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Bassoy EY, Raja R, Rubino TE, Coscia F, Goergen K, Magtibay P, Butler K, Schmitt A, Oberg AL, Curtis M. Identification of TTLL8, POTEE, and PKMYT1 as immunogenic cancer-associated antigens and potential immunotherapy targets in ovarian cancer. Oncoimmunology 2025; 14:2460276. [PMID: 39891409 PMCID: PMC11792853 DOI: 10.1080/2162402x.2025.2460276] [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: 08/29/2024] [Revised: 12/27/2024] [Accepted: 01/24/2025] [Indexed: 02/03/2025] Open
Abstract
Most high-grade serous ovarian cancers (OC) do not respond to current immunotherapies. To identify potential new actionable tumor antigens in OC, we performed immunopeptidomics on a human OC cell line expressing the HLA-A02:01 haplotype, which is commonly expressed across many racial and ethnic groups. From this dataset, we identified TTLL8, POTEE, and PKMYT1 peptides as candidate tumor antigens with low expression in normal tissues and upregulated expression in OC. Using tissue microarrays, we assessed the protein expression of TTLL8 and POTEE and their association with patient outcomes in a large cohort of OC patients. TTLL8 was found to be expressed in 56.7% of OC and was associated with a worse overall prognosis. POTEE was expressed in 97.2% of OC patients and had no significant association with survival. In patient TILs, increases in cytokine production and tetramer-positive populations identified antigen-specific CD8 T cell responses, which were dependent on antigen presentation by HLA class I. Antigen-specific T cells triggered cancer cell killing of antigen-pulsed OC cells. These findings suggest that TTLL8, POTEE, and PKMYT1 are potential targets for the development of antigen-targeted immunotherapy in OC.
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Affiliation(s)
| | - Remya Raja
- Department of Immunology, Mayo Clinic, Phoenix, AZ, USA
| | | | - Fabian Coscia
- Max-Delbruck-Center for Molecular Medicine in the Helmholtz Association (MDC), Spatial Proteomics Group, Berlin, Germany
| | - Krista Goergen
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
| | - Paul Magtibay
- Department of Obstetrics and Gynecology, Mayo Clinic, Phoenix, AZ, USA
| | - Kristina Butler
- Department of Obstetrics and Gynecology, Mayo Clinic, Phoenix, AZ, USA
- College of Medicine and Science, Mayo Clinic, Phoenix, AZ, USA
| | - Alessandra Schmitt
- Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ, USA
| | - Ann L. Oberg
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
| | - Marion Curtis
- Department of Immunology, Mayo Clinic, Phoenix, AZ, USA
- College of Medicine and Science, Mayo Clinic, Phoenix, AZ, USA
- Department of Cancer Biology, Mayo Clinic, Phoenix, AZ, USA
- Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Phoenix, AZ, USA
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Xie Z, Yang T, Zhou C, Xue Z, Wang J, Lu F. Integrative Bioinformatics Analysis and Experimental Study of NLRP12 Reveal Its Prognostic Value and Potential Functions in Ovarian Cancer. Mol Carcinog 2025; 64:383-398. [PMID: 39601513 DOI: 10.1002/mc.23854] [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: 07/26/2024] [Revised: 11/04/2024] [Accepted: 11/08/2024] [Indexed: 11/29/2024]
Abstract
NLRP12 plays a significant role in cellular functional behavior and immune homeostasis, influencing inflammation, tumorigenesis, and prognosis. This study aimed to explore its specific effects on the tumor microenvironment (TME) and its contribution to heterogeneity in ovarian cancer (OV) through bioinformatics analysis and experimental verification. Utilizing various bioinformatics databases and clinical specimens, we investigated NLRP12 expression and its relationship with OV prognosis and immune infiltration. In vitro assays were conducted to assess the impact of NLRP12 on the proliferation and invasion of OV cells. Our findings indicate that NLRP12 is upregulated in OV, with high expression correlating with a negative prognosis. Furthermore, NLRP12 expression demonstrated a positive correlation with the infiltration of various immune cells and the expression of immune checkpoint molecules in OV. Analysis of The Cancer Immunome Atlas (TCIA) database revealed that OV patients with lower NLRP12 expression may exhibit an enhanced response to immunotherapy, particularly CTLA4 blockers, a finding validated in animal experiments. Additionally, the study emphasized the role of NLRP12 in influencing the prognosis of OV patients by promoting epithelial-mesenchymal transition (EMT) in ovarian cancer cells. Finally, we identified a potential therapeutic compound, Schisandrin B (Schi B), which decreases NLRP12 expression in ovarian cancer cells by binding to the transcription factor SPI1 associated with NLRP12. Our findings suggest that NLRP12 serves as a crucial immune-related biomarker predicting poor outcomes in OV, and targeting NLRP12 may represent a promising therapeutic approach for OV patients in the future.
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Affiliation(s)
- Zhihui Xie
- Department of Medical Oncology, Huaihe Hospital of Henan University, Kaifeng, China
| | - Tiantian Yang
- Department of Immunology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Joint National Laboratory for Antibody Drug Engineering, Medical School, Henan University, Kaifeng, China
| | - Chuchu Zhou
- Department of Immunology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Joint National Laboratory for Antibody Drug Engineering, Medical School, Henan University, Kaifeng, China
| | - Zixin Xue
- Department of Immunology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Joint National Laboratory for Antibody Drug Engineering, Medical School, Henan University, Kaifeng, China
| | - Jianjun Wang
- Department of Medical Oncology, Huaihe Hospital of Henan University, Kaifeng, China
| | - Feng Lu
- Department of Medical Oncology, Huaihe Hospital of Henan University, Kaifeng, China
- Department of Immunology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Joint National Laboratory for Antibody Drug Engineering, Medical School, Henan University, Kaifeng, China
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Kabirian R, Tredan O, Marmé F, Paoletti X, Eberst L, Lebreton C, De La Motte Rouge T, Sabatier R, Angelergues A, Fabbro M, Van Gorp T, Mansi L, Gladieff L, Kaczmarek E, Alexandre J, Grellety T, Favier L, Welz J, Frenel JS, Leary A. TEDOVA: vaccine OSE2101 +/- pembrolizumab as maintenance in platinum-sensitive recurrent ovarian cancer. Future Oncol 2024; 20:2699-2708. [PMID: 39155847 PMCID: PMC11572149 DOI: 10.1080/14796694.2024.2386922] [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: 07/29/2024] [Indexed: 08/20/2024] Open
Abstract
Ovarian cancer is a leading cause of death from gynecological cancers worldwide. Platinum-based chemotherapy provides the cornerstone of the medical management. In first line and subsequent relapses, maintenance strategies are offered to prolong intervals between lines of chemotherapy. Current maintenance options involve bevacizumab and poly ADP-ribose polymerase inhibitors, but these lines of therapy can only be used once in the disease course. Patients in first or second platinum sensitive relapse after poly ADP-ribose polymerase inhibitors and bevacizumab represent an area of unmet medical need. This academic sponsored, international Phase II randomized trial is evaluating the combination of a therapeutic cancer vaccine (OSE2101) with anti-PD1 (pembrolizumab) as maintenance therapy, in patients with platinum-sensitive recurrence regardless of number of prior lines and no progression after platinum-based chemotherapy.Clinical Trial Registration: NCT04713514 (ClinicalTrials.gov).
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Affiliation(s)
- Rayan Kabirian
- Department of Medical Oncology, Gustave Roussy, Villejuif, & GINECO, France
| | | | - Frederik Marmé
- Medical Faculty Mannheim, Heidelberg University & AGO Study Group, Germany
| | | | - Lauriane Eberst
- Institut de Cancérologie de Strasbourg Europe, ICANS, Strasbourg, & GINECO, France
| | | | | | - Renaud Sabatier
- Aix-Marseille Univ, CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Department of Medical Oncology, Marseille, & GINECO, France
| | | | - Michel Fabbro
- Institut du Cancer de Montpellier (ICM), Montpellier, & GINECO, France
| | - Toon Van Gorp
- Leuven Cancer Institute, Division of Gynaecological Oncology, University Hospital Leuven, BGOG, Belgium
| | - Laura Mansi
- CHU Besançon – Hôpital jean Minjoz, Besançon, & GINECO, France
| | | | | | - Jérôme Alexandre
- Université de Paris Cité, AP-HP, Hôpital Cochin, Paris, & GINECO, France
| | - Thomas Grellety
- Centre Hospitalier de la Côte Basque, Bayonne, & GINECO, France
| | - Laure Favier
- Centre Georges François Leclerc, Dijon, & GINECO, France
| | - Julia Welz
- Evang. Kliniken Essen-Mitte - ESSEN & AGO Study Group, Germany
| | - Jean-Sébastien Frenel
- Institut de Cancérologie de l'Ouest, Centre René Gauducheau, 44800, Saint Herblain, & GINECO, France
| | - Alexandra Leary
- Department of Medical Oncology, Gustave Roussy, Villejuif, & GINECO, France
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Chen B, Zhao L, Yang R, Xu T. The recent advancements of ferroptosis in the diagnosis, treatment and prognosis of ovarian cancer. Front Genet 2023; 14:1275154. [PMID: 38028615 PMCID: PMC10665572 DOI: 10.3389/fgene.2023.1275154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 10/26/2023] [Indexed: 12/01/2023] Open
Abstract
Ovarian cancer affects the female reproductive system and is the primary cause of cancer related mortality globally. The imprecise and non-specific nature of ovarian cancer symptoms often results in patients being diagnosed at an advanced stage, with metastatic lesions extending beyond the ovary. This presents a significant clinical challenge and imposes a substantial economic burden on both patients and society. Despite advancements in surgery, chemotherapy, and immunotherapy, the prognosis for most patients with ovarian cancer remains unsatisfactory. Therefore, the development of novel treatment strategies is imperative. Ferroptosis, a distinct form of regulated cell death, characterized by iron-dependent lipid peroxidation, differs from autophagy, apoptosis, and necrosis, and may hold promise as a novel cell death. Numerous studies have demonstrated the involvement of ferroptosis in various conventional signaling pathways and biological processes. Recent investigations have revealed the significant contribution of ferroptosis in the initiation, progression, and metastasis of diverse malignant tumors, including ovarian cancer. Moreover, ferroptosis exhibits a synergistic effect with chemotherapy, radiotherapy, and immunotherapy in restraining the proliferation of ovarian cancer cells. The aforementioned implies that ferroptosis holds considerable importance in the management of ovarian cancer and has the potential to serve as a novel therapeutic target. The present review provides a comprehensive overview of the salient features of ferroptosis, encompassing its underlying mechanisms and functional role in ovarian cancer, along with the associated signaling pathways and genes. Furthermore, the review highlights the prospective utility of ferroptosis in the treatment of ovarian cancer.
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Affiliation(s)
| | | | | | - Tianmin Xu
- The Second Hospital of Jilin University, Changchun, China
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Zhang Y, Guo M, Wang L, Weng S, Xu H, Ren Y, Liu L, Guo C, Cheng Q, Luo P, Zhang J, Han X. A tumor-infiltrating immune cells-related pseudogenes signature based on machine-learning predicts outcomes and immunotherapy responses in ovarian cancer. Cell Signal 2023; 111:110879. [PMID: 37659727 DOI: 10.1016/j.cellsig.2023.110879] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 08/09/2023] [Accepted: 08/30/2023] [Indexed: 09/04/2023]
Abstract
Previous researches have provided evidence for the significant involvement of pseudogenes in immune-related functions across different types of cancer. However, the mechanisms by which pseudogenes regulate immunity in ovarian cancer (OV) and their potential impact on clinical outcomes remain unclear. To address this gap in knowledge, our study utilized a novel computational framework to analyze a total of 491 samples from three public datasets. We employed a combination of 10 machine-learning algorithms to construct a signature known as the tumor-infiltrating immune cells-related pseudogenes signature (TIICPS). The TIICPS, consisting of 12 pseudogenes, demonstrated independent prognostic value for overall survival, surpassing conventional clinical traits, 62 published signatures, and TP53 and BRCA mutation status in three cohorts. Patients with low TIICPS exhibited heightened immune-related pathways, intricate genomic alterations, substantial immune infiltration, and greater potential for immunotherapy efficacy. Consequently, TIICPS holds promise as a predictive tool for prognosis and immunotherapy response in ovarian cancer.
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Affiliation(s)
- Yuyuan Zhang
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Interventional Institute of Zhengzhou University, Zhengzhou, Henan 450052, China; Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, Henan 450052, China
| | - Manman Guo
- Reproductive Medical Center, The First Affiliated Hospital of Zhengzhou University, Henan 450052, China
| | - Libo Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Siyuan Weng
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Interventional Institute of Zhengzhou University, Zhengzhou, Henan 450052, China; Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, Henan 450052, China
| | - Hui Xu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Interventional Institute of Zhengzhou University, Zhengzhou, Henan 450052, China; Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, Henan 450052, China
| | - Yuqing Ren
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Long Liu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Chunguang Guo
- Department of Endovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha 410000, China
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou 510000, China
| | - Jian Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou 510000, China
| | - Xinwei Han
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Interventional Institute of Zhengzhou University, Zhengzhou, Henan 450052, China; Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, Henan 450052, China.
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Song Z, Zhang J, Sun Y, Jiang Z, Liu X. Establishment and validation of an immune infiltration predictive model for ovarian cancer. BMC Med Genomics 2023; 16:227. [PMID: 37759229 PMCID: PMC10538244 DOI: 10.1186/s12920-023-01657-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
BACKGROUND The most prevalent mutation in ovarian cancer is the TP53 mutation, which impacts the development and prognosis of the disease. We looked at how the TP53 mutation associates the immunophenotype of ovarian cancer and the prognosis of the disease. METHODS We investigated the state of TP53 mutations and expression profiles in culturally diverse groups and datasets and developed an immune infiltration predictive model relying on immune-associated genes differently expressed between TP53 WT and TP53 MUT ovarian cancer cases. We aimed to construct an immune infiltration predictive model (IPM) to enhance the prognosis of ovarian cancer and investigate the impact of the IPM on the immunological microenvironment. RESULTS TP53 mutagenesis affected the expression of seventy-seven immune response-associated genes. An IPM was implemented and evaluated on ovarian cancer patients to distinguish individuals with low- and high-IPM subgroups of poor survival. For diagnostic and therapeutic use, a nomogram is thus created. According to pathway enrichment analysis, the pathways of the human immune response and immune function abnormalities were the most associated functions and pathways with the IPM genes. Furthermore, patients in the high-risk group showed low proportions of macrophages M1, activated NK cells, CD8+ T cells, and higher CTLA-4, PD-1, PD-L1, and TIM-3 than patients in the low-risk group. CONCLUSIONS The IPM model may identify high-risk patients and integrate other clinical parameters to predict their overall survival, suggesting it is a potential methodology for optimizing ovarian cancer prognosis.
