Medical Center, Kitamoto, Japan
| | - Hiroshi Hamana
- Department of Immunology, University of Toyama, Toyama, Japan
| | - Hiroyuki Kishi
- Department of Immunology, University of Toyama, Toyama, Japan
| | - Daiki Miura
- Drug Development Division, NEC Corporation, Minato-ku, Japan
| | - Yuki Tanaka
- Drug Development Division, NEC Corporation, Minato-ku, Japan
| | - Kousuke Onoue
- Drug Development Division, NEC Corporation, Minato-ku, Japan
| | | | | | | | - Trevor Clancy
- NEC OncoImmunity AS, Oslo Cancer Cluster, Oslo, Norway
| | - Rui Yamaguchi
- Division of Cancer Systems Biology, Aichi Cancer Center Research Institute, Nagoya, Japan
- Division of Cancer Informatics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroaki Kuroda
- Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Kiyoshi Doi
- Department of General Thoracic Surgery, Gifu University School of Medicine Graduate School of Medicine, Gifu, Japan
| | - Hisashi Iwata
- Department of General Thoracic Surgery, Gifu University School of Medicine Graduate School of Medicine, Gifu, Japan
| | - Hirokazu Matsushita
- Division of Translational Oncoimmunology, Aichi Cancer Center Research Institute, Nagoya, Japan
- Division of Cancer Immunogenomics, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Bu J, Zhang Y, Wu S, Li H, Sun L, Liu Y, Zhu X, Qiao X, Ma Q, Liu C, Niu N, Xue J, Chen G, Yang Y, Liu C. KK-LC-1 as a therapeutic target to eliminate ALDH + stem cells in triple negative breast cancer. Nat Commun 2023; 14:2602. [PMID: 37147285 PMCID: PMC10163259 DOI: 10.1038/s41467-023-38097-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 04/14/2023] [Indexed: 05/07/2023] Open
Abstract
Failure to achieve complete elimination of triple negative breast cancer (TNBC) stem cells after adjuvant therapy is associated with poor outcomes. Aldehyde dehydrogenase 1 (ALDH1) is a marker of breast cancer stem cells (BCSCs), and its enzymatic activity regulates tumor stemness. Identifying upstream targets to control ALDH+ cells may facilitate TNBC tumor suppression. Here, we show that KK-LC-1 determines the stemness of TNBC ALDH+ cells via binding with FAT1 and subsequently promoting its ubiquitination and degradation. This compromises the Hippo pathway and leads to nuclear translocation of YAP1 and ALDH1A1 transcription. These findings identify the KK-LC-1-FAT1-Hippo-ALDH1A1 pathway in TNBC ALDH+ cells as a therapeutic target. To reverse the malignancy due to KK-LC-1 expression, we employ a computational approach and discover Z839878730 (Z8) as an small-molecule inhibitor which may disrupt KK-LC-1 and FAT1 binding. We demonstrate that Z8 suppresses TNBC tumor growth via a mechanism that reactivates the Hippo pathway and decreases TNBC ALDH+ cell stemness and viability.
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Affiliation(s)
- Jiawen Bu
- Cancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, 110004, Shenyang, China
| | - Yixiao Zhang
- Cancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, 110004, Shenyang, China
| | - Sijin Wu
- Cancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, 110004, Shenyang, China
- Shenzhen Jingtai Technology Co., Ltd. (XtalPi), International Biomedical Industrial Park (Phase II) 3F, 2 Hongliu Rd, Futian District, 16023, Shenzhen, China
| | - Haonan Li
- School of Bioengineering, Dalian University of Technology, 116023, Dalian, China
| | - Lisha Sun
- Cancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, 110004, Shenyang, China
| | - Yang Liu
- School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 110016, Shenyang, China
- Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, 110016, Shenyang, China
| | - Xudong Zhu
- Cancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, 110004, Shenyang, China
| | - Xinbo Qiao
- Cancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, 110004, Shenyang, China
| | - Qingtian Ma
- Cancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, 110004, Shenyang, China
| | - Chao Liu
- Cancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, 110004, Shenyang, China
| | - Nan Niu
- Cancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, 110004, Shenyang, China
| | - Jinqi Xue
- Cancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, 110004, Shenyang, China
| | - Guanglei Chen
- Cancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, 110004, Shenyang, China
| | - Yongliang Yang
- Cancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, 110004, Shenyang, China.
- School of Bioengineering, Dalian University of Technology, 116023, Dalian, China.
| | - Caigang Liu
- Cancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, 110004, Shenyang, China.
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Zhu X, Bu J, Zhu T, Jiang Y. Targeting KK-LC-1 inhibits malignant biological behaviors of triple-negative breast cancer. J Transl Med 2023; 21:184. [PMID: 36895039 PMCID: PMC9996895 DOI: 10.1186/s12967-023-04030-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 03/01/2023] [Indexed: 03/11/2023] Open
Abstract
BACKGROUND Cancer/testis antigens (CTAs) participate in the regulation of malignant biological behaviors in breast cancer. However, the function and mechanism of KK-LC-1, a member of the CTA family, in breast cancer are still unclear. METHODS Bioinformatic tools, immunohistochemistry, and western blotting were utilized to detect the expression of KK-LC-1 in breast cancer and to explore the prognostic effect of KK-LC-1 expression in breast cancer patients. Cell function assays, animal assays, and next-generation sequencing were utilized to explore the function and mechanism of KK-LC-1 in the malignant biological behaviors of triple-negative breast cancer. Small molecular compounds targeting KK-LC-1 were also screened and drug susceptibility testing was performed. RESULTS KK-LC-1 was significantly highly expressed in triple-negative breast cancer tissues than in normal breast tissues. KK-LC-1 high expression was related to poor survival outcomes in patients with breast cancer. In vitro studies suggested that KK-LC-1 silencing can inhibit triple-negative breast cancer cell proliferation, invasion, migration, and scratch healing ability, increase cell apoptosis ratio, and arrest the cell cycle in the G0-G1 phase. In vivo studies have suggested that KK-LC-1 silencing decreases tumor weight and volume in nude mice. Results showed that KK-CL-1 can regulate the malignant biological behaviors of triple-negative breast cancer via the MAL2/MUC1-C/PI3K/AKT/mTOR pathway. The small-molecule compound Z839878730 had excellent KK-LC-1 targeting ability and cancer cell killing ability. The EC50 value was 9.7 μM for MDA-MB-231 cells and 13.67 µM for MDA-MB-468 cells. Besides, Z839878730 has little tumor-killing effect on human normal mammary epithelial cells MCF10A and can inhibit the malignant biological behaviors of triple-negative breast cancer cells by MAL2/MUC1-C/PI3K/AKT/mTOR pathway. CONCLUSIONS Our findings suggest that KK-LC-1 may serve as a novel therapeutic target for triple-negative breast cancer. Z839878730, which targets KK-LC-1, presents a new path for breast cancer clinical treatment.
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Affiliation(s)
- Xudong Zhu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, People's Republic of China.
- Department of General Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, 110042, Liaoning, People's Republic of China.
| | - Jiawen Bu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, People's Republic of China
| | - Tong Zhu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, People's Republic of China
| | - Yi Jiang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, People's Republic of China
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8
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Alsadat Mahmoudian R, Amirhosein M, Mahmoudian P, Fardi Golyan F, Mokhlessi L, Maftooh M, Khazaei M, Nassiri M, Mahdi Hassanian S, Ghayour-Mobarhan M, Ferns GA, Shahidsales S, Avan A. The therapeutic potential value of Cancer-testis antigens in immunotherapy of gastric cancer. Gene 2023; 853:147082. [PMID: 36464170 DOI: 10.1016/j.gene.2022.147082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 11/15/2022] [Accepted: 11/28/2022] [Indexed: 12/05/2022]
Abstract
Gastric cancer (GC) is the fourth most common cause of mortality and the fifth for incidence, globally. Diagnosis, early prognosis, and therapy remains challenging for this condition, and new tumor-associated antigens are required for its detection and immunotherapy. Cancer-testis antigens (CTAs) are a subfamily of tumor-associated antigens (TAAs) that have been identified as potential biomarkers and targets for cancer immunotherapy. The CTAs-restricted expression pattern in tumor cells and their potential immunogenicity identify them as attractive target candidates in CTA-based diagnosis or prognosis or immunotherapy. To date, numerous studies have reported the dysregulation of CTAs in GC. Several clinical trials have been done to assess CTA-based immunotherapeutic potential in the treatment of GC patients. NY-ESO-1, MAGE, and KK-LC-1 have been used in GC clinical trials. We review recent studies that have investigated the potential of the CTAs in GC regarding the expression, function, aggressive phenotype, prognosis, and immunological responses as well as their possible clinical significance as immunotherapeutic targets with a focus on challenges and future interventions.
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Affiliation(s)
- Reihaneh Alsadat Mahmoudian
- Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Maharati Amirhosein
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Parvaneh Mahmoudian
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Fatemeh Fardi Golyan
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Leila Mokhlessi
- Centre for Biomedical Education and Research, Institute of Pharmacology and Toxicology, Witten/Herdecke University, Witten, Germany.
| | - Mina Maftooh
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Majid Khazaei
- Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Mohammadreza Nassiri
- Recombinant Proteins Research Group, The Research Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran.
| | - Seyed Mahdi Hassanian
- Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Majid Ghayour-Mobarhan
- Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Department of Medical Education, Falmer, Brighton, Sussex BN1 9PH, UK.
| | | | - Amir Avan
- Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Norberg SM, Hinrichs CS. Engineered T cell therapy for viral and non-viral epithelial cancers. Cancer Cell 2023; 41:58-69. [PMID: 36400016 PMCID: PMC9839504 DOI: 10.1016/j.ccell.2022.10.016] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 09/13/2022] [Accepted: 10/17/2022] [Indexed: 11/18/2022]
Abstract
Engineered T cell therapy has shown remarkable efficacy in hematologic malignancies and has the potential for application to common epithelial cancers. Diverse T cell therapy strategies including adoptive transfer of tumor-infiltrating lymphocytes, chimeric antigen receptor (CAR)-T cells, and T cell receptor (TCR)-T cells have been studied in clinical trials. Recent research has established treatment of human papillomavirus (HPV)-associated cancers with TCR-T cells as a model for proof-of-principle studies in epithelial cancers. These studies and others have provided critical insight into mechanisms of tumor regression, therapeutic targets, treatment safety, treatment design, and barriers to curative cell therapies for common types of cancer. This perspective will review and consolidate understanding gained from clinical trials to treat viral and non-viral epithelial cancers with cell and gene therapy and will examine how past experience may guide future strategy in treatment and biomarker discovery.
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Affiliation(s)
- Scott M Norberg
- National Cancer Institute, Center for Immuno-Oncology, Bethesda, MD 20892, USA
| | - Christian S Hinrichs
- Rutgers Cancer Institute of New Jersey, Duncan and Nancy MacMillan Cancer Immunology and Metabolism Center of Excellence, New Brunswick, NJ 08901, USA.
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10
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Kang Y, Gan Y, Jiang Y, You J, Huang C, Chen Q, Xu X, Chen F, Chen L. Cancer-testis antigen KK-LC-1 is a potential biomarker associated with immune cell infiltration in lung adenocarcinoma. BMC Cancer 2022; 22:834. [PMID: 35907786 PMCID: PMC9339200 DOI: 10.1186/s12885-022-09930-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 07/25/2022] [Indexed: 11/25/2022] Open
Abstract
Background Cancer-testis antigens (CTAs) have emerged as potential clinical biomarkers targeting immunotherapy. KK-LC-1 is a member of CTAs, which has been demonstrated in a variety of tumors tissues and been found to elicit immune responses in cancer patients. However, the expression level and immune infiltration role of KK-LC-1 in lung adenocarcinoma (LUAD) remains to be elucidated. Methods In this study, the mRNA expression and overall survival rate of KK-LC-1 were evaluated by the TIMER and TCGA database in LUAD tissues and KK-LC-1 expression was further validated by clinical serum samples using quantitative RT-PCR. The relationship of KK-LC-1 with clinicopathologic parameters was analyzed. ROC curve result showed that miR-1825 was able to distinguish preoperative breast cancer patients from healthy people and postoperative patients. Then, the ROC curves were used to examine the ability of KK-LC-1 to distinguish preoperative LUAD patients from healthy and postoperative patients. The correlation between KK-LC-1 and infiltrating immune cells and immune marker sets was investigated via TIMER, TISIDB database, and CIBERSORT algorithm. The Kaplan-Meier plotter was used to further evaluate the prognostic value based on the expression levels of KK-LC-1 in related immune cells. Results The results showed that KK-LC-1 was significantly over-expressed in LUAD, and high levels of expression of KK-LC-1 were also closely correlated with poor overall survival. We also found that KK-LC-1 associated with TMN stage, NSE and CEA. The ROC curve result showed that KK-LC-1 was able to distinguish preoperative LUAD cancer patients from healthy people and postoperative patients. Moreover, KK-LC-1 had a larger AUC with higher diagnostic sensitivity and specificity than CEA. Based on the TIMER, TISIDB database, and CIBERSORT algorithm, the expression of KK-LC-1 was negatively correlated with CD4+ T cell, Macrophage, and Dendritic Cell in LUAD. Moreover, Based on the TIMER database, KK-LC-1 expression had a remarkable correlation with the type markers of Monocyte, TAM, M1 Macrophage, and M2 Macrophage. Furthermore, KK-LC-1 expression influenced the prognosis of LUAD patients by directly affecting immune cell infiltration by the Kaplan-Meier plotter analysis. Conclusions In conclusion, KK-LC-1 may serve as a promising diagnostic and prognostic biomarker in LUAD and correlate with immune infiltration and prognosis.