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Affiliation(s)
- Zhenxia Song
- Department of Obstetrics, Qingdao women and childeren's hospital, #6 Tongfu Road, Shibei District, Qingdao, Shandong, 266000, P. R. China
| | - Jingwen Zhang
- Department of Obstetrics, Qingdao women and childeren's hospital, #6 Tongfu Road, Shibei District, Qingdao, Shandong, 266000, P. R. China
| | - Yue Sun
- Department of Obstetrics, Qingdao women and childeren's hospital, #6 Tongfu Road, Shibei District, Qingdao, Shandong, 266000, P. R. China
| | - Zhongmin Jiang
- Department of Pathology, Tian Jin Fifth's Central Hospital, #41 Zhejiang Road, Binhai District, Tianjin, 300450, P. R. China
| | - Xiaoning Liu
- Department of Obstetrics, Qingdao women and childeren's hospital, #6 Tongfu Road, Shibei District, Qingdao, Shandong, 266000, P. R. China.
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Zhu Y, Liang L, Li J, Zeng J, Yao H, Wu L. Establishing Molecular Subgroups of CD8+ T Cell-Associated Genes in the Ovarian Cancer Tumour Microenvironment and Predicting the Immunotherapy Response. Biomedicines 2023; 11:2399. [PMID: 37760841 PMCID: PMC10525231 DOI: 10.3390/biomedicines11092399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 08/04/2023] [Accepted: 08/24/2023] [Indexed: 09/29/2023] Open
Abstract
BACKGROUND The mechanism by which infiltrating CD8+ T lymphocytes in the tumour microenvironment influence the survival of patients with ovarian cancer (OC) remains unclear. METHODS To identify biomarkers to optimise OC treatment, 13 immune-cell-line-associated datasets, RNA sequencing data, and clinical data from the GEO, TCGA, and the ICGC were collected. Gene expression in OC was assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) staining. RESULTS We identified 520 genes and three immunological clusters (IC1, IC2, and IC3) associated with CD8+ T cells. Higher IFN scores, immune T cell lytic activity, and immune cell infiltration and upregulated expression of immune-checkpoint-related genes indicated that IC3 is more responsive to immunotherapy, whereas IC1 and IC2 have a poorer prognosis. A 10-gene signature, including SEMA4F, CX3CR1, STX7, PASK, AKIRIN2, HEMGN, GBP5, NSG1, and CXorf65, was constructed, and a multivariate Cox regression analysis revealed a significant association between the 10-gene signature-based risk model and overall survival (p < 0.001). A nomogram was constructed with age and the 10-gene signature. Consistent with the bioinformatics analysis, IHC and qRT-PCR confirmed the accuracy of the signatures in OC tissue samples. The predictive ability of the risk model was demonstrated using the Imvigor210 immunotherapy dataset. CONCLUSIONS The development of a novel gene signature associated with CD8+ T cells could facilitate more accurate prognostics and prediction of the immunotherapeutic response of patients with OC.
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Affiliation(s)
| | | | | | | | - Hongwen Yao
- Department of Gynecologic Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Lingying Wu
- Department of Gynecologic Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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Wang C, Zhang C, Yang S, Xiang J, Zhou D, Xi X. Identification and validation of m5c-related lncRNA risk model for ovarian cancer. J Ovarian Res 2023; 16:96. [PMID: 37183262 PMCID: PMC10184408 DOI: 10.1186/s13048-023-01182-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 05/05/2023] [Indexed: 05/16/2023] Open
Abstract
Ovarian cancer (OC) is one of the common malignant tumors that seriously threaten women's health, and there is a lack of clinical prognostic predictors, while m5c and lncRNA have been shown to be predictive of multiple cancers, including OC. Therefore, our goal was to construct a risk model for OC based on m5c-related lncRNA.340 m5c-related lncRNA were identified and a novel risk model of OC ground on nine m5C-related lncRNA was constructed using LASSO-COX regression analysis. Kaplan-Meier analysis showed there was a significant difference in prognosis between risk groups. We established a nomogram which was a good predictor of overall survival. In addition, GSEA was enriched in multiple pathways and immune function analysis suggested that immune infiltration varies depending on the risk group. In vitro experiments show that AC005562.1, a key lncRNA of the risk model, is highly expressed in OC cells and promotes OC cell proliferation. Finally, we further explored the potential biological markers of m5c-related lncRNA in OC with WGCNA analysis and established a ceRNA network. In conclusion,we have developed a reliable m5c-related prediction model and performed systematic validation and exploration of various aspects. These results can be used for the assessment of OC prognosis and the discovery of novel biomarkers.
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Affiliation(s)
- Chong Wang
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chunxiao Zhang
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shimin Yang
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiangdong Xiang
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dongmei Zhou
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaowei Xi
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Felices M, Wesley E, Bendzick LE, Kodal B, Hopps R, Grzywacz B, Hinderlie P, Miller JS, Geller MA. Reverse Translation Identifies the Synergistic Role of Immune Checkpoint Blockade and IL15 to Enhance Immunotherapy of Ovarian Cancer. Cancer Immunol Res 2023; 11:674-686. [PMID: 36807510 PMCID: PMC10155036 DOI: 10.1158/2326-6066.cir-22-0600] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 12/02/2022] [Accepted: 02/14/2023] [Indexed: 02/22/2023]
Abstract
Immune checkpoint blockade (ICB) has changed the standard of care for many patients with cancer, yet no ICB is approved for ovarian cancer. We hypothesized that maintenance therapy with an IL15 "superagonist" (N-803) and ICB in combination could induce potent immune activation in ovarian cancer. Using flow cytometry, cytometry by time of flight analysis, and cytotoxicity assays, we analyzed patient samples from women with advanced epithelial ovarian cancer treated with N-803 for indications of PD-1/PD-L1 upregulation with this treatment. In addition, ICB and N-803 were evaluated in preclinical studies to determine the functional impact of combination therapy on natural killer (NK) cells in vitro and in vivo. We observed that N-803 stimulated initial NK-cell expansion in patient samples; however, proliferation was not sustained beyond 2 weeks despite continued treatment. This result was reverse translated back to the laboratory to determine the functional relevance of this finding. The addition of ICB with an antibody-dependent cellular cytotoxicity IgG1 antibody against PD-L1 (avelumab) or an IgG4 antibody against PD-1 (pembrolizumab) enhanced N-803 induced NK-cell function in vitro. Using models of human ovarian cancer and NK-cell adoptive transfer in mice, we showed enhanced antitumor control with N-803 and ICB, as well as a combination effect that enhanced NK-cell persistence and expansion in vivo. This work suggests that PD-1/PD-L1 blockade combined with IL15 signaling may overcome resistance to cytokine therapy in ovarian cancer.
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Affiliation(s)
- Martin Felices
- Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, Minnesota
| | - Erin Wesley
- Department of Obstetrics, Gynecology, and Women's Health, University of Minnesota, Minneapolis, Minnesota
| | - Laura E. Bendzick
- Department of Obstetrics, Gynecology, and Women's Health, University of Minnesota, Minneapolis, Minnesota
| | - Behiye Kodal
- Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, Minnesota
| | - Rachel Hopps
- Department of Obstetrics, Gynecology, and Women's Health, University of Minnesota, Minneapolis, Minnesota
| | - Bartosz Grzywacz
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota
| | - Peter Hinderlie
- Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, Minnesota
| | - Jeffrey S. Miller
- Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, Minnesota
| | - Melissa A. Geller
- Department of Obstetrics, Gynecology, and Women's Health, University of Minnesota, Minneapolis, Minnesota
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Zhang W, Ling Y, Li Z, Peng X, Ren Y. Peripheral and tumor-infiltrating immune cells are correlated with patient outcomes in ovarian cancer. Cancer Med 2023; 12:10045-10061. [PMID: 36645174 PMCID: PMC10166954 DOI: 10.1002/cam4.5590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 11/19/2022] [Accepted: 12/21/2022] [Indexed: 01/17/2023] Open
Abstract
OBJECTIVE At present, there is still a lack of reliable biomarkers for ovarian cancer (OC) to guide prognosis prediction and accurately evaluate the dominant population of immunotherapy. In recent years, the relationship between peripheral blood markers and tumor-infiltrating immune cells (TICs) with cancer has attracted much attention. However, the relationship between the survival of OC patients and intratumoral- or extratumoral-associated immune cells remains controversial. METHODS In this study, four machine-learning algorithms were used to predict overall survival in OC patients based on peripheral blood indicators. To further screen out immune-related gene and molecular targets, we systematically explored the correlation between TICs and OC patient survival based on The Cancer Genome Atlas database. Using the TICs score method, patients were divided into a low immune infiltrating cell group and a high immune infiltrating cell group. RESULTS The results showed that there was a significant statistical significance between the peripheral blood indicators and the survival prognosis of OC patients. Survival analysis showed that TICs play a crucial role in the survival of OC patients. Four core genes, CXCL9, CD79A, MS4A1, and MZB1, were identified by cross-PPI and COX regression analysis. Further analysis found that these genes were significantly associated with both TICs and survival in OC patients. CONCLUSIONS These results suggest that both peripheral blood markers and TICs can be used as prognostic predictors in patients with OC, and CXCL9, CD79A, MS4A1, and MZB1 may be potential therapeutic targets for OC immunotherapy.
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Affiliation(s)
- Weiwei Zhang
- Department of Biotherapy and National Clinical Research Center for Geriatrics, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.,Department of Oncology, Cancer Prevention and Treatment Institute of Chengdu, Chengdu Fifth People's Hospital (The Second Clinical Medical College, Affiliated Fifth People's Hospital of Chengdu University of Traditional Chinese Medicine), Chengdu, China
| | - Yawen Ling
- School of Computer Science and Engineering, Shenzhen Institute for Advanced Study, University of Electronic Science and Technology of China, Chengdu, China
| | - Zhidong Li
- School of Computer Science and Engineering, Shenzhen Institute for Advanced Study, University of Electronic Science and Technology of China, Chengdu, China
| | - Xingchen Peng
- Department of Biotherapy and National Clinical Research Center for Geriatrics, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yazhou Ren
- School of Computer Science and Engineering, Shenzhen Institute for Advanced Study, University of Electronic Science and Technology of China, Chengdu, China
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11
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Singla RK, Sharma P, Kumar D, Gautam RK, Goyal R, Tsagkaris C, Dubey AK, Bansal H, Sharma R, Shen B. The role of nanomaterials in enhancing natural product translational potential and modulating endoplasmic reticulum stress in the treatment of ovarian cancer. Front Pharmacol 2022; 13:987088. [PMID: 36386196 PMCID: PMC9643842 DOI: 10.3389/fphar.2022.987088] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 10/03/2022] [Indexed: 10/21/2023] Open
Abstract
Ovarian cancer, and particularly its most frequent type, epithelial ovarian carcinoma, constitutes one of the most dangerous malignant tumors among females. Substantial evidence has described the potential of phytochemicals against ovarian cancer. The effect of natural compounds on endoplasmic reticulum (ER) stress is of great relevance in this regard. In ovarian cancer, the accumulation of misfolded proteins in the ER lumen results in decompensated ER stress. This leads to deregulation in the physiological processes for the posttranslational modification of proteins, jeopardizes cellular homeostasis, and increases apoptotic signaling. Several metabolites and metabolite extracts of phytochemical origin have been studied in the context of ER stress in ovarian cancer. Resveratrol, quercetin, curcumin, fucosterol, cleistopholine, fucoidan, and epicatechin gallate, among others, have shown inhibitory potential against ER stress. The chemical structure of each compound plays an important role concerning its pharmacodynamics, pharmacokinetics, and overall effectiveness. Studying and cross-comparing the chemical features that render different phytochemicals effective in eliciting particular anti-ER stress actions can help improve drug design or develop multipotent combination regimens. Many studies have also investigated the properties of formulations such as nanoparticles, niosomes, liposomes, and intravenous hydrogel based on curcumin and quercetin along with some other phytomolecules in ovarian cancer. Overall, the potential of phytochemicals in targeting genetic mechanisms of ovarian cancer warrants further translational and clinical investigation.
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Affiliation(s)
- Rajeev K. Singla
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Pooja Sharma
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India
- Khalsa College of Pharmacy, Amritsar, India
| | - Dinesh Kumar
- Chitkara University School of Pharmacy, Chitkara University, Himachal Pradesh, India
| | - Rupesh K. Gautam
- Department of Pharmacology, Indore Institute of Pharmacy, IIST Campus, Opposite IIM Indore, Indore, India
| | - Rajat Goyal
- MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, India
| | | | | | - Himangini Bansal
- Delhi Institute of Pharmaceutical Sciences and Research, New Delhi, India
| | - Rohit Sharma
- Department of Rasa Shastra and Bhaishajya Kalpana, Faculty of Ayurveda, Institute of Medical Sciences, BHU, Varanasi, India
| | - Bairong Shen
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
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12
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Li H, Liu ZY, Chen YC, Zhang XY, Wu N, Wang J. Identification and validation of an immune-related lncRNAs signature to predict the overall survival of ovarian cancer. Front Oncol 2022; 12:999654. [PMID: 36313727 PMCID: PMC9596922 DOI: 10.3389/fonc.2022.999654] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 09/27/2022] [Indexed: 12/23/2022] Open
Abstract
Ovarian cancer (OC) is the most lethal gynecological cancer in women. Studies had reported that immune-related lncRNAs signatures were valuable in predicting the survival and prognosis of patients with various cancers. In our study, the prognostic value of immune-related lncRNAs was investigated in OC patients from TCGA-RNA-seq cohort (n=378) and HG-U133_Plus_2 cohort (n=590), respectively. Pearson correlation analysis was implemented to screen the immune-related lncRNA and then univariate Cox regression analysis was performed to explore their prognostic value in OC patients. Five prognostic immune-related lncRNAs were identified as prognostic lncRNAs. Besides, they were inputted into a LASSO Cox regression to establish and validate an immune-related lncRNA prognostic signature in TCGA-RNA-Seq cohort and HG-U133_Plus_2 cohort, respectively. Based on the best cut-off value of risk score, patients were divided into high- and low-risk groups. Survival analysis suggested that patients in the high-risk group had a worse overall survival (OS) than those in the low-risk group in both cohorts. The association between clinicopathological feathers and risk score was then evaluated by using stratification analysis. Moreover, we constructed a nomogram based on risk score, age and stage, which had a strong ability to forecast the OS of the OC patients. The influence of risk score on immune infiltration and immunotherapy response were assessed and the results suggested that patients with high-risk score might recruit multiple immune cells and stromal cells, leading to facilitating immune surveillance evasive. Ultimately, we demonstrated that the risk model was associated with chemotherapy response of multiple antitumor drugs, especially for paclitaxel, metformin and veliparib, which are commonly used in treating OC patients. In conclusion, we constructed a novel immune-related lncRNA signature, which had a potential prognostic value for OC patients and might facilitate personalized counselling for immunotherapy and chemotherapy.
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Affiliation(s)
- He Li
- The Animal Laboratory Center, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- The Central Laboratory, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Zhao-Yi Liu
- The Central Laboratory, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Yong-Chang Chen
- The Central Laboratory, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Xiao-Ye Zhang
- The Central Laboratory, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Nayiyuan Wu
- The Central Laboratory, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- *Correspondence: Jing Wang, ; Nayiyuan Wu,
| | - Jing Wang
- The Central Laboratory, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- Department of Gynecologic Cancer, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- *Correspondence: Jing Wang, ; Nayiyuan Wu,
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13
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Dong M, Qian M, Ruan Z. CUL3/SPOP complex prevents immune escape and enhances chemotherapy sensitivity of ovarian cancer cells through degradation of PD-L1 protein. J Immunother Cancer 2022; 10:e005270. [PMID: 36198437 PMCID: PMC9535172 DOI: 10.1136/jitc-2022-005270] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/07/2022] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Cancer immune escape is a main obstacle in designing effective anticancer therapeutic approaches. Our work was aimed to explore the function of cullin 3 (CUL3) in ovarian cancer cell immune escape and chemosensitivity. METHOD Gain and loss of function assays were conducted to investigate the interactions among CUL3, speckle type POZ protein (SPOP) and programmed death ligand-1 (PD-L1) as well as their effects on ovarian cell malignant phenotypes and chemosensitivity. A mouse model of xenografted ovarian cells was further established for in vivo substantiation. RESULT Poorly-expressed CUL3 and SPOP were found in ovarian cancer. Overexpression of CUL3 reduced malignant features as well as immune escape of ovarian cancer cells but enhanced chemosensitivity. Functionally, CUL3 degraded PD-L1 protein by forming complex with SPOP. Overexpression of CUL3 inhibited tumor formation and enhanced chemosensitivity of ovarian cancer cells in mice by degrading PD-L1 protein. CONCLUSION All in all, CUL3/SPOP formed a complex to promote PD-L1 degradation to inhibit ovarian cancer cell immune escape and increase chemosensitivity, offering a therapeutic target for ovarian cancer treatment.
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Affiliation(s)
- Min Dong
- Department of Obstetrics and Gynecology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Qian
- Department of Obstetrics and Gynecology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhengyi Ruan
- Department of Obstetrics and Gynecology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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14
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Fanale D, Dimino A, Pedone E, Brando C, Corsini LR, Filorizzo C, Fiorino A, Lisanti MC, Magrin L, Randazzo U, Bazan Russo TD, Russo A, Bazan V. Prognostic and Predictive Role of Tumor-Infiltrating Lymphocytes (TILs) in Ovarian Cancer. Cancers (Basel) 2022; 14:4344. [PMID: 36139508 PMCID: PMC9497073 DOI: 10.3390/cancers14184344] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/02/2022] [Accepted: 09/02/2022] [Indexed: 12/12/2022] Open
Abstract
In the last decade, tumor-infiltrating lymphocytes (TILs) have been recognized as clinically relevant prognostic markers for improved survival, providing the immunological basis for the development of new therapeutic strategies and showing a significant prognostic and predictive role in several malignancies, including ovarian cancer (OC). In fact, many OCs show TILs whose typology and degree of infiltration have been shown to be strongly correlated with prognosis and survival. The OC histological subtype with the higher presence of TILs is the high-grade serous carcinoma (HGSC) followed by the endometrioid subtype, whereas mucinous and clear cell OCs seem to contain a lower percentage of TILs. The abundant presence of TILs in OC suggests an immunogenic potential for this tumor. Despite the high immunogenic potential, OC has been described as a highly immunosuppressive tumor with a high expression of PD1 by TILs. Although further studies are needed to better define their role in prognostic stratification and the therapeutic implication, intraepithelial TILs represent a relevant prognostic factor to take into account in OC. In this review, we will discuss the promising role of TILs as markers which are able to reflect the anticancer immune response, describing their potential capability to predict prognosis and therapy response in OC.
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Affiliation(s)
- Daniele Fanale
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Alessandra Dimino
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Erika Pedone
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Chiara Brando
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Lidia Rita Corsini
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Clarissa Filorizzo
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Alessia Fiorino
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Maria Chiara Lisanti
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Luigi Magrin
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Ugo Randazzo
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Tancredi Didier Bazan Russo
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Antonio Russo
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Viviana Bazan
- Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy
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15
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Rocconi RP, Stanbery L, Tang M, Madeira da Silva L, Walter A, Monk BJ, Herzog TJ, Coleman RL, Manning L, Wallraven G, Horvath S, Bognar E, Senzer N, Brun S, Nemunaitis J. ENTPD1/CD39 as a predictive marker of treatment response to gemogenovatucel-T as maintenance therapy in newly diagnosed ovarian cancer. COMMUNICATIONS MEDICINE 2022; 2:106. [PMID: 36051466 PMCID: PMC9424215 DOI: 10.1038/s43856-022-00163-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 07/26/2022] [Indexed: 11/09/2022] Open
Abstract
Background Broadened use of predictive molecular and phenotypic profiling amongst oncologists has facilitated optimal integration of targeted- and immuno-therapeutics into clinical care. However, the use of predictive immunomarkers in ovarian cancer (OC) has not consistently translated into clinical benefit. Vigil (gemogenovatucel-T) is a novel plasmid engineered autologous tumor cell immunotherapy designed to knock down the tumor suppressor cytokines, TGFβ1 and TGFβ2, augment local immune function via increased GMCSF expression and enhance presentation of clonal neoantigen epitopes. Methods: All patients enrolled in the VITAL trial (NCT02346747) of maintenance Vigil vs. placebo as front-line therapy with homologous recombination proficient (HRP) stage IIIB-IV newly diagnosed ovarian cancer underwent NanoString gene expression analysis. Tissue was obtained from surgically resected ovarian tumor tissue following surgical debulking. A statistical algorithm was used to analyze the NanoString gene expression data. Results Using the NanoString Statistical Algorithm (NSA), we identify high expression of ENTPD1/CD39 (which functions as the rate-limiting step in the production of the immune suppressor adenosine from ATP to ADP) as a presumptive predictor of response to Vigil versus placebo regardless of HRP status on the basis of relapse free survival (median not achieved vs 8.1 months, p = 0.00007) and overall survival (median not achieved vs 41.4 months, p = 0.013) extension. Conclusion NSA should be considered for application to investigational targeted therapies in order to identify populations most likely to benefit from treatment, in preparation for efficacy conclusive trials.
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Affiliation(s)
- Rodney P. Rocconi
- University of Alabama at Birmingham, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Mobile, USA
| | | | - Min Tang
- Stat-Beyond Consulting, Irvine, USA
| | - Luciana Madeira da Silva
- Mitchell Cancer Institute, Division of Gynecologic Oncology, University of South Alabama, Mobile, USA
| | - Adam Walter
- Gradalis, Inc, Carrollton, USA
- Promedica, Toledo, USA
| | - Bradley J. Monk
- Arizona Oncology, (US Oncology Network), University of Arizona, Creighton University, Phoenix, USA
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Son J, George GC, Nardo M, Krause KJ, Jazaeri AA, Biter AB, Hong DS. Adoptive cell therapy in gynecologic cancers: A systematic review and meta-analysis. Gynecol Oncol 2022; 165:664-670. [PMID: 35400527 PMCID: PMC9133136 DOI: 10.1016/j.ygyno.2022.03.013] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 03/12/2022] [Accepted: 03/14/2022] [Indexed: 11/25/2022]
Abstract
Adoptive cell therapy (ACT) has shown promise in hematologic and solid tumors. While data supports immunogenicity of gynecologic cancers, the benefit of ACT is not yet clear. To address this question, we performed a comprehensive systematic review and meta-analysis. Eligible studies included those reporting oncologic response or toxicity data in at least one patient with any gynecologic cancer treated with ACT. Chi-square test and multivariable logistic regression were performed to identify predictors of response. We retrieved 281 articles, and 28 studies met our inclusion criteria. These comprised of 401 patients including 238 patients with gynecologic cancers (61.8% ovarian, 34.0% cervical, 2.9% endometrial, and 1.2% other). In patients with gynecologic cancers, response rates to ACT were 8.1% complete response, 18.2% partial response, and 31.4% stable disease, for an objective response rate (ORR) of 26.3%, disease control rate (DCR) of 57.6%, and median response duration of 5.5 months. Patients in studies reporting ≤1 median line of prior therapy had a higher ORR (52.9% vs. 22.6% for >1, p < 0.001), although DCR in the >1 group was still 53.2%. ORRs by ACT type were tumor infiltrating lymphocytes (TIL) 41.4%, natural killer cells 26.7%, peripheral autologous T-cells 18.4%, T-cell receptor-modified T-cells 15.4%, and chimeric antigen receptor T-cells 9.5% (p = 0.001). ORR was significantly improved with inclusion of lymphodepletion (34.8% vs. 15.4% without, p = 0.001). On multivariable analysis controlling for cancer type and lymphodepletion, TIL therapy was predictive of objective response (odds ratio 2.6, p = 0.011). The rate of grade 3 or 4 toxicity was 46.0%. All grade adverse events included fever, hypotension, dyspnea, confusion, hematologic changes, nausea/vomiting, fatigue, and diarrhea. In conclusion, ACT is a promising treatment modality in gynecologic cancer. We observed a particular benefit of TIL therapy and suggest inclusion of lymphodepletion in future trials.
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Affiliation(s)
- Ji Son
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Goldy C George
- Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mirella Nardo
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kate J Krause
- Research Medical Library, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Amir A Jazaeri
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Amadeo B Biter
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - David S Hong
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Systematic Construction and Validation of an Immune-Related Gene-Based Model to Predict Prognosis for Ovarian Cancer. BIOMED RESEARCH INTERNATIONAL 2022; 2022:7356992. [PMID: 35496047 PMCID: PMC9050317 DOI: 10.1155/2022/7356992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 03/14/2022] [Indexed: 11/25/2022]
Abstract
Ovarian cancer (OC) is a malignancy with poor prognosis, stubborn resistance, and frequent recurrence. Recently, it has been widely recognized that immune-related genes (IRGs) have demonstrated their indispensable importance in the occurrence and progression of OC. Given this, this study aimed to identify IRGs with predictive value and build a prognostic model for a more accurate assessment. First, we obtained transcriptome and clinical information of ovarian samples from both TCGA and GTEx databases. After integration, we figured out 10 genes as immune-related prognostic genes (IRPGs) by performing the univariate Cox regression analysis. Subsequently, we established a TF-associated network to investigate its internal mechanism. The prognosis model consisting of 5 IRPGs was constructed later by lasso regression analysis. The comparison of the score with the clinical factors validated its independence and superiority in OC's prognosis. Moreover, the association between the signature and immune cell infiltration demonstrated its ability to image the immune situation of the tumor microenvironment. Finally, the reliability of the risk model was confirmed by the GEO cohort. Together, our study has constructed an independent prognostic model for OC, which may deepen the understanding of the immune microenvironment and help present novel biomarkers or ideas for targeted therapy.
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18
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Xie B, Tan G, Ren J, Lu W, Pervaz S, Ren X, Otoo AA, Tang J, Li F, Wang Y, Wang M. RB1 Is an Immune-Related Prognostic Biomarker for Ovarian Cancer. Front Oncol 2022; 12:830908. [PMID: 35299734 PMCID: PMC8920998 DOI: 10.3389/fonc.2022.830908] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 02/03/2022] [Indexed: 01/06/2023] Open
Abstract
Background Ovarian cancer (OC) is one of the most lethal gynecologic malignancies and a leading cause of death in the world. Thus, this necessitates identification of prognostic biomarkers which will be helpful in its treatment. Methods The gene expression profiles from The Cancer Genome Atlas (TCGA) and GSE31245 were selected as the training cohort and validation cohort, respectively. The Kaplan–Meier (KM) survival analysis was used to analyze the difference in overall survival (OS) between high and low RB transcriptional corepressor 1 (RB1) expression groups. To confirm whether RB1 was an independent risk factor for OC, we constructed a multivariate Cox regression model. Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analyses were conducted to identify the functions of differentially expressed genes (DEGs). The associations of RB1 with immune infiltration and immune checkpoints were studied by the Tumor Immune Estimation Resource (TIMER 2.0) and the Gene Expression Profiling Interactive Analysis (GEPIA). The immunohistochemistry (IHC) was performed to compare the expression level of RB1 in normal tissues and tumor samples, and to predict the prognosis of OC. Results The KM survival curve of the TCGA indicated that the OS in the high-risk group was lower than that in the low-risk group (HR = 1.61, 95% CI: 1.28-2.02, P = 3×10-5), which was validated in GSE31245 (HR = 4.08, 95% CI: 1.21–13.74, P = 0.01) and IHC. Multivariate Cox regression analysis revealed that RB1 was an independent prognostic biomarker (HR = 1.66, 95% CI: 1.31-2.10, P = 2.02×10-5). Enrichment analysis suggested that the DEGs were mainly involved in cell cycle, DNA replication, and mitochondrial transition. The infiltration levels of fibroblast, neutrophil, monocyte and macrophage were positively correlated with RB1. Furthermore, RB1 was associated with immune checkpoint molecules (CTLA4, LAG3, and CD274). The IHC staining revealed higher expression of RB1 in tumor tissues as compared to that in normal tissues (P = 0.019). Overexpression of RB1 was associated with poor prognosis of OC (P = 0.01). Conclusion These findings suggest that RB1 was a novel and immune-related prognostic biomarker for OC, which may be a promising target for OC treatment.
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Affiliation(s)
- Biao Xie
- Department of Biostatistics, School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Guangqing Tan
- Department of Physiology, School of Basic Medical Science, Chongqing Medical University, Chongqing, China
| | - Jingyi Ren
- Department of Physiology, School of Basic Medical Science, Chongqing Medical University, Chongqing, China
| | - Weiyu Lu
- Department of Physiology, School of Basic Medical Science, Chongqing Medical University, Chongqing, China
| | - Sadaf Pervaz
- Joint International Research Laboratory of Reproduction and Development of the Ministry of Education of China, School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Xinyi Ren
- Department of Physiology, School of Basic Medical Science, Chongqing Medical University, Chongqing, China
| | - Antonia Adwoa Otoo
- Joint International Research Laboratory of Reproduction and Development of the Ministry of Education of China, School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Jing Tang
- Department of Bioinformatics, School of Basic Medical Science, Chongqing Medical University, Chongqing, China
| | - Fangfang Li
- Joint International Research Laboratory of Reproduction and Development of the Ministry of Education of China, School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Yingxiong Wang
- Joint International Research Laboratory of Reproduction and Development of the Ministry of Education of China, School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Meijiao Wang
- Department of Physiology, School of Basic Medical Science, Chongqing Medical University, Chongqing, China.,Joint International Research Laboratory of Reproduction and Development of the Ministry of Education of China, School of Public Health and Management, Chongqing Medical University, Chongqing, China
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19
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Liu T, Shen J, He Q, Xu S. Identification of a Novel Immune-Related lncRNA CTD-2288O8.1 Regulating Cisplatin Resistance in Ovarian Cancer Based on Integrated Analysis. Front Genet 2022; 13:814291. [PMID: 35237300 PMCID: PMC8884246 DOI: 10.3389/fgene.2022.814291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 01/17/2022] [Indexed: 11/13/2022] Open
Abstract
Ovarian cancer (OC) is the most lethal gynecological malignancy, in which chemoresistance is a crucial factor leading to the poor prognosis. Recently, immunotherapy has brought new light for the treatment of solid tumors. Hence, as a kind of immunologically active cancer, it is reasonably necessary to explore the potential mechanism between immune characteristics and cisplatin resistance in OC. Our study focused on the important role of cisplatin resistance-related lncRNAs on mediating the OC tumor immune microenvironment (TIME) using an integrative analysis based on the Cancer Genome Atlas (TCGA) database. First, the cisplatin resistance-related differentially expressed lncRNAs (DELs) and mRNAs (DEMs) were preliminarily screened to construct a DEL–DEM co-expression network. Next, the protein–protein interaction (PPI) network and pivot analysis were performed to reveal the relevance of these lncRNAs with tumor immune response. Second, the novel lncRNA CTD-2288O8.1 was identified as a key gene for the OC cisplatin resistance formation by qRT-PCR and survival analysis. Gain- and loss-of-function assays (Cell Counting Kit-8 (CCK-8) assay, wound-healing scratch assay, transwell assay, and colony formation assay) further verified the activity of CTD-2288O8.1 in OC progression as well. Third, gene set enrichment analysis (GSEA) was applied along with the correlation analyses of CTD-2288O8.1 with ImmuneScore, tumor-infiltrating immune cells (TICs), and immune inhibitory checkpoint molecules, illustrating that CTD-2288O8.1 was strongly associated with the TIME and has the potential to predict the effect of OC immunotherapy. In addition, basic experiments demonstrated that the expression of CTD-2288O8.1 impacted the EGFR/AKT signal pathway activity of OC tumor cells. Of greater significance, it promoted the M2 polarization of macrophage, which is a type of the most important components of the TIME in solid tumor. Taking together, our study revealed cisplatin resistance-related lncRNAs closely linked with tumor immunity in OC, underscoring the potential mechanism of the TIME in conferring cisplatin resistance, which provided the research basis for further clinical treatment. CTD-2288O8.1 was identified to mediate cisplatin resistance and affect the response of immunotherapy, which could serve as a promising biomarker for guiding clinical treatment and improving prognosis in OC.