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Affiliation(s)
- Yanli Kang
- Department of Clinical Laboratory, Fujian Provincial hospital, Shengli Clinical Medical College of Fujian Medical University, No.134, East street, Gulou District, Fuzhou, 350001, China
| | - Yuhan Gan
- Department of Clinical Laboratory, Fujian Provincial hospital, Shengli Clinical Medical College of Fujian Medical University, No.134, East street, Gulou District, Fuzhou, 350001, China
| | - Yingfeng Jiang
- Department of Clinical Laboratory, Fujian Provincial hospital, Shengli Clinical Medical College of Fujian Medical University, No.134, East street, Gulou District, Fuzhou, 350001, China
| | - Jianbin You
- Department of Clinical Laboratory, Fujian Provincial hospital, Shengli Clinical Medical College of Fujian Medical University, No.134, East street, Gulou District, Fuzhou, 350001, China
| | - Chen Huang
- Department of Thoracic Surgery, Fujian Provincial hospital, Shengli Clinical Medical College of Fujian Medical University, No.134, East street, Gulou District, Fuzhou, 350001, China
| | - Qianshun Chen
- Department of Thoracic Surgery, Fujian Provincial hospital, Shengli Clinical Medical College of Fujian Medical University, No.134, East street, Gulou District, Fuzhou, 350001, China
| | - Xunyu Xu
- Department of Clinical Laboratory, Fujian Provincial hospital, Shengli Clinical Medical College of Fujian Medical University, No.134, East street, Gulou District, Fuzhou, 350001, China
| | - Falin Chen
- Department of Thoracic Surgery, Fujian Provincial hospital, Shengli Clinical Medical College of Fujian Medical University, No.134, East street, Gulou District, Fuzhou, 350001, China.
| | - Liangyuan Chen
- Department of Clinical Laboratory, Fujian Provincial hospital, Shengli Clinical Medical College of Fujian Medical University, No.134, East street, Gulou District, Fuzhou, 350001, China.
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11
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Alarcon NO, Jaramillo M, Mansour HM, Sun B. Therapeutic Cancer Vaccines—Antigen Discovery and Adjuvant Delivery Platforms. Pharmaceutics 2022; 14:pharmaceutics14071448. [PMID: 35890342 PMCID: PMC9325128 DOI: 10.3390/pharmaceutics14071448] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 06/28/2022] [Accepted: 06/30/2022] [Indexed: 12/15/2022] Open
Abstract
For decades, vaccines have played a significant role in protecting public and personal health against infectious diseases and proved their great potential in battling cancers as well. This review focused on the current progress of therapeutic subunit vaccines for cancer immunotherapy. Antigens and adjuvants are key components of vaccine formulations. We summarized several classes of tumor antigens and bioinformatic approaches of identification of tumor neoantigens. Pattern recognition receptor (PRR)-targeting adjuvants and their targeted delivery platforms have been extensively discussed. In addition, we emphasized the interplay between multiple adjuvants and their combined delivery for cancer immunotherapy.
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Affiliation(s)
- Neftali Ortega Alarcon
- Skaggs Pharmaceutical Sciences Center, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA; (N.O.A.); (M.J.); (H.M.M.)
| | - Maddy Jaramillo
- Skaggs Pharmaceutical Sciences Center, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA; (N.O.A.); (M.J.); (H.M.M.)
| | - Heidi M. Mansour
- Skaggs Pharmaceutical Sciences Center, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA; (N.O.A.); (M.J.); (H.M.M.)
- The University of Arizona Cancer Center, Tucson, AZ 85721, USA
- Department of Medicine, College of Medicine, The University of Arizona, Tucson, AZ 85724, USA
- BIO5 Institute, The University of Arizona, Tucson, AZ 85721, USA
| | - Bo Sun
- Skaggs Pharmaceutical Sciences Center, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA; (N.O.A.); (M.J.); (H.M.M.)
- The University of Arizona Cancer Center, Tucson, AZ 85721, USA
- BIO5 Institute, The University of Arizona, Tucson, AZ 85721, USA
- Correspondence: ; Tel.: +1-520-621-6420
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12
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Bai R, Yuan C. Kita-Kyushu Lung Cancer Antigen-1 (KK-LC-1): A Promising Cancer Testis Antigen. Aging Dis 2022; 13:1267-1277. [PMID: 35855340 PMCID: PMC9286905 DOI: 10.14336/ad.2021.1207] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 12/07/2021] [Indexed: 12/11/2022] Open
Abstract
Cancer has always been a huge problem in the field of human health, and its early diagnosis and treatment are the key to solving this problem. Cancer testis antigens (CTAs) are a family of multifunctional proteins that are specifically expressed in male spermatozoa and tumor cells but not in healthy somatic cells. Studies have found that CTAs are involved in the occurrence and development of tumors, and some CTAs trigger immunogenicity, which suggests a possibility of tumor immunotherapy. The differential expression and function of CTAs in normal tissues and tumor cells can promote the screening of tumor markers and the development of new immunotherapies. This article introduces the expression of Kita-Kyushu lung cancer antigen-1 (KK-LC-1), a new member of the CTA family, in different types of tumors and its role in immunotherapy.
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Affiliation(s)
- Rui Bai
- 1Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Cheng Yuan
- 2Department of Gynecological Oncology, Zhongnan Hospital, Wuhan University, Wuhan, China
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Chen X, Liu F, Yu X, Li L, Yan J, Chen X, Liu Q, Liu B. An auristatin-based peptide-drug conjugate targeting Kita-Kyushu lung cancer antigen 1 for precision chemoradiotherapy in gastric cancer. Eur J Med Chem 2022; 241:114617. [DOI: 10.1016/j.ejmech.2022.114617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 07/13/2022] [Accepted: 07/13/2022] [Indexed: 11/16/2022]
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Li Q, Hu W, Liao B, Song C, Li L. Natural high-avidity T-cell receptor efficiently mediates regression of cancer/testis antigen 83 positive common solid cancers. J Immunother Cancer 2022; 10:jitc-2022-004713. [PMID: 35798537 PMCID: PMC9263944 DOI: 10.1136/jitc-2022-004713] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/13/2022] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND T-cell receptor-engineered T cells (TCR-Ts) have achieved encouraging success in anticancer clinical trials. The antigenic targets, however, were primarily focused on human leukocyte antigen (HLA) A*02:01 restricted epitopes from a few cancer/testis antigens (CTAs) which are not widely expressed in common solid cancers; the tested T-cell receptors (TCRs) were frequently from tumor-infiltrating lymphocytes of old patients and were not assured to have higher avidity. Here, we propose the isolation of high-avidity TCRs against CTAs that are frequently expressed in common solid cancers. METHODS We selected the CT83 protein, which is frequently expressed in common solid cancers, as a model antigen for screening of its specific TCR. The predicted CT83 epitopes with strong or weak binding to HLA-I molecules, popular in the Chinese population, were integrated into three synthetic long peptides. CT83 reactive CD8+ T cells were stimulated with peptide-loaded dendritic cells (DCs) and sorted using the CD137 biomarker for single-cell sequencing to obtain the paired TCRαβ sequence. The higher frequency TCRs were reconstructed for characterization of the CT83 epitope and for assessment of in vitro and in vivo antitumor activities. RESULTS CT83 reactive T cells from young healthy donors (YHDs) were generated by repeated stimulation with DCs and peptides. The single-cell TCR sequencing results of reactive T cells indicated that a single TCR clonotype dominated the paired TCRs. T cells engineered with this dominant TCR led to HLA-A*11:01-restricted recognition of the CT8314-22 epitope, with higher avidity. Functional assays showed powerful cytotoxicity in vitro against the targets of several CT83-positive solid cancer cell lines. Furthermore, TCR-Ts showed therapeutic efficacy in three xenograft solid tumor models. The meta-analysis of gene expression of 92 CTAs indicated that most CTAs did not or at low levels in the thymus, which suggested that those CTAs may experience incomplete thymic central tolerance. CONCLUSIONS High-avidity TCR against CT83 could be isolated from YHDs and efficiently mediate regression of well-established xenograft common solid tumors. The high-avidity TCR repertoire in the peripheral blood of some donors for CT83 and other CTAs provides the basis for the efficient isolation of high-avidity TCRs to target numerous solid cancers.
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Affiliation(s)
- Qingyang Li
- Department of Clinical Oncology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Wei Hu
- T Cell Immune Technology Co., Ltd, Guangzhou, China
| | - Baoyi Liao
- Department of Clinical Oncology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Chanchan Song
- Department of Clinical Oncology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Liangping Li
- Department of Clinical Oncology, the First Affiliated Hospital of Jinan University, Guangzhou, China
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15
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Ichiki Y, Fukuyama T, Ohmiya H, Ueno M, Yanagi S, Kanasaki Y, Goto H, Mikami S, Yamazaki H, Nakanishi K, Ishida T. Relationship between Kita-Kyushu Lung Cancer antigen-1 expression and prognosis of cases with lung squamous cell carcinoma. Transl Cancer Res 2022; 10:5212-5221. [PMID: 35116371 PMCID: PMC8798488 DOI: 10.21037/tcr-21-1581] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 11/04/2021] [Indexed: 12/25/2022]
Abstract
Background Previously, we identified the highly immunogenic cancer testicular antigen named Kita-Kyushu Lung Cancer antigen-1 (KK-LC-1). In this study, we analyzed the effect of KK-LC-1 expression on the prognosis of patients with resected squamous cell lung cancer. Methods Fifty squamous cell lung cancer patients, who received complete resection, were enrolled in this study. The expressions of KK-LC-1, CD8, human leukocyte antigen (HLA) class I, and programmed cell death protein ligand-1 (PD-L1) were assessed via immunohistochemistry staining using the specimens obtained from the participants. The association between the expression of the abovementioned molecules and patient prognosis was investigated. Results KK-LC-1 expression was observed in 21 of 50 recruited cases (42%). However, no significant correlation was found between KK-LC-1 expression and patient prognosis. The prognosis was significantly better in lung cancer cases with KK-LC-1 expression in which CD8+ T cells infiltrated the tumor. Regardless of the HLA class I expression or the PD-L1 expression, the KK-LC-1 expression in squamous cell lung cancer could not be detected as a significant prognostic factor. Furthermore, considering the polarity of the cancer tissue as epithelium, staining of KK-LC-1 tended to be strong in the area corresponding to the basal side of the tumor tissue. The Ki-67 expression was frequently observed in cancer cells on the basal side, which was consistent with the KK-LC-1 expression in representative four cases with KK-LC-1-positive squamous cell lung cancer. Conclusions Our results indicated that lung squamous cell cancer patients with KK-LC-1 expression and the tumor infiltrating CD8+ T cells might exhibit better prognosis. KK-LC-1 might be highly expressed in cancer cells with high proliferative capacity. Larger cohort analysis is still required for further elucidation and validation of the results of this study.
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Affiliation(s)
- Yoshinobu Ichiki
- Department of General Thoracic Surgery, National Hospital Organization, Saitama Hospital, Wako, Japan.,Second Department of Surgery, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan
| | - Takashi Fukuyama
- Division of Biomedical Research, Kitasato University Medical Center, Kitamoto, Japan
| | - Haruki Ohmiya
- Division of Biomedical Research, Kitasato University Medical Center, Kitamoto, Japan
| | - Mari Ueno
- Department of Diagnostic Pathology, National Hospital Organization, Saitama Hospital, Wako, Japan
| | - Shinya Yanagi
- Department of Diagnostic Pathology, National Hospital Organization, Saitama Hospital, Wako, Japan
| | - Yoshiro Kanasaki
- Department of General Thoracic Surgery, National Hospital Organization, Saitama Hospital, Wako, Japan
| | - Hidenori Goto
- Department of General Thoracic Surgery, National Hospital Organization, Saitama Hospital, Wako, Japan
| | - Shuji Mikami
- Department of Diagnostic Pathology, National Hospital Organization, Saitama Hospital, Wako, Japan
| | - Hitoshi Yamazaki
- Division of Pathology, Kitasato University Medical Center, Kitamoto, Japan
| | - Kozo Nakanishi
- Department of General Thoracic Surgery, National Hospital Organization, Saitama Hospital, Wako, Japan
| | - Tsuyoshi Ishida
- Department of Diagnostic Pathology, National Hospital Organization, Saitama Hospital, Wako, Japan
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Hsu R, Baca Y, Xiu J, Wang R, Bodor JN, Kim C, Khan H, Mamdani H, Nagasaka M, Puri S, Liu SV, Korn WM, Nieva JJ. Molecular characterization of Kita-Kyushu lung cancer antigen (KK-LC-1) expressing carcinomas. Oncotarget 2021; 12:2449-2458. [PMID: 34917263 PMCID: PMC8664394 DOI: 10.18632/oncotarget.28132] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 11/10/2021] [Indexed: 12/26/2022] Open
Abstract
Cancer/testis antigens (CTAs) are strongly expressed in some solid tumors but minimally expressed in normal tissue, making them appealing therapeutic targets. KK-LC-1 (CXorf61) has cytoplasmic expression in gastric, breast, and lung cancer. We characterized the molecular subtypes of non-small cell lung cancer (NSCLC) expressing KK-LC-1 to inform rational clinical trials of T-cell receptor therapy (TCR-T) targeting KK-LC-1. 9790 NSCLC tumors that underwent whole transcriptome sequencing (Illumina NovaSeq) and NextGen DNA sequencing (NextSeq, 592 Genes and NovaSEQ, WES) at Caris Life Sciences (Phoenix, AZ) were analyzed. Tumors were split into quartiles based on KK-LC-1 expression and pathological and molecular differences were investigated. Adenocarcinoma had significantly higher KK-LC-1 expression than squamous cell carcinoma (median, 3.25 vs. 1.17 transcripts per million (TPM), p < 0.0001). Tumors with the highest quartile of KK-LC-1 expression had a greater proportion of tumors with high tumor mutation burden (TMB) (≥10 mutations per megabase; 44% vs. 28% in Q1, p < 0.001). Increased KK-LC-1 expression was associated with increased M1 macrophage abundance. Higher levels of KK-LC-1 expression were seen in pan-wild type and KRAS mutated tumors and associated with high TMB. TCR-T therapy directed against KK-LC-1 should be considered in patients whose clinical features reflect these characteristics.
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Affiliation(s)
- Robert Hsu
- Department of Internal Medicine, Division of Medical Oncology, Norris Comprehensive Cancer Center and Hospital, University of Southern California, Los Angeles, California, USA
| | | | - Joanne Xiu
- Caris Life Sciences, Phoenix, Arizona, USA
| | - Rongfu Wang
- Department of Internal Medicine, Division of Medical Oncology, Norris Comprehensive Cancer Center and Hospital, University of Southern California, Los Angeles, California, USA.,Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - J Nicholas Bodor
- Department of Hematology/Oncology, Fox Chase Center, Philadelphia, Pennsylvania, USA
| | - Chul Kim
- Division of Hematology and Oncology, Georgetown Lombardi Comprehensive Cancer Center, Washington, District of Columbia, USA
| | - Hina Khan
- Department of Internal Medicine, Division of Hematology and Oncology, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
| | - Hirva Mamdani
- Department of Oncology, Wayne State University School of Medicine and The Barbara Karmanos Cancer Institute, Detroit, Michigan, USA
| | - Misako Nagasaka
- Department of Oncology, Wayne State University School of Medicine and The Barbara Karmanos Cancer Institute, Detroit, Michigan, USA.,Division of Neurology, Department of Internal Medicine, St. Marianna University, Kawasaki, Kanagawa, Japan
| | - Sonam Puri
- Division of Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA
| | - Stephen V Liu
- Division of Hematology and Oncology, Georgetown Lombardi Comprehensive Cancer Center, Washington, District of Columbia, USA
| | | | - Jorge J Nieva
- Department of Internal Medicine, Division of Medical Oncology, Norris Comprehensive Cancer Center and Hospital, University of Southern California, Los Angeles, California, USA
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Yu X, Yan J, Chen X, Wei J, Yu L, Liu F, Li L, Liu B. Identification of a peptide binding to cancer antigen Kita-kyushu lung cancer antigen 1 from a phage-display library. Cancer Sci 2021; 112:4335-4345. [PMID: 34387029 PMCID: PMC8486176 DOI: 10.1111/cas.15109] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 07/29/2021] [Accepted: 08/10/2021] [Indexed: 12/18/2022] Open
Abstract
Kita‐kyushu lung cancer antigen 1 (KK‐LC‐1) is a kind of cancer‐testis antigen with anti‐tumor potential for clinical application. As a class of small‐molecule antigen conjugate, tumor‐targeting peptides have broad application prospects in gastric cancer diagnosis, imaging, and biological treatment. Here, we screened specific cyclic nonapeptides from a phage‐display library. The targeting peptide with the best affinity was selected and further verified in ex vivo tissue sections. Finally, enrichment of targeting peptides in tumor tissues was observed in vivo, and the dynamic biodistribution process was also observed with micro‐positron emission tomography (micro‐PET)/computed tomography (CT) imaging. Studies showed that the specific cyclic nonapeptide had a high binding capacity for KK‐LC‐1 protein. It has a strong affinity and specificity for KK‐LC‐1‐expressing positive tumor cells. Targeting peptides were significantly enriched at tumor sites in vivo, with very low normal tissue background. These findings demonstrated that the KK‐LC‐1 targeting peptide has high clinical potential.
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Affiliation(s)
- Xiaoxiao Yu
- The Comprehensive Cancer Center, China Pharmaceutical University Nanjing Drum Tower Hospital, Nanjing, China
| | - Jiayao Yan
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Xiaotong Chen
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Jia Wei
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Lixia Yu
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Fangcen Liu
- Department of Pathology of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Lin Li
- Department of Pathology of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Baorui Liu
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
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Azzarà A, Rendeli C, Crivello AM, Brugnoletti F, Rumore R, Ausili E, Sangiorgi E, Gurrieri F. Identification of new candidate genes for spina bifida through exome sequencing. Childs Nerv Syst 2021; 37:2589-2596. [PMID: 33855610 DOI: 10.1007/s00381-021-05153-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 03/29/2021] [Indexed: 12/19/2022]
Abstract
PURPOSE Neural tube defects are a group of birth defects caused by failure of neural tube closure during development. The etiology of NTD, requiring a complex interaction between environmental and genetic factors, is not well understood. METHODS We performed whole-exome sequencing (WES) in six trios, with a single affected proband with spina bifida, to identify rare/novel variants as potential causes of the NTD. RESULTS Our analysis identified four de novo and ten X-linked recessive variants in four of the six probands, all of them in genes previously never implicated in NTD. Among the 14 variants, we ruled out six of them, based on different criteria and pursued the evaluation of eight potential candidates in the following genes: RXRγ, DTX1, COL15A1, ARHGAP36, TKTL1, AMOT, GPR50, and NKRF. The de novo variants where located in the RXRγ, DTX1, and COL15A1 genes while ARHGAP36, TKTL1, AMOT, GPR50, and NKRF carry X-linked recessive variants. This analysis also revealed that four patients presented multiple variants, while we were unable to identify any significant variant in two patients. CONCLUSIONS Our preliminary conclusion support a major role for the de novo variants with respect to the X-linked recessive variants where the X-linked could represent a contribution to the phenotype in an oligogenic model.
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Affiliation(s)
- Alessia Azzarà
- Dipartimento di Scienze della Vita e di Sanità Pubblica, Sezione di Medicina Genomica, Università Cattolica del Sacro Cuore, Roma, Italia. .,Unità di Genetica Medica, Università Campus Bio-Medico, Roma, Italia.
| | - Claudia Rendeli
- Spina Bifida Center, Dipartimento di Scienze della Vita e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italia
| | - Anna Maria Crivello
- Dipartimento di Scienze della Vita e di Sanità Pubblica, Sezione di Medicina Genomica, Università Cattolica del Sacro Cuore, Roma, Italia
| | - Fulvia Brugnoletti
- Dipartimento di Scienze della Vita e di Sanità Pubblica, Sezione di Medicina Genomica, Università Cattolica del Sacro Cuore, Roma, Italia
| | - Roberto Rumore
- Dipartimento di Scienze della Vita e di Sanità Pubblica, Sezione di Medicina Genomica, Università Cattolica del Sacro Cuore, Roma, Italia
| | - Emanuele Ausili
- Spina Bifida Center, Dipartimento di Scienze della Vita e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italia
| | - Eugenio Sangiorgi
- Dipartimento di Scienze della Vita e di Sanità Pubblica, Sezione di Medicina Genomica, Università Cattolica del Sacro Cuore, Roma, Italia.,Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italia
| | - Fiorella Gurrieri
- Unità di Genetica Medica, Università Campus Bio-Medico, Roma, Italia
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19
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Wang Y, Zhang G, Wang R. A Six CT83-Related Genes Based Prognostic Signature for Lung Adenocarcinoma. Comb Chem High Throughput Screen 2021; 25:1565-1575. [PMID: 34259140 DOI: 10.2174/1871520621666210713112630] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 04/09/2021] [Accepted: 05/05/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND This study aims to explore the prognostic values of CT83 and CT83-related genes in lung adenocarcinoma (LUAD). METHODS We downloaded the mRNA profiles of 513 LUAD patients (RNA sequencing data) and 246 NSCLC patients (Affymetrix Human Genome U133 Plus 2.0 Array) from TCGA and GEO databases. According to the median expression of CT83, the TCGA samples were divided into high and low expression groups, and differential expression analysis between them was performed. Functional enrichment analysis of differential expression genes (DEGs) was conducted. Univariate Cox regression analysis and LASSO Cox regression analysis were performed to screen the optimal prognostic DEGs. Then we established the prognostic model. A Nomogram model was constructed to predict the overall survival (OS) probability of LUAD patients. RESULTS CT83 expression was significantly correlated to the prognosis of LUAD patients. A total of 59 DEGs were identified, and a predictive model was constructed based on six optimal CT83-related DEGs, including CPS1, RHOV, TNNT1, FAM83A, IGF2BP1, and GRIN2A, could effectively predict the prognosis of LUAD patients. The nomogram could reliably predict the OS of LUAD patients. Moreover, the six important immune checkpoints (CTLA4, PD1, IDO1, TDO2, LAG3, and TIGIT) were closely correlated with the Risk Score, which was also differentially expressed between the LUAD samples with high and low-Risk Scores, suggesting that the poor prognosis of LUAD patients with high-Risk Score might be due to the immunosuppressive microenvironments. CONCLUSION A prognostic model based on six optimal CT83 related genes could effectively predict the prognosis of LUAD patients.
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Affiliation(s)
- Yongmei Wang
- Department of pathology, Tianjin Haihe Hospital, Tianjin Respiratory Research Institute, Tianjin, 300350, China
| | - Guimin Zhang
- Department of pathology, Tianjin Jinnan Hospital, Tianjin, 300350, China
| | - Ruixian Wang
- Department of pathology, Tianjin Jinnan Hospital, Tianjin, 300350, China
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20
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Chen C, Gao D, Huo J, Qu R, Guo Y, Hu X, Luo L. Multiomics analysis reveals CT83 is the most specific gene for triple negative breast cancer and its hypomethylation is oncogenic in breast cancer. Sci Rep 2021; 11:12172. [PMID: 34108519 PMCID: PMC8190062 DOI: 10.1038/s41598-021-91290-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 05/25/2021] [Indexed: 02/05/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer (BrC) subtype lacking effective therapeutic targets currently. The development of multi-omics databases facilities the identification of core genes for TNBC. Using TCGA-BRCA and METABRIC datasets, we identified CT83 as the most TNBC-specific gene. By further integrating FUSCC-TNBC, CCLE, TCGA pan-cancer, Expression Atlas, and Human Protein Atlas datasets, we found CT83 is frequently activated in TNBC and many other cancers, while it is always silenced in non-TNBC, 120 types of normal non-testis tissues, and 18 types of blood cells. Notably, according to the TCGA-BRCA methylation data, hypomethylation on chromosome X 116,463,019 to 116,463,039 is significantly correlated with the abnormal activation of CT83 in BrC. Using Kaplan-Meier Plotter, we demonstrated that activated CT83 is significantly associated with unfavorably overall survival in BrC and worse outcomes in some other cancers. Furthermore, GSEA suggested that the abnormal activation of CT83 in BrC is probably oncogenic by triggering the activation of cell cycle signaling. Meanwhile, we also noticed copy number variations and mutations of CT83 are quite rare in any cancer type, and its role in immune infiltration is not significant. In summary, we highlighted the significance of CT83 for TNBC and presented a comprehensive bioinformatics strategy for single-gene analysis in cancer.
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Affiliation(s)
- Chen Chen
- grid.452884.7Breast and Thyroid Center, The First People’s Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Fenghuang N Rd, Zunyi, 563000 Guizhou China
| | - Dan Gao
- grid.452884.7Breast and Thyroid Center, The First People’s Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Fenghuang N Rd, Zunyi, 563000 Guizhou China
| | - Jinlong Huo
- grid.452884.7Breast and Thyroid Center, The First People’s Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Fenghuang N Rd, Zunyi, 563000 Guizhou China
| | - Rui Qu
- grid.452884.7Breast and Thyroid Center, The First People’s Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Fenghuang N Rd, Zunyi, 563000 Guizhou China
| | - Youming Guo
- grid.452884.7Breast and Thyroid Center, The First People’s Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Fenghuang N Rd, Zunyi, 563000 Guizhou China
| | - Xiaochi Hu
- grid.452884.7Breast and Thyroid Center, The First People’s Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Fenghuang N Rd, Zunyi, 563000 Guizhou China
| | - Libo Luo
- grid.452884.7Breast and Thyroid Center, The First People’s Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Fenghuang N Rd, Zunyi, 563000 Guizhou China
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21
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Herrera LRM. Reverse Vaccinology Approach in Constructing a Multi-Epitope Vaccine Against Cancer-Testis Antigens Expressed in Non-Small Cell Lung Cancer. Asian Pac J Cancer Prev 2021; 22:1495-1506. [PMID: 34048178 PMCID: PMC8408400 DOI: 10.31557/apjcp.2021.22.5.1495] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Indexed: 12/26/2022] Open
Abstract
Background: The 5-year survival rate of non-small cell lung cancer (NSCLC) patients has not significantly improved despite advancements in the currently applied treatments. Thus, efforts are put forth in developing novel immunotherapeutic agents targeting cancer-testis antigens (CTA) in NSCLC. This work utilized reverse vaccinology approach in designing a novel multi-epitope vaccine targeting melanoma-associated antigen 3 (MAGEA3), MAGEA4, New York esophageal squamous cell carcinoma-1 (NY-ESO-1), and Kita-Kyushu lung cancer antigen 1 (KK-LC1), being the most frequently expressed CTAs in NSCLC. Methods: Epitopes were mapped from the sequences of CTAs. The population coverage (PC) of identified CD4+ and CD8+ epitopes were estimated. Candidate linear B cell (BL), CD4+, and CD8+ epitopes were adjoined in a multi-epitope construct (Mvax) with flagellin domain as an adjuvant. Antigenicity, and cross-reactivity of Mvax were examined. The tertiary structure of Mvax was modelled, and validated. All epitopes included in the vaccine were docked with their human leukocyte antigen (HLA) binders. The immunogenicity of epitopes in Mvax was validated through molecular dynamics analysis. Results: Mvax contains 22 epitopes from MAGEA3, MAGEA4, NY-ESO-1, and KK-LC1. It is classified as antigenic, non-allergen, non-toxic, and possesses physicochemical stability. Epitopes have no significant hits with other human proteins, except for 2 other CTAs frequently expressed in NSCLC. The stretch of BL epitopes in Mvax confers flexibility, and accessibility emphasizing its antigenicity. The tertiary structure analysis showed that Mvax model has good structural quality. All epitopes included in the vaccine are highly immunogenic as indicated by favorable binding affinity, low binding energy, and acceptable root-mean-square deviation (RMSD). CD4+ and CD8+ epitopes have global PC of 81.81%, and 84.15%, respectively. Conclusion: Overall, in silico evaluations show that Mvax is a potential immunotherapeutic agent against NSCLC.