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Affiliation(s)
- Tingwei Liu
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jiacheng Shen
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Qizhi He
- Department of Pathology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
- *Correspondence: Qizhi He, ; Shaohua Xu,
| | - Shaohua Xu
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
- *Correspondence: Qizhi He, ; Shaohua Xu,
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20
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Zhang ZC, Guo JN, Zhang N, Wang ZQ, Lou G, Cui BB, Yang C. Identification and Validation of Immune-Related Gene for Predicting Prognosis and Therapeutic Response in Ovarian Cancer. Front Immunol 2021; 12:763791. [PMID: 34880862 PMCID: PMC8645858 DOI: 10.3389/fimmu.2021.763791] [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: 08/24/2021] [Accepted: 11/01/2021] [Indexed: 11/13/2022] Open
Abstract
Ovarian cancer (OC) is a devastating malignancy with a poor prognosis. The complex tumor immune microenvironment results in only a small number of patients benefiting from immunotherapy. To explore the different factors that lead to immune invasion and determine prognosis and response to immune checkpoint inhibitors (ICIs), we established a prognostic risk scoring model (PRSM) with differential expression of immune-related genes (IRGs) to identify key prognostic IRGs. Patients were divided into high-risk and low-risk groups according to their immune and stromal scores. We used a bioinformatics method to identify four key IRGs that had differences in expression between the two groups and affected prognosis. We evaluated the sensitivity of treatment from three aspects, namely chemotherapy, targeted inhibitors (TIs), and immunotherapy, to evaluate the value of prediction models and key prognostic IRGs in the clinical treatment of OC. Univariate and multivariate Cox regression analyses revealed that these four key IRGs were independent prognostic factors of overall survival in OC patients. In the high-risk group comprising four genes, macrophage M0 cells, macrophage M2 cells, and regulatory T cells, observed to be associated with poor overall survival in our study, were higher. The high-risk group had a high immunophenoscore, indicating a better response to ICIs. Taken together, we constructed a PRSM and identified four key prognostic IRGs for predicting survival and response to ICIs. Finally, the expression of these key genes in OC was evaluated using RT-qPCR. Thus, these genes provide a novel predictive biomarker for immunotherapy and immunomodulation.
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Affiliation(s)
- Zhao-Cong Zhang
- Department of Gynecology Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Jun-Nan Guo
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Ning Zhang
- Department of Gynecology Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Zhi-Qiang Wang
- Department of Gynecology Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Ge Lou
- Department of Gynecology Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Bin-Bin Cui
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Chang Yang
- Department of Gynecology Oncology, Harbin Medical University Cancer Hospital, Harbin, China
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21
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Shen J, Liu T, Lv J, Xu S. Identification of an Immune-Related Prognostic Gene CLEC5A Based on Immune Microenvironment and Risk Modeling of Ovarian Cancer. Front Cell Dev Biol 2021; 9:746932. [PMID: 34712666 PMCID: PMC8547616 DOI: 10.3389/fcell.2021.746932] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Accepted: 09/16/2021] [Indexed: 12/31/2022] Open
Abstract
Objective: To understand the immune characteristics of the ovarian cancer (OC) microenvironment and explore the differences of immune-related molecules and cells to establish an effective risk model and identify the molecules that significantly affected the immune response of OC, to help guide the diagnosis. Methods: First, we calculate the TMEscore which reflects the immune microenvironment, and then analyze the molecular differences between patients with different immune characteristics, and determine the prognostic genes. Then, the risk model was established by least absolute shrinkage and selection operator (LASSO) analysis and combined with clinical data into a nomogram for diagnosis and prediction. Subsequently, the potential gene CLEC5A influencing the immune response of OC was identified from the prognostic genes by integrative immune-stromal analysis. The genomic alteration was explored based on copy number variant (CNV) and somatic mutation data. Results: TMEscore was a prognostic indicator of OC. The prognosis of patients with high TMEscore was better. The risk model based on immune characteristics was a reliable index to predict the prognosis of patients, and the nomogram could comprehensively evaluate the prognosis of patients. Besides, CLEC5A was closely related to the abundance of immune cells, immune response, and the expression of immune checkpoints in the OC microenvironment. OC cells with high expression of CLEC5A increased the polarization of M2 macrophages. CLEC5A expression was significantly associated with TTN and CDK12 mutations and affected the copy number of tumor progression and immune-related genes. Conclusion: The study of immune characteristics in the OC microenvironment and the risk model can reveal the factors affecting the prognosis and guide the clinical hierarchical treatment. CLEC5A can be used as a potential key gene affecting the immune microenvironment remodeling of OC, which provides a new perspective for improving the effect of OC immunotherapy.
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Affiliation(s)
- Jiacheng Shen
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Tingwei Liu
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jia Lv
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Shaohua Xu
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
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22
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Li Y, Wang J, Wang F, Gao C, Cao Y, Wang J. Development and Verification of an Autophagy-Related lncRNA Signature to Predict Clinical Outcomes and Therapeutic Responses in Ovarian Cancer. Front Med (Lausanne) 2021; 8:715250. [PMID: 34671615 PMCID: PMC8521014 DOI: 10.3389/fmed.2021.715250] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 08/30/2021] [Indexed: 12/13/2022] Open
Abstract
Objective: Long noncoding RNAs (lncRNAs) are key regulators during ovarian cancer initiation and progression and are involved in mediating autophagy. In this study, we aimed to develop a prognostic autophagy-related lncRNA signature for ovarian cancer. Methods: Autophagy-related abnormally expressed lncRNAs were screened in ovarian cancer with the criteria values of |correlation coefficient| > 0.4 and p < 0.001. Based on them, a prognostic lncRNA signature was established. The Kaplan–Meier overall survival analysis was conducted in high- and low-risk samples in the training, verification, and entire sets, followed by receiver operating characteristics (ROCs) of 7-year survival. Multivariate Cox regression analysis was used for assessing the predictive independency of this signature after adjusting other clinical features. The associations between the risk scores and immune cell infiltration, PD-L1 expression, and sensitivity of chemotherapy drugs were assessed in ovarian cancer. Results: A total of 66 autophagy-related abnormally expressed lncRNAs were identified in ovarian cancer. An autophagy-related lncRNA signature was constructed for ovarian cancer. High-risk scores were indicative of poorer prognosis compared with the low-risk scores in the training, verification, and entire sets. ROCs of 7-year survival confirmed the well-predictive efficacy of this model. Following multivariate Cox regression analysis, this model was an independent prognostic factor. There were distinct differences in infiltrations of immune cells, PD-L1 expression, and sensitivity of chemotherapy drugs between high- and low-risk samples. Conclusions: This study constructed an autophagy-related lncRNA signature that was capable of predicting clinical outcomes and also therapeutic responses for ovarian cancer.
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Affiliation(s)
- Yan Li
- Department of Obstetrics and Gynecology, The Yancheng Clinical College of Xuzhou Medical University, The First People's Hospital of Yancheng, Yancheng, China
| | - Juan Wang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Fang Wang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Chengzhen Gao
- Department of Obstetrics and Gynecology, The Yancheng Clinical College of Xuzhou Medical University, The First People's Hospital of Yancheng, Yancheng, China
| | - Yuanyuan Cao
- Department of Obstetrics and Gynecology, The Yancheng Clinical College of Xuzhou Medical University, The First People's Hospital of Yancheng, Yancheng, China
| | - Jianhua Wang
- Department of Gastroenterology, The Yancheng Clinical College of Xuzhou Medical University, The First People's Hospital of Yancheng, Yancheng, China
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23
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Lee E, Szvetecz S, Polli R, Grauel A, Chen J, Judge J, Jaiswal S, Maeda R, Schwartz S, Voedisch B, Piksa M, Japutra C, Sadhasivam L, Wang Y, Carrion A, Isim S, Liang J, Nicholson T, Lei H, Fang Q, Steinkrauss M, Walker D, Wagner J, Cremasco V, Wang HQ, Galli GG, Granda B, Mansfield K, Simmons Q, Nguyen AA, Vincent Jordan N. PAX8 lineage-driven T cell engaging antibody for the treatment of high-grade serous ovarian cancer. Sci Rep 2021; 11:14841. [PMID: 34290299 PMCID: PMC8295318 DOI: 10.1038/s41598-021-93992-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 07/05/2021] [Indexed: 12/03/2022] Open
Abstract
High-grade serous ovarian cancers (HGSOC) represent the most common subtype of ovarian malignancies. Due to the frequency of late-stage diagnosis and high rates of recurrence following standard of care treatments, novel therapies are needed to promote durable responses. We investigated the anti-tumor activity of CD3 T cell engaging bispecific antibodies (TCBs) directed against the PAX8 lineage-driven HGSOC tumor antigen LYPD1 and demonstrated that anti-LYPD1 TCBs induce T cell activation and promote in vivo tumor growth inhibition in LYPD1-expressing HGSOC. To selectively target LYPD1-expressing tumor cells with high expression while sparing cells with low expression, we coupled bivalent low-affinity anti-LYPD1 antigen-binding fragments (Fabs) with the anti-CD3 scFv. In contrast to the monovalent anti-LYPD1 high-affinity TCB (VHP354), the bivalent low-affinity anti-LYPD1 TCB (QZC131) demonstrated antigen density-dependent selectivity and showed tolerability in cynomolgus monkeys at the maximum dose tested of 3 mg/kg. Collectively, these data demonstrate that bivalent TCBs directed against LYPD1 have compelling efficacy and safety profiles to support its use as a treatment for high-grade serous ovarian cancers.
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Affiliation(s)
- Emily Lee
- Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Sarah Szvetecz
- Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Ryan Polli
- PKS Oncology, Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Angelo Grauel
- Immuno-Oncology, Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Jayson Chen
- PCS Toxicology, Novartis Institutes for Biomedical Research, East Hanover, NJ, USA
| | - Joyce Judge
- PCS Toxicology, Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Smita Jaiswal
- PCS Toxicology, Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Rie Maeda
- Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Stephanie Schwartz
- Immuno-Oncology, Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Bernd Voedisch
- NIBR Biologics Center, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Mateusz Piksa
- NIBR Biologics Center, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Chietara Japutra
- NIBR Biologics Center, Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Lingheswar Sadhasivam
- NIBR Biologics Center, Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Yiqin Wang
- NIBR Biologics Center, Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Ana Carrion
- NIBR Biologics Center, Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Sinan Isim
- Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Jinsheng Liang
- Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | | | - Hong Lei
- Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Qing Fang
- Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | | | - Dana Walker
- PCS Toxicology, Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Joel Wagner
- Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Viviana Cremasco
- Immuno-Oncology, Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Hui Qin Wang
- Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Giorgio G Galli
- Oncology, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Brian Granda
- NIBR Biologics Center, Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Keith Mansfield
- PCS Toxicology, Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Quincey Simmons
- PCS Toxicology, Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Andrew Anh Nguyen
- NIBR Biologics Center, Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
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Farrag MS, Abdelwahab K, Farrag NS, Elrefaie WE, Emarah Z. Programmed death ligand-1 and CD8 tumor-infiltrating lymphocytes (TILs) as prognostic predictors in ovarian high-grade serous carcinoma (HGSC). J Egypt Natl Canc Inst 2021; 33:16. [PMID: 34241710 DOI: 10.1186/s43046-021-00073-5] [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: 04/14/2021] [Accepted: 06/22/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND P D-L1 is expressed in tumor cells and plays a crucial role in tumor immune escape. Tumor-infiltrating lymphocytes (TILs) as CD8 T cells contribute to reduced tumor growth. Few studies investigated the prognostic effect of PD-L1 and CD8 TILs in ovarian high-grade serous carcinoma (HGSC). In the present study, we analyzed the expression of PD-L1 and CD8 TILs in HGSC by immunohistochemistry, and results were correlated to prognosis. It was carried on 54 cases of ovarian HGSC who attended the Oncology Centre, Mansoura University, Egypt, from 2012 till 2019. RESULTS Nearly 60% of cases showed positive PD-L1 expression in tumor cells. Regarding the clinicopathological characteristics, higher PD-L1 expression was found among patients with residual tumor (82.4%) compared to patients with no residual tumor (54.5%), with marginal statistical significance (p 0.07). PD-L1 was significantly associated with CD8 TILs expression. Higher PD-L1 expression was found among tumors with low expression of CD8 TILs with statistically significant difference (p≤0.001). Disease-free survival (DFS) was significantly lower among the group with positive expression of PD-L1 compared to the group with negative expression of PD-L1 (p 0.01), while overall survival (OS) was not associated with PD-L1 expression. On the other hand, the overall survival (OS) in patients with high CD8 expression was significantly higher than patients with low CD8 expression (p 0.043), while DFS was not significantly different among both CD8 TILS groups. CONCLUSIONS PD-L1 and CD8 TILs may become a promising therapeutic target for patients with ovarian HGSC. More studies are needed to further validate their prognostic effect. Precise identification of patients who will benefit from PD-L1 checkpoint blockade and TILs adaptive immunotherapy is mandatory.
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Affiliation(s)
- Mayada Saad Farrag
- Department of Pathology, Faculty of Medicine, Port Said University, Port Said, Egypt.
| | - Khaled Abdelwahab
- Department of Surgical Oncology, Mansoura Oncology Center, Mansoura University, Mansoura, Egypt
| | - Nesrine Saad Farrag
- Department of Community Medicine and Public Health, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Waleed Elsayed Elrefaie
- Department of Obstetrics and Gynecology, Port Said Faculty of Medicine, Port Said University, Port Said, Egypt
| | - Ziad Emarah
- Department of Medical Oncology, Mansoura Oncology Center, Mansoura University, Mansoura, Egypt
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Morand S, Devanaboyina M, Staats H, Stanbery L, Nemunaitis J. Ovarian Cancer Immunotherapy and Personalized Medicine. Int J Mol Sci 2021; 22:6532. [PMID: 34207103 PMCID: PMC8234871 DOI: 10.3390/ijms22126532] [Citation(s) in RCA: 210] [Impact Index Per Article: 52.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 06/11/2021] [Accepted: 06/13/2021] [Indexed: 12/14/2022] Open
Abstract
Ovarian cancer response to immunotherapy is limited; however, the evaluation of sensitive/resistant target treatment subpopulations based on stratification by tumor biomarkers may improve the predictiveness of response to immunotherapy. These markers include tumor mutation burden, PD-L1, tumor-infiltrating lymphocytes, homologous recombination deficiency, and neoantigen intratumoral heterogeneity. Future directions in the treatment of ovarian cancer include the utilization of these biomarkers to select ideal candidates. This paper reviews the role of immunotherapy in ovarian cancer as well as novel therapeutics and study designs involving tumor biomarkers that increase the likelihood of success with immunotherapy in ovarian cancer.