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Affiliation(s)
- Leana Rich M Herrera
- Department of Physical Sciences, College of Science, Polytechnic University of the Philippines, Manila City, Philippines
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22
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Yang P, Meng M, Zhou Q. Oncogenic cancer/testis antigens are a hallmarker of cancer and a sensible target for cancer immunotherapy. Biochim Biophys Acta Rev Cancer 2021; 1876:188558. [PMID: 33933558 DOI: 10.1016/j.bbcan.2021.188558] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 03/16/2021] [Accepted: 04/26/2021] [Indexed: 02/07/2023]
Abstract
Increasing evidence shows that numerous cancer-testis antigens (CTAs) are uniquely overexpressed in various types of cancer and most CTAs are oncogenic. Overexpression of oncogenic CTAs promotes carcinogenesis, cancer metastasis, and drug resistance. Oncogenic CTAs are generally associated with poor prognosis in cancer patients and are an important hallmark of cancer, making them a crucial target for cancer immunotherapy. CTAs-targeted antibodies, vaccines, and chimeric antigen receptor-modified T cells (CAR-T) have recently been used in cancer treatment and achieved promising outcomes in the preclinical and early clinical trials. However, the efficacy of current CTA-targeted therapeutics is either moderate or low in cancer therapy. CTA-targeted cancer immunotherapy is facing enormous challenges. Several critical scientific problems need to be resolved: (1) the antigen presentation function of MHC-I protein is usually deficient in cancer patients, so that very low amounts of intracellular CTA epitopes are presented to tumor cell membrane surface, leading to weak immune response and subsequent immunity to CTAs; (2) various immunosuppressive cells are rich in tumor tissues leading to diminished tumor immunity; (3) the tumor tissue microenvironment markedly reduces the efficacy of cancer immunotherapy. In the current review paper, the authors propose new strategies and approaches to overcome the barriers of CTAs-targeted immunotherapy and to develop novel potent immune therapeutics against cancer. Finally, we highlight that the oncogenic CTAs have high tumor specificity and immunogenicity, and are sensible targets for cancer immunotherapy. We predict that CTAs-targeted immunotherapy will bring about breakthroughs in cancer therapy in the near future.
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Affiliation(s)
- Ping Yang
- Department of Pathophysiology, School of Medicine, Nantong University, Nantong, Jiangsu 226000, PR China
| | - Mei Meng
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Soochow University, Suzhou, Jiangsu 215123, PR China; 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, PR China
| | - Quansheng Zhou
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Soochow University, Suzhou, Jiangsu 215123, PR China; 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, PR China.
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23
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Ichiki Y, Shigematsu Y, Baba T, Shiota H, Fukuyama T, Nagata Y, So T, Yasuda M, Takenoyama M, Yasumoto K. Development of adoptive immunotherapy with KK-LC-1-specific TCR-transduced γδT cells against lung cancer cells. Cancer Sci 2020; 111:4021-4030. [PMID: 32780528 PMCID: PMC7648040 DOI: 10.1111/cas.14612] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 08/07/2020] [Accepted: 08/09/2020] [Indexed: 12/11/2022] Open
Abstract
The present study analyzed the antitumor effect of γδT cells transduced with the TCR of cancer-specific CTLs to establish forceful cancer-specific adoptive immunotherapy. We cloned the TCRαβ genes from CTLs showing HLA-B15 restricted recognition of Kita-Kyushu lung cancer antigen-1 (KK-LC-1), a cancer/germline gene antigen, identified in a lung adenocarcinoma case (F1121). The TCRαβ and CD8 genes were transduced into γδT cells induced from PBLs of healthy volunteers stimulated with zoledronate and IL-2. The KK-LC-1-specific TCRαβ-CD8 γδT cells showed cytotoxic activity against the KK-LC-1 positive lung cancer cell line F1121L and produced IFN-γ against F1121L and KK-LC-1 peptide-pulsed F1121 EBV-B cells. These responses were blocked by HLA class I and HLA-B/C antibodies. An in vivo assay using NOD/SCID mice with xenotransplantation of human lung cancer cells was performed, and the TCRαβ-CD8 transduced γδT cells (TCRαβ-CD8 γδT cells) were intravenously injected. Growth inhibition of KK-LC-1+ , HLA-B15+ lung cancer cells was confirmed in mice with injection of the TCRαβ-CD8 γδT cells from 1 wk after xenotransplantation of cancer cells but not in those treated 2 wk after xenotransplantation. The resected specimens of the tumor, 2 wk after xenotransplantation, highly expressed FasL but not programmed death ligand-1 (PD-L1) by immunohistochemical staining. FasL highly expressed cancer cells xenotransplanted 2 wk ago were resistant to TCRαβ-CD8 γδT cells injection. These results suggested that apoptosis of Fas-positive TCRαβ-CD8 γδT cells may be induced by a Fas-mediated signal after interacting with FasL-positive cancer cells.
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MESH Headings
- Animals
- Antigens, Neoplasm/immunology
- Cell Line, Tumor
- Cytokines/metabolism
- Disease Models, Animal
- Humans
- Immunomodulation
- Immunotherapy, Adoptive
- Lung Neoplasms/etiology
- Lung Neoplasms/metabolism
- Lung Neoplasms/pathology
- Lung Neoplasms/therapy
- Lymphocytes, Tumor-Infiltrating/immunology
- Lymphocytes, Tumor-Infiltrating/metabolism
- Lymphocytes, Tumor-Infiltrating/pathology
- Mice, Transgenic
- Receptors, Antigen, T-Cell, gamma-delta/metabolism
- T-Lymphocyte Subsets/immunology
- T-Lymphocyte Subsets/metabolism
- T-Lymphocytes, Cytotoxic/immunology
- T-Lymphocytes, Cytotoxic/metabolism
- Transduction, Genetic
- Treatment Outcome
- Xenograft Model Antitumor Assays
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Grants
- Cancer Translational Research Project; Ministry of Health, Labour and Welfare of Japan
- Cancer Research Institute, UOEH Research Grant for Promotion of Occupational Health
- JP20390375 Ministry of Education, Culture, Sports, Science and Technology, Japan
- JP21659327 Ministry of Education, Culture, Sports, Science and Technology, Japan
- JP18K08806 Ministry of Education, Culture, Sports, Science and Technology, Japan
- JP19K09294 Ministry of Education, Culture, Sports, Science and Technology, Japan
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Affiliation(s)
- Yoshinobu Ichiki
- Department of General Thoracic SurgeryNational Hospital Organization, Saitama HospitalWakoJapan
- Second Department of SurgerySchool of MedicineUniversity of Occupational and Environmental HealthKitakyushuJapan
| | - Yoshiki Shigematsu
- Second Department of SurgerySchool of MedicineUniversity of Occupational and Environmental HealthKitakyushuJapan
- Department of Respiratory SurgeryIchinomiya‐Nishi HospitalIchinomiyaJapan
| | - Tetsuro Baba
- Second Department of SurgerySchool of MedicineUniversity of Occupational and Environmental HealthKitakyushuJapan
- Baba ClinicKasuya‐gunJapan
| | - Hironobu Shiota
- Second Department of SurgerySchool of MedicineUniversity of Occupational and Environmental HealthKitakyushuJapan
- Department of General Thoracic SurgeryChiba Rosai HospitalIchiharaJapan
| | - Takashi Fukuyama
- Second Department of SurgerySchool of MedicineUniversity of Occupational and Environmental HealthKitakyushuJapan
- Division of Biomedical ResearchKitasato University Medical CenterKitamotoJapan
| | - Yoshika Nagata
- Second Department of SurgerySchool of MedicineUniversity of Occupational and Environmental HealthKitakyushuJapan
- Department of Breast SurgeryShonan Kamakura General HospitalKamakuraJapan
| | - Tetsuya So
- Second Department of SurgerySchool of MedicineUniversity of Occupational and Environmental HealthKitakyushuJapan
- Department of Thoracic SurgeryShin‐Komonji HospitalKitakyusyuJapan
| | - Manabu Yasuda
- Second Department of SurgerySchool of MedicineUniversity of Occupational and Environmental HealthKitakyushuJapan
- Department of Chest SurgeryIizuka HospitalIizukaJapan
| | - Mitsuhiro Takenoyama
- Second Department of SurgerySchool of MedicineUniversity of Occupational and Environmental HealthKitakyushuJapan
- Department of Thoracic OncologyNational Hospital Organization Kyushu Cancer CenterFukuokaJapan
| | - Kosei Yasumoto
- Second Department of SurgerySchool of MedicineUniversity of Occupational and Environmental HealthKitakyushuJapan
- Kitakyushu Municipal Moji HospitalKitakyushuJapan
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24
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Jakobsen MK, Gjerstorff MF. CAR T-Cell Cancer Therapy Targeting Surface Cancer/Testis Antigens. Front Immunol 2020; 11:1568. [PMID: 32983080 PMCID: PMC7492268 DOI: 10.3389/fimmu.2020.01568] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 06/15/2020] [Indexed: 12/11/2022] Open
Affiliation(s)
- Mie K Jakobsen
- Department of Cancer and Inflammation Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Morten F Gjerstorff
- Department of Cancer and Inflammation Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark.,Department of Oncology, Odense University Hospital, Odense, Denmark.,Academy of Geriatric Cancer Research (AgeCare), Odense University Hospital, Odense, Denmark
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25
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Shida A, Fukuyama T, Futawatari N, Ohmiya H, Ichiki Y, Yamashita T, Nishi Y, Kobayashi N, Yamazaki H, Watanabe M, Takahashi Y. Cancer/testis antigen, Kita-Kyushu lung cancer antigen-1 and ABCD stratification for diagnosing gastric cancers. World J Gastroenterol 2020; 26:424-432. [PMID: 32063691 PMCID: PMC7002902 DOI: 10.3748/wjg.v26.i4.424] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2019] [Revised: 12/23/2019] [Accepted: 01/11/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The ABCD stratification [(combination of serum pepsinogen (PG) levels and titers of antibody (immunoglobulin G, IgG) against Helicobacter pylori (H. pylori)] is effective for the classification of individuals at risk of developing gastric cancer (GC). The Kita–Kyushu lung cancer antigen-1 (KK-LC-1) is a Cancer/Testis antigen frequently expressed in GC.
AIM To evaluate the effectiveness of KK-LC-1 and ABCD stratification in the diagnosis of GC.
METHODS We analyzed the gene expression of KK-LC-1 in surgical specimens obtained from GC tumors. The levels of serum PG I/PG II and IgG against H. pylori were measured. According to their serological status, the patients were classified into the four groups of the ABCD stratification.
RESULTS Of the 77 examined patients, 63 (81.8%) expressed KK-LC-1. The IgG titers of H. pylori and PG II were significantly higher in patients expressing KK-LC-1 than those measured in patients not expressing KK-LC-1 (P = 0.0289 and P = 0.0041, respectively). The expression of KK-LC-1 in group C [PG method (+)/H. pylori infection (+)] was as high as 93.9% high. KK-LC-1 was also detected in group A [-/-].
CONCLUSION The KK-LC-1 expression in GC was associated with H. pylori infection and atrophic status, so that, KK-LC-1 may be a useful marker for the diagnosis of GC.
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Affiliation(s)
- Akiko Shida
- Division of Pathology, Kitasato University, Sagamihara, Kanagawa 252-0374, Japan
| | - Takashi Fukuyama
- Division of Biomedical Research, Kitasato University Medical Center, Kitamoto, Saitama 364-8501, Japan
| | - Nobue Futawatari
- Division of Surgery, Toho University, Ohashi Medical Center, Meguroku, Tokyo 153-8515, Japan
| | - Haruki Ohmiya
- Department of Biological Chemistry and Food Sciences, Faculty of Agriculture, Iwate University, Morioka, Iwate 020-8505, Japan
| | - Yoshinobu Ichiki
- Department of General Thoracic Surgery, National Hospital Organization Saitama Hospital, Wako, Saitama 364-8501, Japan
| | - Tetsuro Yamashita
- Department of Biological Chemistry and Food Sciences, Faculty of Agriculture, Iwate University, Morioka, Iwate 020-8505, Japan
| | - Yatsushi Nishi
- Division of Surgery, Kitasato University Medical Center, Kitamoto, Saitama 364-8501, Japan
| | - Noritada Kobayashi
- Division of Biomedical Research, Kitasato University Medical Center, Kitamoto, Saitama 364-8501, Japan
| | - Hitoshi Yamazaki
- Division of Pathology, Kitasato University Medical Center, Kitamoto, Saitama 364-8501, Japan
| | - Masahiko Watanabe
- Division of Surgery, Kitasato University, Sagamihara, Kanagawa 252-0374, Japan
| | - Yoshihito Takahashi
- Division of Surgery, Kitasato University Medical Center, Kitamoto, Saitama 364-8501, Japan
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26
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Marcinkowski B, Stevanović S, Helman SR, Norberg SM, Serna C, Jin B, Gkitsas N, Kadakia T, Warner A, Davis JL, Rooper L, Hinrichs CS. Cancer targeting by TCR gene-engineered T cells directed against Kita-Kyushu Lung Cancer Antigen-1. J Immunother Cancer 2019; 7:229. [PMID: 31455429 PMCID: PMC6712783 DOI: 10.1186/s40425-019-0678-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 07/15/2019] [Indexed: 12/15/2022] Open
Abstract
T cell receptor (TCR) gene-engineered T cells have shown promise in the treatment of melanoma and synovial cell sarcoma, but their application to epithelial cancers has been limited. The identification of novel therapeutic TCRs for the targeting of these tumors is important for the development of new treatments. Here, we describe the preclinical characterization of a TCR directed against Kita-Kyushu Lung Cancer Antigen-1 (KK-LC-1, encoded by CT83), a cancer germline antigen with frequent expression in human epithelial malignancies including gastric cancer, breast cancer, and lung cancer. Gene-engineered T cells expressing the KK-LC-1 TCR (KK-LC-1 TCR-Ts) demonstrated recognition of CT83+ tumor lines in vitro and mediated regression of established CT83+ xenograft tumors in immunodeficient mouse models. Cross-reactivity studies based on experimental determination of the recognition motifs for the target epitope did not demonstrate cross-reactivity against other human proteins. CT83 gene expression studies in 51 non-neural tissues and 24 neural tissues showed expression restricted exclusively to germ cells. CT83 was however expressed by a range of epithelial cancers, with the highest expression noted in gastric cancer. Collectively, these findings support the further investigation and clinical testing of KK-LC-1 TCR-Ts for gastric cancer and possibly other malignancies.
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Affiliation(s)
- Bridget Marcinkowski
- Experimental Transplantation and Immunology Branch, National Cancer Institute, 10 Center Drive, Room 4B04, Bethesda, MD, 20892, USA
| | - Sanja Stevanović
- Experimental Transplantation and Immunology Branch, National Cancer Institute, 10 Center Drive, Room 4B04, Bethesda, MD, 20892, USA
| | - Sarah R Helman
- Experimental Transplantation and Immunology Branch, National Cancer Institute, 10 Center Drive, Room 4B04, Bethesda, MD, 20892, USA
| | - Scott M Norberg
- Experimental Transplantation and Immunology Branch, National Cancer Institute, 10 Center Drive, Room 4B04, Bethesda, MD, 20892, USA
| | - Carylinda Serna
- Experimental Transplantation and Immunology Branch, National Cancer Institute, 10 Center Drive, Room 4B04, Bethesda, MD, 20892, USA
| | - Benjamin Jin
- Experimental Transplantation and Immunology Branch, National Cancer Institute, 10 Center Drive, Room 4B04, Bethesda, MD, 20892, USA
| | - Nikolaos Gkitsas
- Experimental Transplantation and Immunology Branch, National Cancer Institute, 10 Center Drive, Room 4B04, Bethesda, MD, 20892, USA
| | - Tejas Kadakia
- Experimental Transplantation and Immunology Branch, National Cancer Institute, 10 Center Drive, Room 4B04, Bethesda, MD, 20892, USA
| | - Andrew Warner
- Pathology and Histology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA
| | - Jeremy L Davis
- Surgical Oncology Program, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Lisa Rooper
- Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA
| | - Christian S Hinrichs
- Experimental Transplantation and Immunology Branch, National Cancer Institute, 10 Center Drive, Room 4B04, Bethesda, MD, 20892, USA.
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27
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Shibata T, Lieblong BJ, Sasagawa T, Nakagawa M. The promise of combining cancer vaccine and checkpoint blockade for treating HPV-related cancer. Cancer Treat Rev 2019; 78:8-16. [PMID: 31302573 DOI: 10.1016/j.ctrv.2019.07.001] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Revised: 07/02/2019] [Accepted: 07/03/2019] [Indexed: 12/13/2022]
Abstract
Human papillomavirus (HPV)-associated intraepithelial neoplasia or cancers are ideal candidates for cancer immunotherapy since HPV oncoproteins, such as E6 and E7 proteins of high-risk HPVs, could be utilized as foreign antigens. In HPV-associated cancers as well as nonviral cancers, the cancer cells may evade host immunity through the expression of immune checkpoint molecules, downregulation of human leukocyte antigen, and activation of immune regulatory cells. Because of these immune suppressive mechanisms, HPV therapeutic vaccines have shown little efficacy against HPV-associated cancers, although they have shown efficacy in treating HPV-associated intraepithelial neoplasias. Recently, checkpoint blockade emerged as a promising new treatment for solid cancers; however, these therapies have shown only modest efficacy against HPV-associated cancers. Here we reviewed literature analyzing a combinatory therapy using an immune checkpoint inhibitor and an HPV therapeutic vaccine for treating HPV-associated cancers to compensate for shortfalls of each monotherapy. Complimentary modes of T cell activation would be deployed; as vaccines would directly stimulate the T cells, while checkpoint inhibitors would do so by releasing inhibition. Some promising studies using animal models and early human clinical trials raised a possibility that such combinations may be efficacious in regressing HPV-associated cancers. Epitope spreading (the phenomenon in which non-targeted antigens become new targets of immune response) may play a critical role mechanistically. Currently ongoing studies will shed light as to whether such combination therapy would indeed be a promising new treatment paradigm. Current and future studies must also determine the adverse effect profile of such a combination treatment.
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Affiliation(s)
- Takeo Shibata
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; Department of Obstetrics and Gynecology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
| | - Benjamin J Lieblong
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
| | - Toshiyuki Sasagawa
- Department of Obstetrics and Gynecology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
| | - Mayumi Nakagawa
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
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Wei X, Chen F, Xin K, Wang Q, Yu L, Liu B, Liu Q. Cancer-Testis Antigen Peptide Vaccine for Cancer Immunotherapy: Progress and Prospects. Transl Oncol 2019; 12:733-738. [PMID: 30877975 PMCID: PMC6423365 DOI: 10.1016/j.tranon.2019.02.008] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 02/19/2019] [Accepted: 02/19/2019] [Indexed: 12/31/2022] Open
Abstract
Cancer vaccines, including peptide-based vaccines, have been considered a key tool of effective and protective cancer immunotherapy because of their capacity to provide long-term clinical benefit for tumors. Among a large number of explorations of peptide antigen-based vaccines, cancer-testis antigens (CTAs), which are activated in cancers but silenced in normal tissues (except testis tissue), are considered as ideal targets. Currently, personalized treatment for cancer has become a trend due to its superior clinical efficacy. Thus, we envisage rational selection of CTA peptides to design "personalized" CTA peptide vaccines. This review summarizes the advances in CTA peptide vaccine research and discusses the feasibility of establishing "personalized" CTA peptide vaccines.
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Affiliation(s)
- Xiao Wei
- The Comprehensive Cancer Center of Drum Tower Hospital, Nanjing Medical University
| | - Fangjun Chen
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University
| | - Kai Xin
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University
| | - Qin Wang
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University
| | - Lixia Yu
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University
| | - Baorui Liu
- The Comprehensive Cancer Center of Drum Tower Hospital, Nanjing Medical University; The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University
| | - Qin Liu
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University.
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Kaufmann J, Wentzensen N, Brinker TJ, Grabe N. Large-scale in-silico identification of a tumor-specific antigen pool for targeted immunotherapy in triple-negative breast cancer. Oncotarget 2019; 10:2515-2529. [PMID: 31069014 PMCID: PMC6493464 DOI: 10.18632/oncotarget.26808] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 02/15/2019] [Indexed: 12/16/2022] Open
Abstract
Since the advent of cetuximab, clinical cancer treatment has evolved from the standard, relatively nonspecific chemo- and radiotherapy with significant cytotoxic side effects towards immunotherapeutic approaches with selective, target-mechanism-based effects. Antibody therapies as the most successful form of cancer immunotherapy led to approved treatments for specific cancer types with increased patient survival. Thus, the identification of tumor antigens with high immunogenicity is in central focus now. In this study, we applied computational methods to comprehensively discover overexpressed molecular targets with high therapeutic relevance for clinical, immunotherapeutic cancer treatment in triple-negative breast cancer (TNBC). By actively modeling potential negative side effects utilizing expression data of 29 different, normal human tissues, we were able to develop a highly-specific coverage of TNBC patients with RNA targets. We identified here more than 400 potential tumor-specific antigens suitable for targeted therapy, including several already identified as potential targets for TNBC and other solid tumors. A specific cocktail of MAGEB4, CT83, TLX3, ACTL8, PRDM13 achieved almost 94% patient coverage in TNBC. Overall, these results show that our approach can identify and prioritize TNBC targets suitable for targeted therapy. Therefore, our method has the potential to lead to new and more effective immunotherapeutic cancer treatment.
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Affiliation(s)
- Jessica Kaufmann
- Hamamatsu Tissue Imaging and Analysis Center (TIGA), BIOQUANT, University of Heidelberg, Heidelberg, Germany.,Medical Oncology Department, Universitätsklinik Heidelberg, National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Nicolas Wentzensen
- National Cancer Institute, Division of Cancer Epidemiology & Genetics, Clinical Genetics Branch, NCI Shady Grove, Bethesda, Maryland, USA
| | - Titus J Brinker
- National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Dermatology, University Hospital Heidelberg, Heidelberg, Germany
| | - Niels Grabe
- Hamamatsu Tissue Imaging and Analysis Center (TIGA), BIOQUANT, University of Heidelberg, Heidelberg, Germany.,Medical Oncology Department, Universitätsklinik Heidelberg, National Center for Tumor Diseases (NCT), Heidelberg, Germany
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Chen Z, Zuo X, Pu L, Zhang Y, Han G, Zhang L, Wu Z, You W, Qin J, Dai X, Shen H, Wang X, Wu J. Hypomethylation-mediated activation of cancer/testis antigen KK-LC-1 facilitates hepatocellular carcinoma progression through activating the Notch1/Hes1 signalling. Cell Prolif 2019; 52:e12581. [PMID: 30895661 PMCID: PMC6536599 DOI: 10.1111/cpr.12581] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 01/06/2019] [Accepted: 01/13/2019] [Indexed: 12/15/2022] Open
Abstract
Objectives Kita‐Kyushu lung cancer antigen‐1 (KK‐LC‐1) is a cancer/testis antigen reactivated in several human malignancies. So far, the major focus of studies on KK‐LC‐1 has been on its potential as diagnostic biomarker and immunotherapy target. However, its biological functions and molecular mechanisms in cancer progression remain unknown. Materials and Methods Expression of KK‐LC‐1 in HCC was analysed using RT‐qPCR, Western blot and immunohistochemistry. The roles of KK‐LC‐1 on HCC progression were examined by loss‐of‐function and gain‐of‐function approaches. Pathway inhibitor DAPT was employed to confirm the regulatory effect of KK‐LC‐1 on the downstream Notch signalling. The interaction of KK‐LC‐1 with presenilin‐1 was determined by co‐immunoprecipitation. The association of CpG island methylation status with KK‐LC‐1 reactivation was evaluated by methylation‐specific PCR, bisulphite sequencing PCR and 5‐Aza‐dC treatment. Results We identified that HCC tissues exhibited increased levels of KK‐LC‐1. High KK‐LC‐1 level independently predicted poor survival outcome. KK‐LC‐1 promoted cell growth, migration, invasion and epithelial‐mesenchymal transition in vitro and in vivo. KK‐LC‐1 modulated the Notch1/Hes1 pathway to exacerbate HCC progression through physically interacting with presenilin‐1. Upregulation of KK‐LC‐1 in HCC was attributed to hypomethylated CpG islands. Conclusions This study identified that hypomethylation‐induced KK‐LC‐1 overexpression played an important role in HCC progression and independently predicted poor survival. We defined the KK‐LC‐1/presenilin‐1/Notch1/Hes1 as a novel signalling pathway that was involved in the growth and metastasis of HCC.
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Affiliation(s)
- Zhiqiang Chen
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Xueliang Zuo
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China.,Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Liyong Pu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Yao Zhang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Guoyong Han
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Long Zhang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Zhengshan Wu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Wei You
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Jianjie Qin
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Xinzheng Dai
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Hongbing Shen
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.,Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Xuehao Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Jindao Wu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China.,State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
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Jin S, Cao S, Li J, Meng Q, Wang C, Yao L, Lang Y, Cao J, Shen J, Pan B, Hu J, Yu Y. Cancer/testis antigens (CTAs) expression in resected lung cancer. Onco Targets Ther 2018; 11:4491-4499. [PMID: 30122941 PMCID: PMC6078192 DOI: 10.2147/ott.s159491] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Background Increasing evidence shows cancer/testis antigens (CTAs) play a key role in oncogenesis. Our pre-study finds that MAGEA1, MAGEA10, MAGEB2, KK-LC-1, and CTAG1A/B have high expression frequencies at the protein level. We aim to explore their prognostic role and correlations with clinical characteristics in resected lung cancer at the mRNA level. Methods Thirty-eight surgical lung cancer samples were included. Validation study was performed based on The Cancer Genome Atlas database. The prognostic roles of CTAs were evaluated by Kaplan–Meier and multivariate analysis. Results High expression of MAGEA1 (16.7% vs 65.0%, P=0.004), MAGEA10 (61.1% vs 95.0%, P=0.016), MAGEB2 (55.6% vs 95.0%, P=0.007), and KK-LC-1 (16.7% vs 55.0%, P=0.020) was closely correlated with lymph node metastasis at diagnosis. Patients with TNM stage II or III had a higher expression of MAGEA10 (57.1% vs 91.7%, P=0.034) and KK-LC-1 (14.3% vs 50.0%, P=0.039) compared with patients in TNM stage I. High CTAG1A/B expression showed unfavorable prognosis in all cases (P<0.05). Subgroup analysis showed high CTAG1A/B expression was a negative prognostic factor of survival (P=0.031) in patients with TNM stage II or III. Although no statistical significance was reached, high CTAG1A/B also showed a similar prognostic trend in lung adenocarcinoma (ADC) and squamous cell carcinoma. The Cancer Genome Atlas database showed the negative prognostic role of CTAG1A/B was mainly induced by CTAG1B (NY-ESO-1, P=0.047) and high CTAG1B expression (hazard ratio =2.733, 95% CI: 1.348–5.541, P=0.005) was an independent negative prognostic factor of lung ADC. Conclusion CTAs represent potential candidate targets for immunotherapy and their expression was closely correlated with tumor stage. High CTAG1B expression was an independent negative prognostic factor of lung ADC.
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Affiliation(s)
- Shi Jin
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China,
| | - Shoubo Cao
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China, .,Department of Medical Oncology, Linyi People's Hospital, Linyi, China
| | - Jianhua Li
- Department of Neurosurgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Qingwei Meng
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China,
| | - Chunyan Wang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China, .,Department of Medical Oncology, Linyi People's Hospital, Linyi, China
| | - Lei Yao
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yaoguo Lang
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Jingyan Cao
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China,
| | - Jing Shen
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China,
| | - Bo Pan
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China,
| | - Jing Hu
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China,
| | - Yan Yu
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China,
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Jin S, Cao S, Grigorev A, Li J, Meng Q, Wang C, Feng M, Hu J, Jiang F, Yu Y. Establishment of cancer/testis antigen profiling based on clinicopathological characteristics in resected pathological stage III non-small cell lung cancer. Cancer Manag Res 2018; 10:2031-2046. [PMID: 30038519 PMCID: PMC6053259 DOI: 10.2147/cmar.s164043] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Background Cancer/testis antigen (CTA) expression was found to be highly heterogeneous in previous studies. We aimed to establish a precision CTA profiling in resected stage III non-small cell lung cancer (NSCLC) and demonstrate the best CTA combination covering the widest range of NSCLC cases. Materials and methods The expression of 10 CTAs was evaluated in 200 resected stage III NSCLC tissue specimens at protein level. Hierarchical clustering and python programming language analyses was used to demonstrate CTA expression and coverage. Results The most commonly expressed CTAs for total cases were MAGEA1 (60.0%), MAGEA10 (50.0%), and KK-LC-1 (47.5%). CTA expression was histology dependent, and concurrent expression was common. The best 2, 3, and 4 CTA combination covered 72.0%, 76.5%, and 79.5% of total cases, respectively. Stratified analysis based on variable clinicopathological characteristics achieved the maximum coverage of 92.3% with only 2 CTA combination in patients with features of male sex, positive smoking history, and adenocarcinoma, compared with a 85.0% coverage when 10 CTAs were assessed. Selected CTA expression was correlated with prognosis based on subgroup analysis. No significant difference was found between CTA expression and epidermal growth factor receptor mutant status. Conclusion We established an individualized CTA profiling in resected stage III NSCLC based on 10 CTA expression. With the help of computer programming language, the goal of the maximum CTA expression coverage was reached by using the least CTA combination based on sex, smoking history, and histology. These results were significant for the further study of CTA-specific T-cell immunotherapy.