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Affiliation(s)
- Susan Morand
- Department of Medicine, University of Toledo, Toledo, OH 43614, USA; (S.M.); (M.D.); (H.S.)
| | - Monika Devanaboyina
- Department of Medicine, University of Toledo, Toledo, OH 43614, USA; (S.M.); (M.D.); (H.S.)
| | - Hannah Staats
- Department of Medicine, University of Toledo, Toledo, OH 43614, USA; (S.M.); (M.D.); (H.S.)
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ROS Cocktails as an Adjuvant for Personalized Antitumor Vaccination? Vaccines (Basel) 2021; 9:vaccines9050527. [PMID: 34069708 PMCID: PMC8161309 DOI: 10.3390/vaccines9050527] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 05/15/2021] [Accepted: 05/17/2021] [Indexed: 12/22/2022] Open
Abstract
Cancer is the second leading cause of death worldwide. Today, the critical role of the immune system in tumor control is undisputed. Checkpoint antibody immunotherapy augments existing antitumor T cell activity with durable clinical responses in many tumor entities. Despite the presence of tumor-associated antigens and neoantigens, many patients have an insufficient repertoires of antitumor T cells. Autologous tumor vaccinations aim at alleviating this defect, but clinical success is modest. Loading tumor material into autologous dendritic cells followed by their laboratory expansion and therapeutic vaccination is promising, both conceptually and clinically. However, this process is laborious, time-consuming, costly, and hence less likely to solve the global cancer crisis. Therefore, it is proposed to re-focus on personalized anticancer vaccinations to enhance the immunogenicity of autologous therapeutic tumor vaccines. Recent work re-established the idea of using the alarming agents of the immune system, oxidative modifications, as an intrinsic adjuvant to broaden the antitumor T cell receptor repertoire in cancer patients. The key novelty is the use of gas plasma, a multi-reactive oxygen and nitrogen species-generating technology, for diversifying oxidative protein modifications in a, so far, unparalleled manner. This significant innovation has been successfully used in proof-of-concept studies and awaits broader recognition and implementation to explore its chances and limitations of providing affordable personalized anticancer vaccines in the future. Such multidisciplinary advance is timely, as the current COVID-19 crisis is inexorably reflecting the utmost importance of innovative and effective vaccinations in modern times.
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Screening and Identification of an Immune-Associated lncRNA Prognostic Signature in Ovarian Carcinoma: Evidence from Bioinformatic Analysis. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6680036. [PMID: 33997040 PMCID: PMC8110384 DOI: 10.1155/2021/6680036] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 04/15/2021] [Accepted: 04/21/2021] [Indexed: 12/24/2022]
Abstract
Backgrounds The dysregulated long noncoding RNAs (lncRNAs) have been described to be crucial regulators in the progression of ovarian carcinoma. The infiltration status of immune cells is also related to the clinical outcomes in ovarian carcinoma. The present research is aimed at constructing an immune-associated lncRNA signature with potential prognostic value for ovarian carcinoma patients. Methods We obtained 379 ovarian carcinoma cases with available clinical data and transcriptome data from The Cancer Genome Atlas database to evaluate the infiltration status of immune cells, thereby generating high and low immune cell infiltration groups. According to the expression of the immune-associated lncRNA signature, the risk score of each case was calculated. The high- and low-risk groups were classified using the median risk score as threshold. Results A total of 169 immune-associated lncRNAs that differentially expressed in ovarian carcinoma were included. According to the Lasso regression analysis and Cox univariate and multivariate analyses, 5 immune-associated lncRNAs, including AC134312.1, AL133467.1, CHRM3-AS2, LINC01722, and LINC02207, were identified as a predictive signature with significant prognostic value in ovarian carcinoma. The following Kaplan-Meier analysis, ROC analysis, and Cox univariate and multivariate analyses further suggested that the predicted signature may be an independent prognosticator for patients with ovarian carcinoma. The following gene set enrichment analysis showed that this 5 immune-associated lncRNAs signature was significantly related to the hedgehog pathway, basal cell carcinoma, Wnt signaling pathway, cytokine receptor interaction, antigen processing and presentation, and T cell receptor pathway. Conclusion : This study suggested a predictive model with 5 immune-associated lncRNAs that has an independent prognostic value for ovarian carcinoma patients.
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Dholakia J, Scalise C, Arend RC. Assessing Preclinical Research Models for Immunotherapy for Gynecologic Malignancies. Cancers (Basel) 2021; 13:1694. [PMID: 33918476 PMCID: PMC8038292 DOI: 10.3390/cancers13071694] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 03/26/2021] [Accepted: 03/31/2021] [Indexed: 12/21/2022] Open
Abstract
Gynecologic malignancies are increasing in incidence, with a plateau in clinical outcomes necessitating novel treatment options. Immunotherapy and modulation of the tumor microenvironment are rapidly developing fields of interest in gynecologic oncology translational research; examples include the PD-1 (programmed cell death 1) and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) axes and the Wnt pathway. However, clinical successes with these agents have been modest and lag behind immunotherapy successes in other malignancies. A thorough contextualization of preclinical models utilized in gynecologic oncology immunotherapy research is necessary in order to effectively and efficiently develop translational medicine. These include murine models, in vitro assays, and three-dimensional human-tissue-based systems. Here, we provide a comprehensive review of preclinical models for immunotherapy in gynecologic malignancies, including benefits and limitations of each, in order to inform study design and translational research models. Improved model design and implementation will optimize preclinical research efficiency and increase the translational value to positive findings, facilitating novel treatments that improve patient outcomes.
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Affiliation(s)
| | | | - Rebecca C. Arend
- Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (J.D.); (C.S.)
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Zhang T, Zheng S, Liu Y, Li X, Wu J, Sun Y, Liu G. DNA damage response and PD-1/PD-L1 pathway in ovarian cancer. DNA Repair (Amst) 2021; 102:103112. [PMID: 33838550 DOI: 10.1016/j.dnarep.2021.103112] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 03/17/2021] [Accepted: 03/27/2021] [Indexed: 12/15/2022]
Abstract
Ovarian cancer has a poor prognosis due to drug resistance, relapse and metastasis. In recent years, immunotherapy has been applied in numerous cancers clinically. However, the effect of immunotherapy monotherapy in ovarian cancer is limited. DNA damage response (DDR) is an essential factor affecting the efficacy of tumor immunotherapy. Defective DNA repair may lead to carcinogenesis and tumor genomic instability, but on the other hand, it may also portend particular vulnerability of tumors and can be used as biomarkers for immunotherapy patient selection. Programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway mediates tumor immune escape, which may be a promising target for immunotherapy. Therefore, further understanding of the mechanism of PD-L1 expression after DDR may help guide the development of immunotherapy in ovarian cancer. In this review, we present the DNA damage repair pathway and summarize how DNA damage repair affects the PD-1/PD-L1 pathway in cancer cells. And then we look for biomarkers that affect efficacy or prognosis. Finally, we review the progress of PD-1/PD-L1-based immunotherapy in combination with other therapies that may affect the DDR pathway in ovarian cancer.
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Affiliation(s)
- Tianyu Zhang
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, No. 154 Anshan Road, Tianjin, 300052, China; Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin, 300052, China.
| | - Shuangshuang Zheng
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, No. 154 Anshan Road, Tianjin, 300052, China; Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin, 300052, China.
| | - Yang Liu
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, No. 154 Anshan Road, Tianjin, 300052, China; Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin, 300052, China.
| | - Xiao Li
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, No. 154 Anshan Road, Tianjin, 300052, China; Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin, 300052, China.
| | - Jing Wu
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, No. 154 Anshan Road, Tianjin, 300052, China; Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin, 300052, China.
| | - Yue Sun
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, No. 154 Anshan Road, Tianjin, 300052, China; Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin, 300052, China.
| | - Guoyan Liu
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, No. 154 Anshan Road, Tianjin, 300052, China; Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin, 300052, China.
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30
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Wang S, Wang C, Liu O, Hu Y, Li X, Lin B. Prognostic value of immune-related cells and genes in the tumor microenvironment of ovarian cancer, especially CST4. Life Sci 2021; 277:119461. [PMID: 33811900 DOI: 10.1016/j.lfs.2021.119461] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 03/20/2021] [Accepted: 03/27/2021] [Indexed: 01/03/2023]
Abstract
Ovarian cancer (OC) is the most common gynecological malignant tumor with the highest mortality rate. However, identification of effective immune therapeutic targets and biomarkers are beset by many challenges. CIBERSORT was used to calculate the abundance of 22 immune cell types in 379 OC samples, and indicated that three immune cell types were associated with poor prognoses. Further analysis revealed that 17 hub genes were associated with these three cell types. We screened differentially expressed immune-related prognostic gene associated with clinicopathological factors, which was CST4. We used clinical specimens to detect the expression of CST4, and determined that CST4 was both highly expressed in OC patients and associated with poor prognoses. Our findings indicated that infiltration of immune cells affected the survival of patients with OC, provided therapeutic targets represented by CST4, deepened our understanding of the immune microenvironment of OC, and enhanced the theoretical basis of immunotherapy.
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Affiliation(s)
- Shuang Wang
- Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated to China Medical University, Liaoning, China; Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China
| | - Caixia Wang
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Ouxuan Liu
- Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated to China Medical University, Liaoning, China; Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China
| | - Yuexin Hu
- Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated to China Medical University, Liaoning, China; Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China
| | - Xiao Li
- Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated to China Medical University, Liaoning, China; Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China
| | - Bei Lin
- Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated to China Medical University, Liaoning, China; Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China.
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James NE, Miller K, LaFranzo N, Lips E, Woodman M, Ou J, Ribeiro JR. Immune Modeling Analysis Reveals Immunologic Signatures Associated With Improved Outcomes in High Grade Serous Ovarian Cancer. Front Oncol 2021; 11:622182. [PMID: 33747935 PMCID: PMC7973276 DOI: 10.3389/fonc.2021.622182] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 02/10/2021] [Indexed: 12/14/2022] Open
Abstract
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy worldwide, as patients are typically diagnosed at a late stage and eventually develop chemoresistant disease following front-line platinum-taxane based therapy. Only modest results have been achieved with PD-1 based immunotherapy in ovarian cancer patients, despite the fact that immunological responses are observed in EOC patients. Therefore, the goal of this present study was to identify novel immune response genes and cell subsets significantly associated with improved high grade serous ovarian cancer (HGSOC) patient prognosis. A transcriptomic-based immune modeling analysis was employed to determine levels of 8 immune cell subsets, 10 immune escape genes, and 22 co-inhibitory/co-stimulatory molecules in 26 HGSOC tumors. Multidimensional immune profiling analysis revealed CTLA-4, LAG-3, and Tregs as predictive for improved progression-free survival (PFS). Furthermore, the co-stimulatory receptor ICOS was also found to be significantly increased in patients with a longer PFS and positively correlated with levels of CTLA-4, PD-1, and infiltration of immune cell subsets. Both ICOS and LAG-3 were found to be significantly associated with improved overall survival in The Cancer Genome Atlas (TCGA) ovarian cancer cohort. Finally, PVRL2 was identified as the most highly expressed transcript in our analysis, with immunohistochemistry results confirming its overexpression in HGSOC samples compared to normal/benign. Results were corroborated by parallel analyses of TCGA data. Overall, this multidimensional immune modeling analysis uncovers important prognostic immune factors that improve our understanding of the unique immune microenvironment of ovarian cancer.
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Affiliation(s)
- Nicole E. James
- Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants Hospital of Rhode Island, Providence, RI, United States
| | - Katherine Miller
- Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants Hospital of Rhode Island, Providence, RI, United States
- Department of Obstetrics and Gynecology, Warren-Alpert Medical School of Brown University, Providence, RI, United States
| | | | - Erin Lips
- Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants Hospital of Rhode Island, Providence, RI, United States
- Department of Obstetrics and Gynecology, Warren-Alpert Medical School of Brown University, Providence, RI, United States
| | - Morgan Woodman
- Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants Hospital of Rhode Island, Providence, RI, United States
| | - Joyce Ou
- Department of Obstetrics and Gynecology, Warren-Alpert Medical School of Brown University, Providence, RI, United States
- Department of Pathology, Women and Infants Hospital of Rhode Island, Providence, RI, United States
| | - Jennifer R. Ribeiro
- Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants Hospital of Rhode Island, Providence, RI, United States
- Department of Obstetrics and Gynecology, Warren-Alpert Medical School of Brown University, Providence, RI, United States
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Lin J, Xu X, Sun D, Li T. Development and Validation of an Immune-Related Gene-Pair Model of High-Grade Serous Ovarian Cancer After Platinum-Based Chemotherapy. Front Oncol 2021; 10:626555. [PMID: 33680950 PMCID: PMC7928280 DOI: 10.3389/fonc.2020.626555] [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: 11/06/2020] [Accepted: 12/29/2020] [Indexed: 11/28/2022] Open
Abstract
Background High-grade serous ovarian cancer (HGSOC) is a common cause of death from gynecological cancer, with an overall survival rate that has not significantly improved in decades. Reliable bio-markers are needed to identify high-risk HGSOC to assist in the selection and development of treatment options. Method The study included ten HGSOC cohorts, which were merged into four separate cohorts including a total of 1,526 samples. We used the relative expression of immune genes to construct the gene-pair matrix, and the least absolute shrinkage and selection operator regression was performed to build the prognosis model using the training set. The prognosis of the model was verified in the training set (363 cases) and three validation sets (of 251, 354, and 558 cases). Finally, the differences in immune cell infiltration and gene enrichment pathways between high and low score groups were identified. Results A prognosis model of HGSOC overall survival rate was constructed in the training set, and included data for 35 immune gene-related gene pairs and the regression coefficients. The risk stratification of HGSOC patients was successfully performed using the training set, with a p-value of Kaplan-Meier of < 0.001. A score from this model is an independent prognostic factor of HGSOC, and prognosis was evaluated in different clinical subgroups. This model was also successful for the other three validation sets, and the results of Kaplan-Meier analysis were statistically significant (p < 0.05). The model can also predict patient progression-free survival with HGSOC to reflect tumor growth status. There was a lower infiltration level of M1 macrophages in the high-risk group compared to that in the low-risk group (p < 0.001). Finally, the immune-related pathways were enriched in the low-risk group. Conclusion The prognostic model based on immune-related gene pairs developed is a potential prognostic marker for high-grade serous ovarian cancer treated with platinum. The model has robust prognostic ability and wide applicability. More prospective studies will be needed to assess the practical application of this model for precision therapy.
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Affiliation(s)
- Jiaxing Lin
- Department of Urology, The First Hospital of China Medical University, Shenyang, China
| | - Xiao Xu
- Department of Pediatric Intensive Care Unit, The Shengjing Hospital of China Medical University, Shenyang, China
| | - Dan Sun
- Department of Urology, The First Hospital of China Medical University, Shenyang, China
| | - Tianren Li
- Department of Gynaecology, The First Hospital of China Medical University, Shenyang, China
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Duwa R, Jeong JH, Yook S. Immunotherapeutic strategies for the treatment of ovarian cancer: current status and future direction. J IND ENG CHEM 2021. [DOI: 10.1016/j.jiec.2020.11.015] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Wilson AL, Moffitt LR, Wilson KL, Bilandzic M, Wright MD, Gorrell MD, Oehler MK, Plebanski M, Stephens AN. DPP4 Inhibitor Sitagliptin Enhances Lymphocyte Recruitment and Prolongs Survival in a Syngeneic Ovarian Cancer Mouse Model. Cancers (Basel) 2021; 13:487. [PMID: 33513866 PMCID: PMC7865851 DOI: 10.3390/cancers13030487] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/12/2021] [Accepted: 01/19/2021] [Indexed: 02/07/2023] Open
Abstract
Immunity plays a key role in epithelial ovarian cancer (EOC) progression with a well-documented correlation between patient survival and high intratumoral CD8+ to T regulatory cell (Treg) ratios. We previously identified dysregulated DPP4 activity in EOCs as a potentially immune-disruptive influence contributing to a reduction in CXCR3-mediated T-cell infiltration in solid tumours. We therefore hypothesized that inhibition of DPP4 activity by sitagliptin, an FDA-approved inhibitor, would improve T-cell infiltration and function in a syngeneic ID8 mouse model of EOC. Daily oral sitagliptin at 50 mg/kg was provided to mice with established primary EOCs. Sitagliptin treatment decreased metastatic tumour burden and significantly increased overall survival and was associated with significant changes to the immune landscape. Sitagliptin increased overall CXCR3-mediated CD8+ T-cell trafficking to the tumour and enhanced the activation and proliferation of CD8+ T-cells in tumour tissue and the peritoneal cavity. Substantial reductions in suppressive cytokines, including CCL2, CCL17, CCL22 and IL-10, were also noted and were associated with reduced CD4+ CD25+ Foxp3+ Treg recruitment in the tumour. Combination therapy with paclitaxel, however, typical of standard-of-care for patients in palliative care, abolished CXCR3-specific T-cell recruitment stimulated by sitagliptin. Our data suggest that sitagliptin may be suitable as an adjunct therapy for patients between chemotherapy cycles as a novel approach to enhance immunity, optimise T-cell-mediated function and improve overall survival.
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Affiliation(s)
- Amy L. Wilson
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton 3168, Australia; (A.L.W.); (L.R.M.); (M.B.)
- Department of Molecular and Translational Sciences, Monash Health, Clayton 3168, Australia
- Department of Immunology and Pathology, Monash University, Clayton 3800, Australia;
| | - Laura R. Moffitt
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton 3168, Australia; (A.L.W.); (L.R.M.); (M.B.)
- Department of Molecular and Translational Sciences, Monash Health, Clayton 3168, Australia
| | - Kirsty L. Wilson
- School of Health and Biomedical Sciences, RMIT University, Bundoora 3083, Australia;
| | - Maree Bilandzic
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton 3168, Australia; (A.L.W.); (L.R.M.); (M.B.)
- Department of Molecular and Translational Sciences, Monash Health, Clayton 3168, Australia
| | - Mark D. Wright
- Department of Immunology and Pathology, Monash University, Clayton 3800, Australia;
| | - Mark D. Gorrell
- Centenary Institute, Faculty of Medicine and Health, University of Sydney, Camperdown 2006, Australia;
| | - Martin K. Oehler
- Department of Gynaecological Oncology, Royal Adelaide Hospital, Adelaide 5000, Australia;
| | - Magdalena Plebanski
- School of Health and Biomedical Sciences, RMIT University, Bundoora 3083, Australia;
| | - Andrew N. Stephens
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton 3168, Australia; (A.L.W.); (L.R.M.); (M.B.)
- Department of Molecular and Translational Sciences, Monash Health, Clayton 3168, Australia
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Yan S, Fang J, Chen Y, Xie Y, Zhang S, Zhu X, Fang F. Comprehensive analysis of prognostic gene signatures based on immune infiltration of ovarian cancer. BMC Cancer 2020; 20:1205. [PMID: 33287740 PMCID: PMC7720540 DOI: 10.1186/s12885-020-07695-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Accepted: 11/26/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Ovarian cancer (OV) is one of the most common malignant tumors of gynecology oncology. The lack of effective early diagnosis methods and treatment strategies result in a low five-year survival rate. Also, immunotherapy plays an important auxiliary role in the treatment of advanced OV patient, so it is of great significance to find out effective immune-related tumor markers for the diagnosis and treatment of OV. METHODS Based on the consensus clustering analysis of single-sample gene set enrichment analysis (ssGSEA) score transformed via The Cancer Genome Atlas (TCGA) mRNA profile, we obtained two groups with high and low levels of immune infiltration. Multiple machine learning methods were conducted to explore prognostic genes associated with immune infiltration. Simultaneously, the correlation between the expression of mark genes and immune cells components was explored. RESULTS A prognostic classifier including 5 genes (CXCL11, S1PR4, TNFRSF17, FPR1 and DHRS95) was established and its robust efficacy for predicting overall survival was validated via 1129 OV samples. Some significant variations of copy number on gene loci were found between two risk groups and it showed that patients with fine chemosensitivity has lower risk score than patient with poor chemosensitivity (P = 0.013). The high and low-risk groups showed significantly different distribution (P < 0.001) of five immune cells (Monocytes, Macrophages M1, Macrophages M2, T cells CD4 menory and T cells CD8). CONCLUSION The present study identified five prognostic genes associated with immune infiltration of OV, which may provide some potential clinical implications for OV treatment.
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Affiliation(s)
- Shibai Yan
- Department of Medical Oncology, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, China
| | - Juntao Fang
- Laboratory of Experimental Cardiology, Department of Cardiology, University Medical Center Utrecht, Utrecht, 3584, CX, The Netherlands
| | - Yongcai Chen
- Department of Obstetrics and Gynecology, The First People's Hospital of Foshan, 81 Lingnan North Avenue, Foshan, 528000, Guangdong, China
| | - Yong Xie
- Department of Obstetrics and Gynecology, The First People's Hospital of Foshan, 81 Lingnan North Avenue, Foshan, 528000, Guangdong, China
| | - Siyou Zhang
- Department of Obstetrics and Gynecology, The First People's Hospital of Foshan, 81 Lingnan North Avenue, Foshan, 528000, Guangdong, China
| | - Xiaohui Zhu
- Department of Pharmacology, College of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, Guangdong, China.
| | - Feng Fang
- Department of Obstetrics and Gynecology, The First People's Hospital of Foshan, 81 Lingnan North Avenue, Foshan, 528000, Guangdong, China.
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O’Dwyer J, O’Cearbhaill RE, Wylie R, O’Mahony S, O’Dwyer M, Duffy GP, Dolan EB. Enhancing delivery of small molecule and cell-based therapies for ovarian cancer using advanced delivery strategies. ADVANCED THERAPEUTICS 2020; 3:2000144. [PMID: 33709016 PMCID: PMC7942751 DOI: 10.1002/adtp.202000144] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Indexed: 12/17/2022]
Abstract
Ovarian cancer is the most lethal gynecological malignancy with a global five-year survival rate of 30-50%. First-line treatment involves cytoreductive surgery and administration of platinum-based small molecules and paclitaxel. These therapies were traditionally administered via intravenous infusion, although intraperitoneal delivery has also been investigated. Initial clinical trials of intraperitoneal administration for ovarian cancer indicated significant improvements in overall survival compared to intravenous delivery, but this result is not consistent across all studies performed. Recently cell-based immunotherapy has been of interest for ovarian cancer. Direct intraperitoneal delivery of cell-based immunotherapies might prompt local immunoregulatory mechanisms to act synergistically with the delivered immunotherapy. Based on this theory, pre-clinical in vivo studies have delivered these cell-based immunotherapies via the intraperitoneal route, with promising results. However, successful intraperitoneal delivery of cell-based immunotherapy and clinical adoption of this technique will depend on overcoming challenges of intraperitoneal delivery and finding the optimal combinations of dose, therapeutic and delivery route. We review the potential advantages and disadvantages of intraperitoneal delivery of cell-based immunotherapy for ovarian cancer and the pre-clinical and clinical work performed so far. Potential advanced delivery strategies, which might improve the efficacy and adoption of intraperitoneal delivery of therapy for ovarian cancer, are also outlined.
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Affiliation(s)
- Joanne O’Dwyer
- Department of Biomedical Engineering, School of Engineering, College of Science and Engineering, National University of Ireland Galway, Ireland; Anatomy & Regenerative Medicine Institute, School of Medicine, College of Medicine Nursing and Health Sciences, National University of Ireland Galway, Ireland
| | - Roisin E. O’Cearbhaill
- Anatomy & Regenerative Medicine Institute, School of Medicine, College of Medicine Nursing and Health Sciences, National University of Ireland Galway, Ireland; Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York City, New York, USA
| | - Robert Wylie
- Anatomy & Regenerative Medicine Institute, School of Medicine, College of Medicine Nursing and Health Sciences, National University of Ireland Galway, Ireland
| | - Saoirse O’Mahony
- Department of Biomedical Engineering, School of Engineering, College of Science and Engineering, National University of Ireland Galway, Ireland
| | - Michael O’Dwyer
- Apoptosis Research Centre, National University of Ireland Galway, Ireland
| | - Garry P. Duffy
- Anatomy & Regenerative Medicine Institute, School of Medicine, College of Medicine Nursing and Health Sciences, National University of Ireland Galway, Ireland
| | - Eimear B. Dolan
- Department of Biomedical Engineering, School of Engineering, College of Science and Engineering, National University of Ireland Galway, Ireland
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Sheng M, Tong H, Lu X, Shanshan N, Zhang X, Reddy BA, Shu P. Integrative network analysis identifies an immune-based prognostic signature as the determinant for the mesenchymal subtype in epithelial ovarian cancer. Medicine (Baltimore) 2020; 99:e22549. [PMID: 33031300 PMCID: PMC10545305 DOI: 10.1097/md.0000000000022549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 08/20/2020] [Accepted: 09/03/2020] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Epithelial ovarian cancer (EOC) has been classified into four molecular subtypes, of which the mesenchymal subtype has the poorest survival. Our goal is to develop an immune-based prognostic signature by incorporating molecular subtypes for EOC patients. METHODS The gene expression profiles of EOC samples were collected from seven public datasets as well as an internal retrospective validation cohort, containing 1192 EOC patients. Network analysis was applied to integrate the mesenchymal modalities and immune signature to establish an immune-based prognostic signature for EOC (IPSEOC). The signature was trained and validated in eight independent datasets. RESULTS Seven immune genes were identified as key regulators of the mesenchymal subtype and were used to construct the IPSEOC. The IPSEOC significantly divided patients into high- and low-risk groups in discovery (OS: P < .0001), 6 independent public validation sets (OS: P = .04 to P = .002), and an internal retrospective validation cohort (OS: P = .025). Furthermore, pathway analysis revealed that differences between risk groups were mainly activation of mesenchymal-related signalling. Moreover, a significant correlation existed between the IPSEOC values versus clinical phenotypes including late tumor stages, drug resistance. CONCLUSION We propose an immune-based signature, which is a promising prognostic biomarker in ovarian cancer. Prospective studies are needed to further validate its analytical accuracy and test the clinical utility.
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Affiliation(s)
| | | | | | | | - Xingguo Zhang
- Molecular Laboratory, Beilun People's Hospital, Ningbo, China
| | - B. Ashok Reddy
- Division of Oncology, Liveon Biolabs, Antharasanahally, Tumakuru, Karnataka, India
| | - Peng Shu
- Molecular Laboratory, Beilun People's Hospital, Ningbo, China
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Huang C, Li H, Feng Y, Li X, Zhang Z, Jiang C, Wang J, Yang C, Fu Y, Mu M, Zhao S, Wang Z, Kuang Y, Hou H, Wang Y, Guo W, Xu J, Yang H, Zhou L, Tong A, Guo G. Combination therapy with B7H3-redirected bispecific antibody and Sorafenib elicits enhanced synergistic antitumor efficacy. Theranostics 2020; 10:10498-10512. [PMID: 32929362 PMCID: PMC7482810 DOI: 10.7150/thno.49480] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Accepted: 08/05/2020] [Indexed: 02/05/2023] Open
Abstract
Rationale: Current traditional treatment options are frequently ineffective to fight against ovarian cancer due to late diagnosis and high recurrence. Therefore, there is a vital need for the development of novel therapeutic agents. B7H3, an immune checkpoint protein, is highly expressed in various cancers, representing it a promising target for cancer immunotherapy. Although targeting B7H3 by bispecific T cell-engaging antibodies (BiTE) has achieved successes in hematological malignancies during recent years, attempts to use them for the treatment of solid cancers are less favorable, in part due to the heterogeneity of tumors. Sorafenib is an unselective inhibitor of multiple kinases currently being tested in clinical trials for several tumors, including ovarian cancer which showed limited activity and inevitable side effect for ovarian cancer treatment. However, it is able to enhance antitumor immune response, which indicates sorafenib may improve the efficiency of immunotherapy. Methods: We evaluated the expression of B7H3 in ovarian cancer using online database and validated its expression of tumor tissues by immunohistochemistry staining. Then, B7H3 expression and the effects of sorafenib on ovarian cancer cell lines were determined by flow cytometry. In addition, 2D and 3D ovarian cancer models were established to test the combined therapeutic effect in vitro. Finally, the efficiency of B7H3×CD3 BiTE alone and its combination with sorafenib were evaluated both in vitro and in vivo. Results: Our data showed that B7H3 was highly expressed in ovarian cancer compared with normal samples. Treatment with sorafenib inhibited ovarian cancer cell proliferation and induced a noticeable upregulation of B7H3 expression level. Further study suggested that B7H3×CD3 BiTE was effective in mediating T cell killing to cancer cells. Combined treatment of sorafenib and B7H3×CD3 BiTE had synergistic anti-tumor effects in ovarian cancer models. Conclusions: Overall, our study indicates that combination therapy with sorafenib and B7H3×CD3 BiTE may be a new therapeutic option for the further study of preclinical treatment of OC.
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Heredia-Soto V, López-Guerrero J, Redondo A, Mendiola M. The hallmarks of ovarian cancer: Focus on angiogenesis and micro-environment and new models for their characterisation. EJC Suppl 2020; 15:49-55. [PMID: 33240442 PMCID: PMC7573462 DOI: 10.1016/j.ejcsup.2019.11.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 10/28/2019] [Accepted: 11/16/2019] [Indexed: 12/12/2022] Open
Abstract
Cancers develop by sustained growth, migration and invasion properties of tumour cells, supported by complex interactions with stromal cells within the tumour micro-environment. This review is focused on the latest discoveries regarding the highlighted role of angiogenesis and tumour micro-environment in ovarian cancer. This cancer milieu encompasses non-cancerous cells present in the tumour or nearby, including vessel-forming cells, fibroblasts and immune cells amongst others that work in a cooperative way with cancer cells, impacting tumour behaviour. Angiogenesis, migration and invasion, and more recently immune evasion, are cancer hallmarks clearly dependent on these supporting cells. Moreover, these stromal cells are more genetically stable than tumour cells and thus represent an attractive therapeutic target. A better understanding of the stromal cells function, and their complex interplay with cancer cells, will open additional areas to target, as the tumour-host interface.