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Affiliation(s)
- Shi Jin
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People's Republic of China,
| | - Shoubo Cao
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People's Republic of China, .,Department of Medical Oncology, Linyi People's Hospital, Linyi City, People's Republic of China
| | - Aleksei Grigorev
- School of Computer Science and Technology, Harbin Institute of Technology, Harbin, People's Republic of China
| | - Jianhua Li
- Department of Neurosurgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China
| | - Qingwei Meng
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People's Republic of China,
| | - Chunyan Wang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People's Republic of China, .,Department of Medical Oncology, Linyi People's Hospital, Linyi City, People's Republic of China
| | - Meiyan Feng
- Department of Pathology, Harbin Medical University Cancer Hospital, Harbin, People's Republic of China,
| | - Jing Hu
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People's Republic of China,
| | - Feng Jiang
- School of Computer Science and Technology, Harbin Institute of Technology, Harbin, People's Republic of China
| | - Yan Yu
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People's Republic of China,
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Ye Z, Liang Y, Ma Y, Lin B, Cao L, Wang B, Zhang Z, Yu H, Li J, Huang M, Zhou K, Zhang Q, Liu X, Zeng J. Targeted photodynamic therapy of cancer using a novel gallium (III) tris (ethoxycarbonyl) corrole conjugated-mAb directed against cancer/testis antigens 83. Cancer Med 2018; 7:3057-3065. [PMID: 29856138 PMCID: PMC6051178 DOI: 10.1002/cam4.1601] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 05/10/2018] [Accepted: 05/15/2018] [Indexed: 12/20/2022] Open
Abstract
Photodynamic therapy (PDT) is a noninvasive, highly selective approach to the treatment of tumors. However, its therapeutic effect is limited by long‐lasting skin phototoxicity. Therefore, to compromise this shortcoming, it is preferable to deliver photosensitizers selectively to tumor cells with the aid of antibodies specific against tumor‐associated antigens. Cancer/testis antigens 83 (CT83), also called KK‐LC‐1 or CXorf61, recognized by cytotoxic T lymphocytes (CTL), has become a promising target for immunotherapy. Herein, we developed and characterized a novel mouse CT83 mAb 7G4 with a high affinity with Gallium (III) 5, 10, 15‐tris (ethoxycarbonyl) corrole (1‐Ga), a new and promising photosensitizer in PDT. The enzyme‐linked immunosorbent assay (ELISA), flow cytometry and cytotoxicity activity assays revealed that 7G4‐1‐Ga was able to recognize human CT83 with high specificity. Furthermore, 7G4‐1‐Ga showed greater cytotoxicity to CT83‐expressing human cancer cells in vitro than 1‐Ga. These results suggest that the antibody‐conjugated photosensitizer between anti‐CT83 mAb and 1‐Ga may have a good application in PDT, where the destruction of CT83‐expressing tumor is required.
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Affiliation(s)
- Ziyu Ye
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
| | - Yanfang Liang
- Department of Pathology, The Fifth People's Hospital of Dongguan, Dongguan Hospital Affiliated to Medical College of Jinan University, Dongguan, China
| | - Yan Ma
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
| | - Bihua Lin
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China.,Collaborative Innovation Center for Antitumor Active Substance Research and Development, Guangdong Medical University, Zhanjiang, China
| | - Longbin Cao
- Department of Pathology, The Fifth People's Hospital of Dongguan, Dongguan Hospital Affiliated to Medical College of Jinan University, Dongguan, China
| | - Bin Wang
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
| | - Zhao Zhang
- Department of Chemistry, South China University of Technology, Guangzhou, China
| | - Haibo Yu
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
| | - Jixia Li
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China.,Collaborative Innovation Center for Antitumor Active Substance Research and Development, Guangdong Medical University, Zhanjiang, China
| | - Mingyuan Huang
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
| | - Keyuan Zhou
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China.,Collaborative Innovation Center for Antitumor Active Substance Research and Development, Guangdong Medical University, Zhanjiang, China
| | - Qunzhou Zhang
- Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA
| | - Xinguang Liu
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China.,Institute of Aging Research, Guangdong Medical University, Dongguan, China
| | - Jincheng Zeng
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China.,Collaborative Innovation Center for Antitumor Active Substance Research and Development, Guangdong Medical University, Zhanjiang, China
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Fukuyama T, Futawatari N, Yamamura R, Yamazaki T, Ichiki Y, Ema A, Ushiku H, Nishi Y, Takahashi Y, Otsuka T, Yamazaki H, Koizumi W, Yasumoto K, Kobayashi N. Expression of KK-LC-1, a cancer/testis antigen, at non-tumour sites of the stomach carrying a tumour. Sci Rep 2018; 8:6131. [PMID: 29666402 PMCID: PMC5904109 DOI: 10.1038/s41598-018-24514-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Accepted: 03/27/2018] [Indexed: 02/07/2023] Open
Abstract
Kita-Kyushu lung cancer antigen-1 (KK-LC-1) is a cancer/testis antigen (CTA) and predominant target for cancer immunotherapy. Our previous study indicated that KK-LC-1 was expressed in 82% of gastric cancers, and also in 79% of early stage of gastric cancers, with a correlation to Helicobacter pylori (H. pylori) infection. In addition, we found that KK-LC-1 was occasionally expressed at non-tumour sites of stomachs carrying tumours. Here, we investigated the characteristics of KK-LC-1 expression at non-tumour sites and the clinical utility of these phenomena. The gene expression of KK-LC-1 was detected at the non-tumour sites including pyloric glands. The most detectable corpus/gland subset had a KK-LC-1 expression rate of 77% in the pyloric gland of the lower corpus where H. pylori preferentially exists. KK-LC-1 expression rates were 67% or 32% with or without intestinal metaplasia, which also induced by H. pylori, respectively. Consequently, KK-LC-1 would be detected at the pre-cancerous condition of the stomach, and may be a useful marker to predict gastric cancer.
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Affiliation(s)
- Takashi Fukuyama
- Division of Biomedical Research, Kitasato University Medical Center, Kitamoto, Japan.
| | - Nobue Futawatari
- Department of Surgery, Sagamihara National Hospital, Sagamihara, Japan
| | - Rui Yamamura
- Division of Biomedical Research, Kitasato University Medical Center, Kitamoto, Japan
| | - Taiga Yamazaki
- Division of Biomedical Research, Kitasato University Medical Center, Kitamoto, Japan
| | - Yoshinobu Ichiki
- Second Department of Surgery, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Akira Ema
- Department of Surgery, School of Medicine, Kitasato University, Sagamihara, Japan
| | - Hideki Ushiku
- Department of Surgery, School of Medicine, Kitasato University, Sagamihara, Japan.,Division of Surgery, Kitasato University Medical Center, Kitamoto, Japan
| | - Yatsushi Nishi
- Division of Surgery, Kitasato University Medical Center, Kitamoto, Japan
| | - Yoshihito Takahashi
- Department of Surgery, School of Medicine, Kitasato University, Sagamihara, Japan.,Division of Surgery, Kitasato University Medical Center, Kitamoto, Japan
| | - Toshikazu Otsuka
- Division of Gastroenterology, Kitasato University Medical Center, Kitamoto, Japan
| | - Hitoshi Yamazaki
- Division of Pathology, Kitasato University Medical Center, Kitamoto, Japan
| | - Wasaburo Koizumi
- Department of Gastroenterology, School of Medicine, Kitasato University, Sagamihara, Japan
| | | | - Noritada Kobayashi
- Division of Biomedical Research, Kitasato University Medical Center, Kitamoto, Japan
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Futawatari N, Fukuyama T, Yamamura R, Shida A, Takahashi Y, Nishi Y, Ichiki Y, Kobayashi N, Yamazaki H, Watanabe M. Early gastric cancer frequently has high expression of KK-LC-1, a cancer-testis antigen. World J Gastroenterol 2017; 23:8200-8206. [PMID: 29290656 PMCID: PMC5739926 DOI: 10.3748/wjg.v23.i46.8200] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Revised: 10/30/2017] [Accepted: 11/14/2017] [Indexed: 02/07/2023] Open
Abstract
AIM To assess cancer-testis antigens (CTAs) expression in gastric cancer patients and examined their associations with clinicopathological factors.
METHODS Eighty-three gastric cancer patients were evaluated in this study. Gastric cancer specimens were evaluated for the gene expression of CTAs, Kitakyushu lung cancer antigen-1 (KK-LC-1), melanoma antigen (MAGE)-A1, MAGE-A3 and New York esophageal cancer-1 (NY-ESO-1), by reverse transcription PCR. Clinicopathological background information, such as gender, age, tumor size, macroscopic type, tumor histology, depth of invasion, lymph node metastasis, lymphatic invasion, venous invasion, and pathological stage, was obtained. Statistical comparisons between the expression of each CTA and each clinicopathological background were performed using the χ2 test.
RESULTS The expression rates of KK-LC-1, MAGE-A1, MAGE-A3, and NY-ESO-1 were 79.5%, 32.5%, 39.8%, and 15.7%, respectively. In early stage gastric cancer specimens, the expression of KK-LC-1 was 79.4%, which is comparable to the 79.6% observed in advanced stage specimens. The expression of KK-LC-1 was not significantly associated with clinicopathological factors, while there were considerable differences in the expression rates of MAGE-A1 and MAGE-A3 with vs without lymphatic invasion (MAGE-A1, 39.3% vs 13.6%, P = 0.034; MAGE-A3, 47.5% vs 18.2%, P = 0.022) and/or vascular invasion (MAGE-A1, 41.5% vs 16.7%, P = 0.028; MAGE-A3, 49.1% vs 23.3%, P = 0.035) and, particularly, MAGE-A3, in patients with early vs advanced stage (36.5% vs 49.0%, P = 0.044), respectively. Patients expressing MAGE-A3 and NY-ESO-1 were older than those not expressing MAGE-A3 and NY-ESO-1 (MAGE-A3, 73.7 ± 7.1 vs 67.4 ± 12.3, P = 0.009; NY-ESO-1, 75.5 ± 7.2 vs 68.8 ± 11.2, P = 0.042).
CONCLUSION The KK-LC-1 expression rate was high even in patients with stage I cancer, suggesting that KK-LC-1 is a useful biomarker for early diagnosis of gastric cancer.
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Affiliation(s)
- Nobue Futawatari
- Department of Surgery, Sagamihara National Hospital, Sagamihara, Kanagawa 252-0392, Japan
- Department of Surgery, School of Medicine, Kitasato University, Sagamihara, Kanagawa 252-0374, Japan
| | - Takashi Fukuyama
- Division of Biomedical Research, Kitasato University Medical Center, Kitamoto, Saitama 364-8501, Japan
| | - Rui Yamamura
- Division of Biomedical Research, Kitasato University Medical Center, Kitamoto, Saitama 364-8501, Japan
| | - Akiko Shida
- Department of Surgery, School of Medicine, Kitasato University, Sagamihara, Kanagawa 252-0374, Japan
| | - Yoshihito Takahashi
- Department of Surgery, Kitasato University Medical Center, Kitamoto, Saitama 364-8501, Japan
| | - Yatsushi Nishi
- Department of Surgery, Kitasato University Medical Center, Kitamoto, Saitama 364-8501, Japan
| | - Yoshinobu Ichiki
- Second Department of Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 807-8555, Japan
| | - Noritada Kobayashi
- Division of Biomedical Research, Kitasato University Medical Center, Kitamoto, Saitama 364-8501, Japan
| | - Hitoshi Yamazaki
- Department of Pathology, Kitasato University Medical Center, Kitamoto, Saitama 364-8501, Japan
| | - Masahiko Watanabe
- Department of Surgery, School of Medicine, Kitasato University, Sagamihara, Kanagawa 252-0374, Japan
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36
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Cohen AS, Khalil FK, Welsh EA, Schabath MB, Enkemann SA, Davis A, Zhou JM, Boulware DC, Kim J, Haura EB, Morse DL. Cell-surface marker discovery for lung cancer. Oncotarget 2017; 8:113373-113402. [PMID: 29371917 PMCID: PMC5768334 DOI: 10.18632/oncotarget.23009] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Accepted: 11/11/2017] [Indexed: 12/15/2022] Open
Abstract
Lung cancer is the leading cause of cancer deaths in the United States. Novel lung cancer targeted therapeutic and molecular imaging agents are needed to improve outcomes and enable personalized care. Since these agents typically cannot cross the plasma membrane while carrying cytotoxic payload or imaging contrast, discovery of cell-surface targets is a necessary initial step. Herein, we report the discovery and characterization of lung cancer cell-surface markers for use in development of targeted agents. To identify putative cell-surface markers, existing microarray gene expression data from patient specimens were analyzed to select markers with differential expression in lung cancer compared to normal lung. Greater than 200 putative cell-surface markers were identified as being overexpressed in lung cancers. Ten cell-surface markers (CA9, CA12, CXorf61, DSG3, FAT2, GPR87, KISS1R, LYPD3, SLC7A11 and TMPRSS4) were selected based on differential mRNA expression in lung tumors vs. non-neoplastic lung samples and other normal tissues, and other considerations involving known biology and targeting moieties. Protein expression was confirmed by immunohistochemistry (IHC) staining and scoring of patient tumor and normal tissue samples. As further validation, marker expression was determined in lung cancer cell lines using microarray data and Kaplan–Meier survival analyses were performed for each of the markers using patient clinical data. High expression for six of the markers (CA9, CA12, CXorf61, GPR87, LYPD3, and SLC7A11) was significantly associated with worse survival. These markers should be useful for the development of novel targeted imaging probes or therapeutics for use in personalized care of lung cancer patients.
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Affiliation(s)
- Allison S Cohen
- Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Farah K Khalil
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Eric A Welsh
- Biomedical Informatics Shared Resource, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Matthew B Schabath
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Steven A Enkemann
- Molecular Genomics Shared Resource, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Andrea Davis
- Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Jun-Min Zhou
- Biostatistics Shared Resource, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - David C Boulware
- Biostatistics Shared Resource, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Jongphil Kim
- Department of Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.,Department of Oncologic Sciences, College of Medicine, University of South Florida, Tampa, FL, USA
| | - Eric B Haura
- Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - David L Morse
- Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.,Department of Oncologic Sciences, College of Medicine, University of South Florida, Tampa, FL, USA.,Department of Physics, College of Arts and Sciences, University of South Florida, Tampa, FL, USA
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Stevanović S, Pasetto A, Helman SR, Gartner JJ, Prickett TD, Howie B, Robins HS, Robbins PF, Klebanoff CA, Rosenberg SA, Hinrichs CS. Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer. Science 2017; 356:200-205. [PMID: 28408606 DOI: 10.1126/science.aak9510] [Citation(s) in RCA: 295] [Impact Index Per Article: 36.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 03/16/2017] [Indexed: 12/11/2022]
Abstract
Immunotherapy has clinical activity in certain virally associated cancers. However, the tumor antigens targeted in successful treatments remain poorly defined. We used a personalized immunogenomic approach to elucidate the global landscape of antitumor T cell responses in complete regression of human papillomavirus-associated metastatic cervical cancer after tumor-infiltrating adoptive T cell therapy. Remarkably, immunodominant T cell reactivities were directed against mutated neoantigens or a cancer germline antigen, rather than canonical viral antigens. T cells targeting viral tumor antigens did not display preferential in vivo expansion. Both viral and nonviral tumor antigen-specific T cells resided predominantly in the programmed cell death 1 (PD-1)-expressing T cell compartment, which suggests that PD-1 blockade may unleash diverse antitumor T cell reactivities. These findings suggest a new paradigm of targeting nonviral antigens in immunotherapy of virally associated cancers.
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Affiliation(s)
- Sanja Stevanović
- Experimental Transplantation and Immunology Branch, National Cancer Institute, Bethesda, MD 20892, USA.
| | - Anna Pasetto
- Surgery Branch, National Cancer Institute, Bethesda, MD 20892, USA
| | - Sarah R Helman
- Experimental Transplantation and Immunology Branch, National Cancer Institute, Bethesda, MD 20892, USA
| | - Jared J Gartner
- Surgery Branch, National Cancer Institute, Bethesda, MD 20892, USA
| | - Todd D Prickett
- Surgery Branch, National Cancer Institute, Bethesda, MD 20892, USA
| | - Bryan Howie
- Adaptive Biotechnologies, Seattle, WA 98102, USA
| | - Harlan S Robins
- Adaptive Biotechnologies, Seattle, WA 98102, USA.,Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Paul F Robbins
- Surgery Branch, National Cancer Institute, Bethesda, MD 20892, USA
| | - Christopher A Klebanoff
- Center for Cell Engineering and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.,Parker Institute for Cancer Immunotherapy, New York, NY 10065, USA
| | | | - Christian S Hinrichs
- Experimental Transplantation and Immunology Branch, National Cancer Institute, Bethesda, MD 20892, USA.
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38
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Fukuyama T, Futawatari N, Ichiki Y, Shida A, Yamazaki T, Nishi Y, Nonoguchi H, Takahashi Y, Yamazaki H, Kobayashi N. Correlation Between Expression of the Cancer/Testis Antigen KK-LC-1 and Helicobacter pylori Infection in Gastric Cancer. In Vivo 2017; 31:403-407. [PMID: 28438869 PMCID: PMC5461451 DOI: 10.21873/invivo.11073] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Revised: 03/23/2017] [Accepted: 03/24/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND/AIM Our previous study indicated that Kita-kyushu lung cancer antigen-1 (KK-LC-1) is a cancer/testis antigen (CTA) expressed in 82% of gastric cancer cases. Here, we investigated the relationship between KK-LC-1 expression and Helicobacter pylori infection in Japanese patients with gastric cancer. PATIENTS AND METHODS We examined CTA expression in 25 surgical gastric cancer specimens and anti-H. pylori IgGs in the serum of each patient. RESULTS KK-LC-1 was expressed in 80% of tumor samples, markedly higher than melanoma antigen gene (MAGE)-A1, MAGE-A3, MAGE-A4, synovial sarcoma, X breakpoint 4 (SSX4) and New York esophageal squamous cell carcinoma-1 (NY-ESO-1). Anti-H. pylori IgG titers from the KK-LC-1-positive patients were significantly higher (67.5±7.6) than those from KK-LC-1-negative patients (15.8±7.5, p<0.01) although there were no significant differences between patients positive and negative for MAGE-A1, -A3 and-A4, SSX4 and NY-ESO-1. CONCLUSION As far as we are aware, this is the first report of a correlation between a carcinogen and CTA expression in clinical samples. KK-LC-1 was frequently expressed in gastric cancer caused by H. pylori infection. The risk diagnosis for gastric cancer might be more accurate if KK-LC-1 expression status were also considered.
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Affiliation(s)
- Takashi Fukuyama
- Division of Biomedical Research, Kitasato University Medical Center, Kitamoto, Japan
| | - Nobue Futawatari
- Department of Surgery, Sagamihara National Hospital, Sagamihara, Japan
- Department of Surgery, School of Medicine, Kitasato University, Sagamihara, Japan
| | - Yoshinobu Ichiki
- Second Department of Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Akiko Shida
- Department of Surgery, School of Medicine, Kitasato University, Sagamihara, Japan
| | - Taiga Yamazaki
- Division of Biomedical Research, Kitasato University Medical Center, Kitamoto, Japan
| | - Yatsushi Nishi
- Department of Surgery, Kitasato University Medical Center, Kitamoto, Japan
| | - Hiroshi Nonoguchi
- Division of Biomedical Research, Kitasato University Medical Center, Kitamoto, Japan
| | - Yoshihito Takahashi
- Department of Surgery, School of Medicine, Kitasato University, Sagamihara, Japan
- Department of Surgery, Kitasato University Medical Center, Kitamoto, Japan
| | - Hitoshi Yamazaki
- Department of Pathology, Kitasato University Medical Center, Kitamoto, Japan
| | - Noritada Kobayashi
- Division of Biomedical Research, Kitasato University Medical Center, Kitamoto, Japan
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Paret C, Simon P, Vormbrock K, Bender C, Kölsch A, Breitkreuz A, Yildiz Ö, Omokoko T, Hubich-Rau S, Hartmann C, Häcker S, Wagner M, Roldan DB, Selmi A, Türeci Ö, Sahin U. CXorf61 is a target for T cell based immunotherapy of triple-negative breast cancer. Oncotarget 2016; 6:25356-67. [PMID: 26327325 PMCID: PMC4694836 DOI: 10.18632/oncotarget.4516] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2015] [Accepted: 07/15/2015] [Indexed: 12/15/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is a high medical need disease with limited treatment options. CD8+ T cell-mediated immunotherapy may represent an attractive approach to address TNBC. The objectives of this study were to assess the expression of CXorf61 in TNBCs and healthy tissues and to evaluate its capability to induce T cell responses. We show by transcriptional profiling of a broad comprehensive set of normal human tissue that CXorf61 expression is strictly restricted to testis. 53% of TNBC patients express this antigen in at least 30% of their tumor cells. In CXorf61-negative breast cancer cell lines CXorf61 expression is activated by treatment with the hypomethylating agent 5-aza-2′-deoxycytidine. By vaccination of HLA-A*02-transgenic mice with CXorf61 encoding RNA we obtained high frequencies of CXorf61-specific T cells. Cloning and characterization of T cell receptors (TCRs) from responding T cells resulted in the identification of the two HLA-A*0201-restricted T cell epitopes CXorf6166–74 and CXorf6179–87. Furthermore, by in vitro priming of human CD8+ T cells derived from a healthy donor recognizing CXorf6166–74 we were able to induce a strong antigen-specific immune response and clone a human TCR recognizing this epitope. In summary, our data confirms this antigen as promising target for T cell based therapies.
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Affiliation(s)
- Claudia Paret
- TRON gGmbH, Translational Oncology at the University Medical Center, Johannes Gutenberg-University, Mainz, Germany
| | - Petra Simon
- BioNTech Cell & Gene Therapies, An der Goldgrube 12, Mainz, Germany
| | - Kirsten Vormbrock
- TRON gGmbH, Translational Oncology at the University Medical Center, Johannes Gutenberg-University, Mainz, Germany
| | - Christian Bender
- TRON gGmbH, Translational Oncology at the University Medical Center, Johannes Gutenberg-University, Mainz, Germany
| | - Anne Kölsch
- TRON gGmbH, Translational Oncology at the University Medical Center, Johannes Gutenberg-University, Mainz, Germany
| | | | - Özlem Yildiz
- BioNTech Cell & Gene Therapies, An der Goldgrube 12, Mainz, Germany
| | - Tana Omokoko
- BioNTech Cell & Gene Therapies, An der Goldgrube 12, Mainz, Germany
| | - Stefanie Hubich-Rau
- Experimental Oncology, Department of Medicine III, Johannes Gutenberg-University, Mainz, Germany
| | - Christoph Hartmann
- TRON gGmbH, Translational Oncology at the University Medical Center, Johannes Gutenberg-University, Mainz, Germany.,Experimental Oncology, Department of Medicine III, Johannes Gutenberg-University, Mainz, Germany
| | - Sabine Häcker
- TRON gGmbH, Translational Oncology at the University Medical Center, Johannes Gutenberg-University, Mainz, Germany
| | - Meike Wagner
- TRON gGmbH, Translational Oncology at the University Medical Center, Johannes Gutenberg-University, Mainz, Germany.,Experimental Oncology, Department of Medicine III, Johannes Gutenberg-University, Mainz, Germany
| | - Diana Barea Roldan
- Experimental Oncology, Department of Medicine III, Johannes Gutenberg-University, Mainz, Germany
| | - Abderaouf Selmi
- TRON gGmbH, Translational Oncology at the University Medical Center, Johannes Gutenberg-University, Mainz, Germany
| | - Özlem Türeci
- TRON gGmbH, Translational Oncology at the University Medical Center, Johannes Gutenberg-University, Mainz, Germany
| | - Ugur Sahin
- TRON gGmbH, Translational Oncology at the University Medical Center, Johannes Gutenberg-University, Mainz, Germany.,BioNTech Cell & Gene Therapies, An der Goldgrube 12, Mainz, Germany.,Experimental Oncology, Department of Medicine III, Johannes Gutenberg-University, Mainz, Germany
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40
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Li J, Sordella R, Powers S. Effectors and potential targets selectively upregulated in human KRAS-mutant lung adenocarcinomas. Sci Rep 2016; 6:27891. [PMID: 27301828 PMCID: PMC4908391 DOI: 10.1038/srep27891] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 05/26/2016] [Indexed: 12/11/2022] Open
Abstract
Genetic and proteomic analysis of human tumor samples can provide an important compliment to information obtained from model systems. Here we examined protein and gene expression from the Cancer Genome and Proteome Atlases (TCGA and TCPA) to characterize proteins and protein-coding genes that are selectively upregulated in KRAS-mutant lung adenocarcinomas. Phosphoprotein activation of several MAPK signaling components was considerably stronger in KRAS-mutants than any other group of tumors, even those with activating mutations in receptor tyrosine kinases (RTKs) and BRAF. Co-occurring mutations in KRAS-mutants were associated with differential activation of PDK1 and PKC-alpha. Genes showing strong activation in RNA-seq data included negative regulators of RTK/RAF/MAPK signaling along with potential oncogenic effectors including activators of Rac and Rho proteins and the receptor protein-tyrosine phosphatase genes PTPRM and PTPRE. These results corroborate RAF/MAPK signaling as an important therapeutic target in KRAS-mutant lung adenocarcinomas and pinpoint new potential targets.
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Affiliation(s)
- Jinyu Li
- Department of Pathology, Stony Brook University, Stony Brook, NY, 11794, USA
| | | | - Scott Powers
- Department of Pathology, Stony Brook University, Stony Brook, NY, 11794, USA.,Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA
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41
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Hickman ES, Lomax ME, Jakobsen BK. Antigen Selection for Enhanced Affinity T-Cell Receptor-Based Cancer Therapies. ACTA ACUST UNITED AC 2016; 21:769-85. [PMID: 26993321 DOI: 10.1177/1087057116637837] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 03/15/2016] [Indexed: 12/11/2022]
Abstract
Evidence of adaptive immune responses in the prevention of cancer has been accumulating for decades. Spontaneous T-cell responses occur in multiple indications, bringing the study of de novo expressed cancer antigens to the fore and highlighting their potential as targets for cancer immunotherapy. Circumventing the immune-suppressive mechanisms that maintain tumor tolerance and driving an antitumor cytotoxic T-cell response in cancer patients may eradicate the tumor or block disease progression. Multiple strategies are being pursued to harness the cytotoxic potential of T cells clinically. Highly promising results are now emerging. The focus of this review is the target discovery process for cancer immune therapeutics based on affinity-matured T-cell receptors (TCRs). Target cancer antigens in the context of adoptive cell transfer technologies and soluble biologic agents are discussed. To appreciate the impact of TCR-based technology and understand the TCR discovery process, it is necessary to understand key differences between TCR-based therapy and other immunotherapy approaches. The review first summarizes key advances in the cancer immunotherapy field and then discusses the opportunities that TCR technology provides. The nature and breadth of molecular targets that are tractable to this approach are discussed, together with the challenges associated with finding them.
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42
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Fauteux F, Hill JJ, Jaramillo ML, Pan Y, Phan S, Famili F, O'Connor-McCourt M. Computational selection of antibody-drug conjugate targets for breast cancer. Oncotarget 2016; 7:2555-71. [PMID: 26700623 PMCID: PMC4823055 DOI: 10.18632/oncotarget.6679] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Accepted: 11/21/2015] [Indexed: 01/03/2023] Open
Abstract
The selection of therapeutic targets is a critical aspect of antibody-drug conjugate research and development. In this study, we applied computational methods to select candidate targets overexpressed in three major breast cancer subtypes as compared with a range of vital organs and tissues. Microarray data corresponding to over 8,000 tissue samples were collected from the public domain. Breast cancer samples were classified into molecular subtypes using an iterative ensemble approach combining six classification algorithms and three feature selection techniques, including a novel kernel density-based method. This feature selection method was used in conjunction with differential expression and subcellular localization information to assemble a primary list of targets. A total of 50 cell membrane targets were identified, including one target for which an antibody-drug conjugate is in clinical use, and six targets for which antibody-drug conjugates are in clinical trials for the treatment of breast cancer and other solid tumors. In addition, 50 extracellular proteins were identified as potential targets for non-internalizing strategies and alternative modalities. Candidate targets linked with the epithelial-to-mesenchymal transition were identified by analyzing differential gene expression in epithelial and mesenchymal tumor-derived cell lines. Overall, these results show that mining human gene expression data has the power to select and prioritize breast cancer antibody-drug conjugate targets, and the potential to lead to new and more effective cancer therapeutics.