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Affiliation(s)
- V. Heredia-Soto
- Translational Oncology Research Laboratory, La Paz University Hospital Biomedical Research Institute, IdiPAZ, Paseo de La Castellana 261, 28046, Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer, CIBERONC, Instituto de Salud Carlos III, Monforte de Lemos 5, Madrid, 28029, Spain
| | - J.A. López-Guerrero
- Laboratory of Molecular Biology, Fundación Instituto Valenciano de Oncología, Carrer Del Professor Beltrán Báguena, 8, 46009, Valencia, Spain
| | - A. Redondo
- Translational Oncology Research Laboratory, La Paz University Hospital Biomedical Research Institute, IdiPAZ, Paseo de La Castellana 261, 28046, Madrid, Spain
- Medical Oncology Department, La Paz University Hospital, Paseo de La Castellana 261, 28046, Madrid, Spain
- Faculty of Medicine, Cátedra UAM-Amgen, Universidad Autónoma de Madrid, Madrid, Spain
| | - M. Mendiola
- Centro de Investigación Biomédica en Red de Cáncer, CIBERONC, Instituto de Salud Carlos III, Monforte de Lemos 5, Madrid, 28029, Spain
- Molecular Pathology and Therapeutic Targets Research Laboratory, La Paz University Hospital Biomedical Research Institute, IdiPAZ, Paseo de La Castellana 261, 28046, Madrid, Spain
- Molecular Pathology Diagnostic Section, Medical and Molecular Medicine Institute, INGEMM, Paseo de La Castellana 261, 28046, Madrid, Spain
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Liu Q, Yang W, Luo N, Liu J, Wu Y, Ding J, Li C, Cheng Z. LPS and IL-8 activated umbilical cord blood-derived neutrophils inhibit the progression of ovarian cancer. J Cancer 2020; 11:4413-4420. [PMID: 32489460 PMCID: PMC7255365 DOI: 10.7150/jca.41035] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Accepted: 04/02/2020] [Indexed: 01/06/2023] Open
Abstract
Background: Immunotherapy including immune checkpoint blockade, cancer vaccines, and adoptive cell therapy. However, no immune therapies support ovarian cancer. It is not clear whether the neutrophils, the component of the immune system derived from umbilical cord blood play a role in inhibiting the progression of ovarian cancer. Methods: We investigate the impact of LPS and IL-8 activated neutrophils derived from umbilical cord blood(UCB)on ovarian cancer progression. After co-culture LPS and IL-8 activated UCB-derived neutrophils with ovarian cancer cell line SKOV3 and OVCAR3, CCK8, Transwell assay, and Flow Cytometry was performed to detect cell proliferation, migration, invasion, and apoptosis of ovarian cancer cell lines SKOV3 and OVCAR3. Furthermore, RT-PCR and western blotting assay were used to analyze the mechanism of metastasis and apoptosis of ovarian cancer cell lines respectively to support previous function experiments. Results: We demonstrate LPS and IL-8 activated neutrophils derived from umbilical cord blood inhibit proliferation, invasion migration and promote apoptosis of SKOV3 and OVCAR3. Meanwhile, LPS and IL-8 activated UCB-derived neutrophils significantly decreased BAX and increased BCL2 expression in SKOV3 and OVCAR3 which account for the mechanism of apoptosis. Moreover, LPS and IL-8 activated UCB derived neutrophils significantly up-regulated E-cadherin and downregulated N-cadherin, MMP2 expression in SKOV3 and OVCAR3. Conclusion: Taken together, these results approved that LPS and IL-8 activated neutrophils from UCB may be the novel strategy in immune therapy for ovarian cancer.
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Affiliation(s)
- Qi Liu
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Weihong Yang
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Ning Luo
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Jie Liu
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Yuliang Wu
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Jinye Ding
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Caixia Li
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Zhongping Cheng
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.,Institute of Gynecological Minimally Invasive Medicine, Tongji University School of Medicine, Shanghai, China
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Cheng S, Xu C, Jin Y, Li Y, Zhong C, Ma J, Yang J, Zhang N, Li Y, Wang C, Yang Z, Wang Y. Artificial Mini Dendritic Cells Boost T Cell-Based Immunotherapy for Ovarian Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2020; 7:1903301. [PMID: 32274314 PMCID: PMC7141030 DOI: 10.1002/advs.201903301] [Citation(s) in RCA: 96] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 01/15/2020] [Indexed: 05/17/2023]
Abstract
Ovarian cancer is the most lethal gynecological malignancy with high recurrence rates and low survival rates, remaining a disease of high unmet need. Cancer immunotherapy, which harnesses the potential of the immune system to attack tumors, has emerged as one of the most promising treatment options in recent years. As an important form of immunotherapy, dendritic cell (DC)-based vaccines have demonstrated the ability to induce an immune response, while clinical efficacy of DC vaccines remains unsubstantiated as long-term benefit is only reported in a restricted proportion of patients. Here, a biomimetic nanovaccine derived from DCs is developed through cell membrane coating nanotechnology. This nanovaccine, denoted "mini DC," inherits the ability of antigen presentation and T cells' stimulation from DCs and is shown to elicit enhanced activation of T cells both in vitro and in vivo. In a mouse model of ovarian cancer, mini DCs exhibit superior therapeutic and prophylactic efficacy against cancer including delayed tumor growth and reduced tumor metastasis compared with DC vaccine. These findings suggest that mini DCs may serve as a facile and potent vaccine to boost anticancer immunotherapy.
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Affiliation(s)
- Shanshan Cheng
- Department of Obstetrics and GynecologyShanghai Key Laboratory of Gynecologic OncologyRenji HospitalSchool of MedicineShanghai Jiaotong UniversityShanghai200127P. R. China
| | - Cong Xu
- Department of Obstetrics and GynecologyShanghai Key Laboratory of Gynecologic OncologyRenji HospitalSchool of MedicineShanghai Jiaotong UniversityShanghai200127P. R. China
| | - Yue Jin
- Department of Obstetrics and GynecologyShanghai Key Laboratory of Gynecologic OncologyRenji HospitalSchool of MedicineShanghai Jiaotong UniversityShanghai200127P. R. China
| | - Yu Li
- Department of Obstetrics and GynecologyShanghai Key Laboratory of Gynecologic OncologyRenji HospitalSchool of MedicineShanghai Jiaotong UniversityShanghai200127P. R. China
| | - Cheng Zhong
- Department of Obstetrics and GynecologyShanghai Key Laboratory of Gynecologic OncologyRenji HospitalSchool of MedicineShanghai Jiaotong UniversityShanghai200127P. R. China
| | - Jun Ma
- Department of Obstetrics and GynecologyShanghai Key Laboratory of Gynecologic OncologyRenji HospitalSchool of MedicineShanghai Jiaotong UniversityShanghai200127P. R. China
| | - Jiani Yang
- Department of Obstetrics and GynecologyShanghai Key Laboratory of Gynecologic OncologyRenji HospitalSchool of MedicineShanghai Jiaotong UniversityShanghai200127P. R. China
| | - Nan Zhang
- Department of Obstetrics and GynecologyShanghai Key Laboratory of Gynecologic OncologyRenji HospitalSchool of MedicineShanghai Jiaotong UniversityShanghai200127P. R. China
| | - Yuan Li
- Department of Obstetrics and GynecologyShanghai Key Laboratory of Gynecologic OncologyRenji HospitalSchool of MedicineShanghai Jiaotong UniversityShanghai200127P. R. China
| | - Chao Wang
- Department of Obstetrics and GynecologyShanghai Key Laboratory of Gynecologic OncologyRenji HospitalSchool of MedicineShanghai Jiaotong UniversityShanghai200127P. R. China
| | - Zhiyou Yang
- Department of Obstetrics and GynecologyShanghai Key Laboratory of Gynecologic OncologyRenji HospitalSchool of MedicineShanghai Jiaotong UniversityShanghai200127P. R. China
| | - Yu Wang
- Department of Obstetrics and GynecologyShanghai Key Laboratory of Gynecologic OncologyRenji HospitalSchool of MedicineShanghai Jiaotong UniversityShanghai200127P. R. China
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Cai D, Li J, Liu D, Hong S, Qiao Q, Sun Q, Li P, Lyu N, Sun T, Xie S, Guo L, Ni L, Jin L, Dong C. Tumor-expressed B7-H3 mediates the inhibition of antitumor T-cell functions in ovarian cancer insensitive to PD-1 blockade therapy. Cell Mol Immunol 2019; 17:227-236. [PMID: 31611650 DOI: 10.1038/s41423-019-0305-2] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Accepted: 09/17/2019] [Indexed: 12/15/2022] Open
Abstract
Although PD-L1/PD-1 blockade therapy has been approved to treat many types of cancers, the majority of patients with solid tumors do not respond well, but the underlying reason remains unclear. Here, we studied ovarian cancer (OvCa), a tumor type generally resistant to current immunotherapies, to investigate PD-1-independent immunosuppression. We found that PD-L1 was not highly expressed in the tumor microenvironment (TME) of human OvCa. Instead, B7-H3, another checkpoint molecule, was highly expressed by both tumor cells and tumor-infiltrating antigen-presenting cells (APCs), which correlated with T-cell exhaustion in patients. Using ID8 OvCa mouse models, we found that B7-H3 expressed on tumor cells, but not host cells, had a dominant role in suppressing antitumor immunity. Therapeutically, B7-H3 blockade, but not PD-1 blockade, prolonged the survival of ID8 tumor-bearing mice. Collectively, our results demonstrate that tumor-expressed B7-H3 inhibits the function of CD8+ T cells and suggest that B7-H3 may be a target in patients who are not responsive to PD-L1/PD-1 inhibition, particularly OvCa patients.
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Affiliation(s)
- Dongli Cai
- Obstetrics & Gynecology Hospital, Fudan University, Shanghai, 200011, China.,Institute for Immunology and School of Medicine, Tsinghua University, Beijing, 100084, China
| | - Jiaming Li
- Suzhou Kanova Biopharmaceutical Co., Ltd, Suzhou, 215000, China
| | - Dingfeng Liu
- Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 201204, China
| | - Shanjuan Hong
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, 100084, China
| | - Qin Qiao
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, 100084, China
| | - Qinli Sun
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, 100084, China
| | - Pingping Li
- Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 201204, China
| | - Nanan Lyu
- Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Tiantian Sun
- Suzhou Kanova Biopharmaceutical Co., Ltd, Suzhou, 215000, China
| | - Shan Xie
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, 100084, China
| | - Li Guo
- Suzhou Kanova Biopharmaceutical Co., Ltd, Suzhou, 215000, China
| | - Ling Ni
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, 100084, China.
| | - Liping Jin
- Obstetrics & Gynecology Hospital, Fudan University, Shanghai, 200011, China. .,Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 201204, China.
| | - Chen Dong
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, 100084, China. .,Beijing Key Lab for Immunological Research on Chronic Diseases, Beijing, 100084, China.
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Gou R, Zhu L, Zheng M, Guo Q, Hu Y, Li X, Liu J, Lin B. Annexin A8 can serve as potential prognostic biomarker and therapeutic target for ovarian cancer: based on the comprehensive analysis of Annexins. J Transl Med 2019; 17:275. [PMID: 31474227 PMCID: PMC6717992 DOI: 10.1186/s12967-019-2023-z] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 08/13/2019] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Annexins are involved in vesicle trafficking, cell proliferation and apoptosis, but their functional mechanisms in ovarian cancer remain unclear. In this study, we analyzed Annexins in ovarian cancer using different databases and selected Annexin A8 (ANXA8), which showed the greatest prognostic value, for subsequent validation in immunohistochemical (IHC) assays. METHODS The mRNA expression levels, genetic variations, prognostic values and gene-gene interaction network of Annexins in ovarian cancer were analyzed using the Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), cBioPortal, Kaplan-Meier plotter and GeneMANIA database. ANXA8 was selected for analyzing the biological functions and pathways of its co-expressed genes, and its correlation with immune system responses via the Database for Annotation, Visualization, and Integrated Discovery (DAVID) and the TISIDB database, respectively. We validated the expression of ANXA8 in ovarian cancer via IHC assays and analyzed its correlation with clinicopathological parameters and prognosis. RESULTS ANXA2/3/8/11 mRNA expression levels were significantly upregulated in ovarian cancer, and ANXA5/6/7 mRNA expression levels were significantly downregulated. Prognostic analysis suggested that significant correlations occurred between ANXA2/4/8/9 mRNA upregulation and poor overall survival, and between ANXA8/9/11 mRNA upregulation and poor progression-free survival in patients with ovarian serous tumors. Taken together, results suggested that ANXA8 was most closely associated with ovarian cancer tumorigenesis and progression. Further analyses indicated that ANXA8 may be involved in cell migration, cell adhesion, and vasculature development, as well as in the regulation of PI3K-Akt, focal adhesion, and proteoglycans. Additionally, ANXA8 expression was significantly correlated with lymphocytes and immunomodulators. The IHC results showed that ANXA8 expression was higher in the malignant tumor group than in the borderline and benign tumor groups and normal ovary group, and high ANXA8 expression was an independent risk factor for survival and prognosis of ovarian cancer patients (P = 0.013). CONCLUSIONS Members of the Annexin family display varying degrees of abnormal expressions in ovarian cancer. ANXA8 was significantly highly expressed in ovarian cancer, and high ANXA8 expression was significantly correlated with poor prognosis. Therefore, ANXA8 is a high candidate as a novel biomarker and therapeutic target for ovarian cancer.
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Affiliation(s)
- Rui Gou
- Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated to China Medical University, Shenyang, 110004, Liaoning, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China
| | - Liancheng Zhu
- Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated to China Medical University, Shenyang, 110004, Liaoning, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China
| | - Mingjun Zheng
- Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated to China Medical University, Shenyang, 110004, Liaoning, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China
| | - Qian Guo
- Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated to China Medical University, Shenyang, 110004, Liaoning, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China
| | - Yuexin Hu
- Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated to China Medical University, Shenyang, 110004, Liaoning, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China
| | - Xiao Li
- Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated to China Medical University, Shenyang, 110004, Liaoning, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China
| | - Juanjuan Liu
- Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated to China Medical University, Shenyang, 110004, Liaoning, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China
| | - Bei Lin
- Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated to China Medical University, Shenyang, 110004, Liaoning, China. .,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China.