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Affiliation(s)
- François Fauteux
- Information and Communication Technologies, National Research Council Canada, Ottawa, Ontario, Canada
| | - Jennifer J. Hill
- Human Health Therapeutics, National Research Council Canada, Ottawa, Ontario, Canada
| | - Maria L. Jaramillo
- Human Health Therapeutics, National Research Council Canada, Montreal, Quebec, Canada
| | - Youlian Pan
- Information and Communication Technologies, National Research Council Canada, Ottawa, Ontario, Canada
| | - Sieu Phan
- Information and Communication Technologies, National Research Council Canada, Ottawa, Ontario, Canada
| | - Fazel Famili
- Information and Communication Technologies, National Research Council Canada, Ottawa, Ontario, Canada
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43
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Li K, Zhang Q, Zhang Y, Yang J, Zheng J. T-cell-associated cellular immunotherapy for lung cancer. J Cancer Res Clin Oncol 2015; 141:1249-58. [PMID: 25381064 DOI: 10.1007/s00432-014-1867-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Accepted: 10/27/2014] [Indexed: 12/29/2022]
Abstract
PURPOSE The aim of the present study was to discuss recent findings on the role of T cells in lung cancer to provide information on their potential application, especially in cellular immunotherapy. METHODS Data on the different types of T cells that are currently used for the treatment of lung cancer were obtained by searching the PUBMED database. RESULTS Cytotoxic T lymphocytes, natural killer T cells, γδ T cells, lymphokine-activated killer cells, tumor-infiltrating lymphocytes, cytokine-induced killer cells and gene-modified T cells were analyzed to determine the benefits and drawbacks of their application in the treatment of lung cancer. Advances in the study of their antitumor mechanisms and directions for future research were discussed. CONCLUSIONS T cells are critical for tumorigenesis and therefore important targets for the treatment of lung cancer. T-cell-associated cellular immunotherapy opens up a window of opportunity for the development of complementary methods to traditional lung cancer treatments, which warrants further investigation to improve the clinical outcomes of lung cancer patients.
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MESH Headings
- Cytokine-Induced Killer Cells/immunology
- Cytokine-Induced Killer Cells/transplantation
- Cytotoxicity, Immunologic/physiology
- Humans
- Immunotherapy, Adoptive/methods
- Killer Cells, Lymphokine-Activated/immunology
- Killer Cells, Lymphokine-Activated/transplantation
- Killer Cells, Natural/immunology
- Killer Cells, Natural/transplantation
- Lung Neoplasms/immunology
- Lung Neoplasms/therapy
- Lymphocytes, Tumor-Infiltrating/immunology
- Lymphocytes, Tumor-Infiltrating/transplantation
- T-Lymphocytes/immunology
- T-Lymphocytes/transplantation
- T-Lymphocytes, Cytotoxic/immunology
- T-Lymphocytes, Cytotoxic/transplantation
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Affiliation(s)
- Ke Li
- Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College, West Huaihai Road 84#, Xuzhou, 221002, Jiangsu, China
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44
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Coulie PG, Van den Eynde BJ, van der Bruggen P, Boon T. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat Rev Cancer 2014; 14:135-46. [PMID: 24457417 DOI: 10.1038/nrc3670] [Citation(s) in RCA: 834] [Impact Index Per Article: 75.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
In this Timeline, we describe the characteristics of tumour antigens that are recognized by spontaneous T cell responses in cancer patients and the paths that led to their identification. We explain on what genetic basis most, but not all, of these antigens are tumour specific: that is, present on tumour cells but not on normal cells. We also discuss how strategies that target these tumour-specific antigens can lead either to tumour-specific or to crossreactive T cell responses, which is an issue that has important safety implications in immunotherapy. These safety issues are even more of a concern for strategies targeting antigens that are not known to induce spontaneous T cell responses in patients.
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Affiliation(s)
- Pierre G Coulie
- 1] de Duve Institute and the Université catholique de Louvain, B-1200 Brussels, Belgium. [2] WELBIO (Walloon Excellence in Lifesciences and Biotechnology), B-1200 Brussels, Belgium
| | - Benoît J Van den Eynde
- 1] de Duve Institute and the Université catholique de Louvain, B-1200 Brussels, Belgium. [2] Ludwig Institute for Cancer Research, B-1200 Brussels, Belgium. [3] WELBIO (Walloon Excellence in Lifesciences and Biotechnology), B-1200 Brussels, Belgium
| | - Pierre van der Bruggen
- 1] de Duve Institute and the Université catholique de Louvain, B-1200 Brussels, Belgium. [2] Ludwig Institute for Cancer Research, B-1200 Brussels, Belgium. [3] WELBIO (Walloon Excellence in Lifesciences and Biotechnology), B-1200 Brussels, Belgium
| | - Thierry Boon
- 1] de Duve Institute and the Université catholique de Louvain, B-1200 Brussels, Belgium. [2] Ludwig Institute for Cancer Research, B-1200 Brussels, Belgium
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45
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Jiang JH, Gao Q, Shen XZ, Yu Y, Gu FM, Yan J, Pan JF, Jin F, Fan J, Zhou J, Huang XW. An X-chromosomal association study identifies a susceptibility locus at Xq22.1 for hepatitis B virus-related hepatocellular carcinoma. Clin Res Hepatol Gastroenterol 2013; 37:586-95. [PMID: 24209690 DOI: 10.1016/j.clinre.2013.09.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2013] [Revised: 09/01/2013] [Accepted: 09/17/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND OBJECTIVE Genetic epidemiological data in hepatocellular carcinoma (HCC) pedigrees indicate a pattern of X-linked recessive inheritance of HCC susceptibility genes. This study is designed to test the hypothesis that there are genes conferring susceptibility to HCC located on the X-chromosome. METHODS An X-chromosomal association study was conducted among Chinese men recruited from an area with a high prevalence of HCC. The candidate gene was further investigated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). RESULTS By analyzing 5454 X-chromosome single nucleotide polymorphisms (SNPs) in 50 HCC patients and 50 controls, we found two promising regions in which the associated SNPs clustered, located at Xq22.1 and Xq26.2. We further selected 35 tag SNPs (tSNPs) from these two regions for additional genotyping analysis in another independent set of 290 cases and 242 controls. Notably, SNP rs5945919 at Xq22.1 exhibited a significant association with HBV-related HCC (odds ratio [OR]=2.22, 95% confidence interval [CI]=1.15-4.30, P=0.016). The expressions of the three genes near the rs5945919 locus, RAB40AL, BEX1, and NXF3, were analyzed by qRT-PCR between another 24 HCC tissues and paired peritumoral liver tissues. The results indicated that NXF3, rather than RAB40AL and BEX1, mRNA level was found to be more abundant in HCC tissue than in peritumoral liver tissue. CONCLUSIONS Our findings implicated Xq22.1 as a novel susceptibility locus for HCC and NXF3 as a candidate risk factor for relevant HCC.
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Affiliation(s)
- Jia-Hao Jiang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P.R. China
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46
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Chiriva-Internati M, Pandey A, Saba R, Kim M, Saadeh C, Lukman T, Chiaramonte R, Jenkins M, Cobos E, Jumper C, Alalawi R. Cancer testis antigens: a novel target in lung cancer. Int Rev Immunol 2013; 31:321-43. [PMID: 23083344 DOI: 10.3109/08830185.2012.723512] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Lung cancer is the main cause of cancer mortality worldwide. This is mainly due to the fact that it is diagnosed in advanced stage patients, which are no more surgically curable. Consequently, searching for novel treatments and new modalities for early diagnosis offers great promise to improve the clinical outcome. Recently, a new group of antigens, the cancer testis antigens, have been described as possible early diagnostic tools and therapeutic targets in cancer therapy.This review will report emerging evidences of cancer testis antigens deregulation in lung cancer and explore the state of the art of their currently known role and potential as markers for early diagnosis and disease progression and targets of an immunotherapeutic approach aiming to improve the cure rate of this tumor.
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Affiliation(s)
- Maurizio Chiriva-Internati
- Department of Internal Medicine, Division of Hematology & Oncology and Pulmonary and Critical Care Medicine, The Southwest Cancer Treatment and Research Center, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
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Stouffs K, Lissens W. X chromosomal mutations and spermatogenic failure. Biochim Biophys Acta Mol Basis Dis 2012; 1822:1864-72. [DOI: 10.1016/j.bbadis.2012.05.012] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2011] [Revised: 02/24/2012] [Accepted: 05/14/2012] [Indexed: 01/11/2023]
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Shan Q, Lou X, Xiao T, Zhang J, Sun H, Gao Y, Cheng S, Wu L, Xu N, Liu S. A cancer/testis antigen microarray to screen autoantibody biomarkers of non-small cell lung cancer. Cancer Lett 2012; 328:160-7. [PMID: 22922091 DOI: 10.1016/j.canlet.2012.08.019] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2012] [Revised: 08/08/2012] [Accepted: 08/15/2012] [Indexed: 01/03/2023]
Abstract
Cancer/testis antigens (CTAs) are highly immunogenic in many tumors, especially in non-small cell lung cancer (NSCLC). A low-density protein microarray, which consisted of 72 CTAs and six non-CTAs, was used to screen for lung cancer-related autoantibodies. The CTA panel of NY-ESO-1, XAGE-1, ADAM29 and MAGEC1, had sensitivity and specificity values of 33% and 96%, respectively. When examined in a test set, this panel of markers had sensitivity and specificity values of 36% and 89%, respectively. This array of markers preferentially detected NSCLC, but did not detect breast cancer, and non-cancer lung disease.
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Affiliation(s)
- Qiang Shan
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 101318, China
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Baba T, Shiota H, Kuroda K, Shigematsu Y, Ichiki Y, Uramoto H, Hanagiri T, Tanaka F. Cancer/testis antigen expression as a predictor for epidermal growth factor receptor mutation and prognosis in lung adenocarcinoma. Eur J Cardiothorac Surg 2012; 43:759-64. [PMID: 22826471 DOI: 10.1093/ejcts/ezs426] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVES Immune therapy targeting cancer/testis (CT) antigens improve the survival in several types of solid tumours. The expression of CT antigens is related to poor survival in non-small-cell lung cancer (NSCLC). The epidermal growth factor receptor (EGFR) mutation is the best predictive factor for the sensitivity to tyrosine kinase inhibitors in lung adenocarcinoma. The aim of this study was to elucidate the correlation between the expression of CT antigens and clinicopathological factors, including the EGFR mutation, and to analyse the prognosis in lung adenocarcinoma. METHODS Data were collected from a total of 281 lung adenocarcinoma patients who underwent surgery. Among them, 125 cases, whose specimens were too small to extract sufficient DNA and/or RNA, and 2 cases with the coexistence of another histological lung cancer were excluded. A total of 154 patients were reviewed. The expression of CT antigens (melanoma-associated antigen gene [MAGE]-A4 and KK-LC-1) and the EGFR-activating mutation (L858R point mutation in exon 21 and inframe deletion in exon 19) was evaluated by using polymerase chain reaction amplification. RESULTS The expression of MAGE-A4 and KK-LC-1 was detected in 14 (9%) and 54 patients (35%) with adenocarcinoma. The EGFR-activating mutation was found in 64 patients (42%). Univariate and multivariate analyses demonstrated that tumours expressing at least one CT antigen were associated with no EGFR mutation (odds ratio = 0.3; 95% confidence interval, 0.14-0.71; P < 0.01). A survival analysis was performed in 135 patients who underwent complete resection and the 5-year overall survival rate was 71.1% in those with any expression of CT antigens and 83.2% in those without expression of the genes (P < 0.04). CONCLUSION Two different therapeutic targets, EGFR-activating mutation and CT antigen, have a negative relationship with each other.
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Affiliation(s)
- Tetsuro Baba
- Second Department of Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
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Fukuyama T, Yamazaki T, Fujita T, Uematsu T, Ichiki Y, Kaneko H, Suzuki T, Kobayashi N. Helicobacter pylori, a carcinogen, induces the expression of melanoma antigen-encoding gene (Mage)-A3, a cancer/testis antigen. Tumour Biol 2012; 33:1881-7. [PMID: 22773374 DOI: 10.1007/s13277-012-0448-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2012] [Accepted: 06/22/2012] [Indexed: 12/14/2022] Open
Abstract
Cancer/testis antigens (CTAs) are known to be expressed in various cancer types but are minimally or not expressed in normal tissues except for germline tissues. CTAs are attractive targets for cancer immunotherapy and diagnosis because of their restricted expression. The mechanisms of CTAs expression are unclear because the inducers of CTAs expression remain to be elucidated. We hypothesized that carcinogens may induce the cellular expression of CTAs. To prove this, we attempted to inoculate Helicobacter pylori, a known carcinogen, in Meth-A cells, normal gastric cells, and normal splenocytes and induce the expression of a CTA. Melanoma antigen-encoding gene (Mage)-A3, one of the CTAs, was not expressed in both normal cells but in Meth-A cells inoculated with H. pylori. Furthermore, we performed limiting dilution using Meth-A cells inoculated with H. pylori and established derivative clone from Meth-A designated as Meth-A/pylori/3C3 which permanently express Mage-A3 after excluding H. pylori. We herein report the first successful induction of a CTA in a cell line via exposure to a carcinogenic agent. Furthermore, the establishment of Meth-A/pylori/3C3, which is Meth-A expressing Mage-A3, is considered to contribute to the resolution of the mechanism of CTAs expression.
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Affiliation(s)
- Takashi Fukuyama
- Division of Biomedical Research, Kitasato Institute Medical Center Hospital, Kitasato University, Arai 6-100, Kitamoto 364-8501, Japan.
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