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Hartl CA, Bertschi A, Puerto RB, Andresen C, Cheney EM, Mittendorf EA, Guerriero JL, Goldberg MS. Combination therapy targeting both innate and adaptive immunity improves survival in a pre-clinical model of ovarian cancer. J Immunother Cancer 2019; 7:199. [PMID: 31362778 PMCID: PMC6668091 DOI: 10.1186/s40425-019-0654-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Accepted: 06/27/2019] [Indexed: 02/06/2023] Open
Abstract
Background Despite major advancements in immunotherapy among a number of solid tumors, response rates among ovarian cancer patients remain modest. Standard treatment for ovarian cancer is still surgery followed by taxane- and platinum-based chemotherapy. Thus, there is an urgent need to develop novel treatment options for clinical translation. Methods Our approach was to analyze the effects of standard chemotherapy in the tumor microenvironment of mice harboring orthotopic, syngeneic ID8-Vegf-Defb29 ovarian tumors in order to mechanistically determine a complementary immunotherapy combination. Specifically, we interrogated the molecular and cellular consequences of chemotherapy by analyzing gene expression and flow cytometry data. Results These data show that there is an immunosuppressive shift in the myeloid compartment, with increased expression of IL-10 and ARG1, but no activation of CD3+ T cells shortly after chemotherapy treatment. We therefore selected immunotherapies that target both the innate and adaptive arms of the immune system. Survival studies revealed that standard chemotherapy was complemented most effectively by a combination of anti-IL-10, 2′3’-cGAMP, and anti-PD-L1. Immunotherapy dramatically decreased the immunosuppressive myeloid population while chemotherapy effectively activated dendritic cells. Together, combination treatment increased the number of activated T and dendritic cells as well as expression of cytotoxic factors. It was also determined that the immunotherapy had to be administered concurrently with the chemotherapy to reverse the acute immunosuppression caused by chemotherapy. Mechanistic studies revealed that antitumor immunity in this context was driven by CD4+ T cells, which acquired a highly activated phenotype. Our data suggest that these CD4+ T cells can kill cancer cells directly via granzyme B-mediated cytotoxicity. Finally, we showed that this combination therapy is also effective at delaying tumor growth substantially in an aggressive model of lung cancer, which is also treated clinically with taxane- and platinum-based chemotherapy. Conclusions This work highlights the importance of CD4+ T cells in tumor immunology. Furthermore, the data support the initiation of clinical trials in ovarian cancer that target both innate and adaptive immunity, with a focus on optimizing dosing schedules. Electronic supplementary material The online version of this article (10.1186/s40425-019-0654-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Christina A Hartl
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.,Breast Tumor Immunology Laboratory, Susan F. Smith Center for Women's Cancers, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Adrian Bertschi
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Regina Bou Puerto
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Carolin Andresen
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Emily M Cheney
- Breast Tumor Immunology Laboratory, Susan F. Smith Center for Women's Cancers, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Elizabeth A Mittendorf
- Breast Tumor Immunology Laboratory, Susan F. Smith Center for Women's Cancers, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.,Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, 02215, USA.,Breast Oncology Program, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Jennifer L Guerriero
- Breast Tumor Immunology Laboratory, Susan F. Smith Center for Women's Cancers, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
| | - Michael S Goldberg
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
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Crawford A, Haber L, Kelly MP, Vazzana K, Canova L, Ram P, Pawashe A, Finney J, Jalal S, Chiu D, Colleton CA, Garnova E, Makonnen S, Hickey C, Krueger P, DelFino F, Potocky T, Kuhnert J, Godin S, Retter MW, Duramad P, MacDonald D, Olson WC, Fairhurst J, Huang T, Martin J, Lin JC, Smith E, Thurston G, Kirshner JR. A Mucin 16 bispecific T cell–engaging antibody for the treatment of ovarian cancer. Sci Transl Med 2019; 11:11/497/eaau7534. [DOI: 10.1126/scitranslmed.aau7534] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 12/18/2018] [Accepted: 05/02/2019] [Indexed: 01/02/2023]
Abstract
Advanced ovarian cancer is frequently treated with combination chemotherapy, but high recurrence rates show the need for therapies that can produce durable responses and extend overall survival. Bispecific antibodies that interact with tumor antigens on cancer cells and activating receptors on immune cells offer an innovative immunotherapy approach. Here, we describe a human bispecific antibody (REGN4018) that binds both Mucin 16 (MUC16), a glycoprotein that is highly expressed on ovarian cancer cells, and CD3, thus bridging MUC16-expressing cells with CD3+ T cells. REGN4018 induced T cell activation and killing of MUC16-expressing tumor cells in vitro. Binding and cytotoxicity of REGN4018 in vitro were minimally affected by high concentrations of CA-125, the shed form of MUC16, which is present in patients. In preclinical studies with human ovarian cancer cells and human T cells in immunodeficient mice, REGN4018 potently inhibited growth of intraperitoneal ovarian tumors. Moreover, in a genetically engineered immunocompetent mouse expressing human CD3 and human MUC16 [humanized target (HuT) mice], REGN4018 inhibited growth of murine tumors expressing human MUC16, and combination with an anti–PD-1 antibody enhanced this efficacy. Immuno-PET imaging demonstrated localization of REGN4018 in MUC16-expressing tumors and in T cell–rich organs such as the spleen and lymph nodes. Toxicology studies in cynomolgus monkeys showed minimal and transient increases in serum cytokines and C-reactive protein after REGN4018 administration, with no overt toxicity. Collectively, these data demonstrate potent antitumor activity and good tolerability of REGN4018, supporting clinical evaluation of REGN4018 in patients with MUC16-expressing advanced ovarian cancer.
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Cho Y, Milane L, Amiji MM. Genetic and epigenetic strategies for advancing ovarian cancer immunotherapy. Expert Opin Biol Ther 2019; 19:547-560. [DOI: 10.1080/14712598.2019.1602605] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- Youngwoo Cho
- School of Pharmacy, Bouve College of Health Sciences, Northeastern University, Boston, MA, USA
| | - Lara Milane
- Department of Pharmaceutical Science, Bouve College of Health Sciences, Northeastern University, Boston, MA, USA
| | - Mansoor M. Amiji
- Department of Pharmaceutical Science, School of Pharmacy, Bouve College of Health Sciences, Northeastern University, Boston, MA, USA
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Shen S, Wang G, Zhang R, Zhao Y, Yu H, Wei Y, Chen F. Development and validation of an immune gene-set based Prognostic signature in ovarian cancer. EBioMedicine 2019; 40:318-326. [PMID: 30594555 PMCID: PMC6412087 DOI: 10.1016/j.ebiom.2018.12.054] [Citation(s) in RCA: 183] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 12/16/2018] [Accepted: 12/21/2018] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Ovarian cancer (OV) is the most lethal gynecological cancer in women. We aim to develop a generalized, individualized immune prognostic signature that can stratify and predict overall survival for ovarian cancer. METHODS The gene expression profiles of ovarian cancer tumor tissue samples were collected from 17 public cohorts, including 2777 cases totally. Single sample gene set enrichment (ssGSEA) analysis was used for the immune genes from ImmPort database to develop an immune-based prognostic score for OV (IPSOV). The signature was trained and validated in six independent datasets (n = 519, 409, 606, 634, 415, 194). FINDINGS The IPSOV significantly stratified patients into low- and high-immune risk groups in the training set and in the 5 validation sets (HR range: 1.71 [95%CI: 1.32-2.19; P = 4.04 × 10-5] to 2.86 [95%CI: 1.72-4.74; P = 4.89 × 10-5]). Further, we compared IPSOV with nine reported ovarian cancer prognostic signatures as well as the clinical characteristics including stage, grade and debulking status. The IPSOV achieved the highest mean C-index (0.625) compared with the other signatures (0.516 to 0.602) and clinical characteristics (0.555 to 0.583). Further, we integrated IPSOV with stage, grade and debulking, which showed improved prognostic accuracy than clinical characteristics only. INTERPRETATION The proposed clinical-immune signature is a promising biomarker for estimating overall survival in ovarian cancer. Prospective studies are needed to further validate its analytical accuracy and test the clinical utility. FUND: This work was supported by National Key Research and Development Program of China, National Natural Science Foundation of China and Natural Science Foundation of the Jiangsu Higher Education Institutions of China.
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Affiliation(s)
- Sipeng Shen
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, China; Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Guanrong Wang
- National Health and Family Planning Commission Contraceptives Adverse Reaction Surveillance Center, Jiangsu Institute of Planned Parenthood Research, China
| | - Ruyang Zhang
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, China; Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Yang Zhao
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, China; Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Hao Yu
- Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Yongyue Wei
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, China; Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Feng Chen
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, China; Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
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Asiedu GB, Ridgeway JL, Carroll K, Jatoi A, Radecki Breitkopf C. "Ultimately, mom has the call": Viewing clinical trial decision making among patients with ovarian cancer through the lens of relational autonomy. Health Expect 2018; 21:981-989. [PMID: 29655265 PMCID: PMC6250882 DOI: 10.1111/hex.12691] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/09/2018] [Indexed: 02/02/2023] Open
Abstract
OBJECTIVE This study employs the concept of relational autonomy to understand how relational encounters with family members (FMs) and care providers may shape decisions around ovarian cancer patients' clinical trial (CT) participation. The study also offers unique insights into how FMs view patients' decision making. METHODS In-depth interviews were conducted with 33 patients with ovarian cancer who had been offered a CT and 39 FMs. Data were inductively analysed using a thematic approach and deductively informed by constructs derived from the theory of relational autonomy (RA). RESULTS Patients' relationships, experiences and social status were significant resources that shaped their decisions. Patients did not give equal weight to all relationships and created boundaries around whom to include in decision making. Doctors' recommendations and perceived enthusiasm were described as influential in CT decisions. Both patients with ovarian cancer and their FMs maintained that patients have the "final say," indicating an individualistic autonomy. However, maintaining the "final say" in the decision-making process is constitutive of patients' relationships, emphasizing a relational approach to autonomy. FMs support patients' autonomy and they do so particularly when they believe the patient is capable of making the right choices. CONCLUSIONS Although ethical principles underlying informed consent for CT participation emphasize individual autonomy, greater attention to relational autonomy is warranted for a more comprehensive understanding of CT decision making.
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Affiliation(s)
- Gladys B. Asiedu
- Robert D. and Patricia E. Kern Center for the Science of Health Care DeliveryMayo ClinicRochesterMNUSA
- Department of Health Sciences ResearchMayo ClinicRochesterMNUSA
| | - Jennifer L. Ridgeway
- Robert D. and Patricia E. Kern Center for the Science of Health Care DeliveryMayo ClinicRochesterMNUSA
| | - Katherine Carroll
- Robert D. and Patricia E. Kern Center for the Science of Health Care DeliveryMayo ClinicRochesterMNUSA
- College of Arts and Social SciencesAustralian National UniversityCanberraACTAustralia
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VISTA expressed in tumour cells regulates T cell function. Br J Cancer 2018; 120:115-127. [PMID: 30382166 PMCID: PMC6325144 DOI: 10.1038/s41416-018-0313-5] [Citation(s) in RCA: 146] [Impact Index Per Article: 20.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 09/24/2018] [Accepted: 10/02/2018] [Indexed: 12/13/2022] Open
Abstract
Background V-domain Ig suppressor of T cell activation (VISTA) is a novel inhibitory immune-checkpoint protein. VISTA expression on tumour cells and the associated regulatory mechanisms remain unclear. We investigated VISTA expression and function in tumour cells, and evaluated its mechanism and activity. Methods VISTA in tumour cells was assessed by tissue microarray analysis, immunohistochemical staining and western blot. A series of in vitro assays were used to determine the function of tumour-expressed VISTA. In vivo efficacy was evaluated in syngeneic models. Results VISTA was highly expressed in human ovarian and endometrial cancers. Upregulation of VISTA in endometrial cancer was related to the methylation status of the VISTA promoter. VISTA in tumour cells suppressed T cell proliferation and cytokine production in vitro, and decreased the tumour-infiltrating CD8+ T cells in vivo. Anti-VISTA antibody prolonged the survival of tumour-bearing mice. Conclusions This is the first demonstration that VISTA is highly expressed in human ovarian and endometrial cancer cells, and that anti-VISTA antibody treatment significantly prolongs the survival of mice bearing tumours expressing high levels of VISTA. The data suggest that VISTA is a novel immunosuppressive factor within the tumour microenvironment, as well as a new target for cancer immunotherapy.
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Immune Modulatory Potential of Anti-idiotype Antibodies as a Surrogate of Foot-and-Mouth Disease Virus Antigen. mSphere 2018; 3:3/5/e00522-18. [PMID: 30333183 PMCID: PMC6193604 DOI: 10.1128/msphere.00522-18] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Foot-and-mouth disease (FMD) is a contagious viral disease of animals. Multiple serotypes and antigenic variation in the viral genome are probably the factors that reduce control of the disease. Currently, the vaccines employed against FMD use killed virus. The inactivation or killing of the virus makes it less immunogenic and reduces its immunoprophylactic potential. To cope with this situation, the present study was designed, anti-idiotype FMD virus antigen was prepared, and the immunogenic potential of the antigen was compared to that of commercial killed-virus vaccines. The overall results showed that a persistent and strong immune response occurred with anti-idiotype FMD virus antigen. Thus, anti-idiotype FMD virus antigen may serve as a potential surrogate of FMD virus vaccines. The immunoprophylactic potential of anti-idiotype (anti-id) foot-and-mouth disease (FMD) antigen (Ag) was evaluated in the calves. The idiotype antibodies (Ab1) were produced in experimental goats by injecting inactivated FMD virus. The Fab (fragment antigen binding) of Ab1 was injected into the layer birds to raise anti-id antibodies (Ab2). The Ab2 was purified from egg yolks. The Fab component of Ab2 was emulsified in Montanide (1:1) and used as a surrogate of FMD virus. The immune response to Montanide adjuvanted monovalent and trivalent anti-id FMD virus antigen was determined in mice. The comparative immune potentiation potentials of Montanide adjuvanted trivalent anti-id FMD virus antigen and trivalent FMD vaccine were determined in mice and calves. Montanide adjuvanted monovalent anti-id FMD virus antigens produced mean Ab titers of 78.80%, 81.30%, and 81.20% for serotypes A, Asia 1, and O, respectively, at 45 days postimmunization (p.i.) in mice. Montanide adjuvanted trivalent anti-id FMD Ag in mice produced the highest Ab titer, 81.60%, at day 45 compared to the 77.50% titer measured for Montanide adjuvanted FMD vaccine at day 45 p.i. A slow decrease of 1% to 2% was recorded for the Ab titer of Montanide adjuvanted trivalent anti-id FMD virus antigen in mice at day 60. In calves, the titer corresponding to the immune response seen with Montanide adjuvanted trivalent anti-id FMD virus antigen (80%) was persistent whereas the titer of Montanide adjuvanted FMD vaccine decreased to 74% at day 60 p.i. Anti-id FMD virus antigen induced a strong and persistent immunogenic response in terms of Ab titer compared to the inactivated virus vaccine. Anti-id FMD virus antigen may serve as a surrogate of FMD virus vaccine. IMPORTANCE Foot-and-mouth disease (FMD) is a contagious viral disease of animals. Multiple serotypes and antigenic variation in the viral genome are probably the factors that reduce control of the disease. Currently, the vaccines employed against FMD use killed virus. The inactivation or killing of the virus makes it less immunogenic and reduces its immunoprophylactic potential. To cope with this situation, the present study was designed, anti-idiotype FMD virus antigen was prepared, and the immunogenic potential of the antigen was compared to that of commercial killed-virus vaccines. The overall results showed that a persistent and strong immune response occurred with anti-idiotype FMD virus antigen. Thus, anti-idiotype FMD virus antigen may serve as a potential surrogate of FMD virus vaccines.
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