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Zhang Y, Li X, Chen H, Li J, Guo X, Fang Y, Chen L, Li K, Zhang Y, Kong F, Chen A, Lyu J, Zhang W, Wang Z. Cancer Cell-Derived Exosomal miR-500a-3p Modulates Hepatic Stellate Cell Activation and the Immunosuppressive Microenvironment. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2404089. [PMID: 39574357 PMCID: PMC11727405 DOI: 10.1002/advs.202404089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 11/01/2024] [Indexed: 01/14/2025]
Abstract
Hepatocellular carcinoma (HCC) mainly depends on liver fibrosis/cirrhosis, which is regulated by tumor cells and the tumor microenvironment (TME), and is a crucial factor in tumor progression. This study aimed to identify abnormally expressed miR-500a-3p in the hepatitis-cirrhosis-HCC pathway and explored the roles of miR-500a-3p in HCC progression. A clinical cohort of patients with HCC is studied retrospectively. Subsequently, the role of miR-500a-3p transported by HCC exosomes in hepatic stellate cell (HSC) activation, hepatoma growth and invasion, and immune cell differentiation is determined by in vitro and in vivo experiments. In clinical tissues, miR-500a-3p is significantly enriched in HCC and cirrhosis tissues, and co-expression of the immune marker CD4 or PD-L1 significantly correlates with low survival rates in patients. Extracellular miR-500a-3p is taken up by HSC and PBMC, which promotes the secretion of the cytokines TGF-β1 and IL-10, increases PD-L1 expression in HSC, and stabilizes PD-1 expression in PBMC to affect the TME. Moreover, miR-500a-3p is associated with CD4+ T-cell exhaustion and Treg differentiation and is significantly associated with increased tumorigenicity in in situ mouse HCC models. Mechanistically, HCC-derived exosomal miR-500a-3p directly influences SOCS2 to regulate the JAK3/STAT5A/STAT5B signaling pathway. MiR-500a-3p promotes the growth and migration of HCC through the SOCS2/JAK3/STAT5A/STAT5B axis.
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Affiliation(s)
- Yu Zhang
- Cancer CenterDepartment of GastroenterologyZhejiang Provincial People's Hospital (Affiliated People's Hospital)Hangzhou Medical CollegeHangzhouZhejiang310014China
| | - Xin Li
- School of Ophthalmology and Optometry and Eye HospitalWenzhou Medical UniversityWenzhouZhejiang325035China
| | - Huiyan Chen
- Laboratory Medicine CenterAllergy CenterDepartment of Transfusion MedicineZhejiang Provincial People's Hospital (Affiliated People's Hospital)Hangzhou Medical CollegeHangzhou310014China
| | - Jiawei Li
- School of Ophthalmology and Optometry and Eye HospitalWenzhou Medical UniversityWenzhouZhejiang325035China
| | - Xiaohuan Guo
- Laboratory Medicine CenterAllergy CenterDepartment of Transfusion MedicineZhejiang Provincial People's Hospital (Affiliated People's Hospital)Hangzhou Medical CollegeHangzhou310014China
| | - Yilin Fang
- Laboratory Medicine CenterAllergy CenterDepartment of Transfusion MedicineZhejiang Provincial People's Hospital (Affiliated People's Hospital)Hangzhou Medical CollegeHangzhou310014China
| | - Linjie Chen
- Laboratory Medicine CenterAllergy CenterDepartment of Transfusion MedicineZhejiang Provincial People's Hospital (Affiliated People's Hospital)Hangzhou Medical CollegeHangzhou310014China
| | - Kaiqiang Li
- Laboratory Medicine CenterAllergy CenterDepartment of Transfusion MedicineZhejiang Provincial People's Hospital (Affiliated People's Hospital)Hangzhou Medical CollegeHangzhou310014China
| | - Yi Zhang
- Laboratory Medicine CenterAllergy CenterDepartment of Transfusion MedicineZhejiang Provincial People's Hospital (Affiliated People's Hospital)Hangzhou Medical CollegeHangzhou310014China
| | - Fei Kong
- Laboratory Medicine CenterAllergy CenterDepartment of Transfusion MedicineZhejiang Provincial People's Hospital (Affiliated People's Hospital)Hangzhou Medical CollegeHangzhou310014China
| | - Aodong Chen
- School of Ophthalmology and Optometry and Eye HospitalWenzhou Medical UniversityWenzhouZhejiang325035China
| | - Jianxin Lyu
- Laboratory Medicine CenterAllergy CenterDepartment of Transfusion MedicineZhejiang Provincial People's Hospital (Affiliated People's Hospital)Hangzhou Medical CollegeHangzhou310014China
| | - Wei Zhang
- Department of General SurgeryThe second affiliated hospital of Zhejiang Chinese Medical UniversityHangzhou310015China
| | - Zhen Wang
- Laboratory Medicine CenterAllergy CenterDepartment of Transfusion MedicineZhejiang Provincial People's Hospital (Affiliated People's Hospital)Hangzhou Medical CollegeHangzhou310014China
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Kitsel Y, Petre EN, Wong P, Sotirchos V, Vakiani E, Dimopoulos PM, Ganesh K, Rousseau B, Sofocleous CT. Systemic Immunological Changes After Yttrium-90 Radioembolization: A Pilot Prospective Observational Study-Clinical Insights. Cardiovasc Intervent Radiol 2024; 47:1461-1470. [PMID: 39406871 DOI: 10.1007/s00270-024-03870-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 09/19/2024] [Indexed: 11/08/2024]
Abstract
PURPOSE To prospectively investigate levels of circulating cytokines, changes in frequencies of various immune cell subsets and expression of proliferation and checkpoint molecules on T cells in the peripheral blood after yttrium-90 radioembolization (TARE) of colorectal cancer liver metastases (CLM). MATERIALS AND METHODS We prospectively collected, isolated, and froze peripheral blood mononuclear cells (PBMC) and plasma samples from 15 patients immediately before, immediately after, 3 and 6 weeks post-TARE of CLM. Plasma samples were assessed for various cytokines using a multiplex immunoassay platform. PBMC samples were analyzed in a monocyte/dendritic cell (DC)/B cell flow panel and a T cell activation/exhaustion flow phenotyping panel. We compared the levels at the respective time points using Wilcoxon signed rank test. RESULTS IFN-g significantly decreased immediately after (mean 1.62 vs. 3.02 at baseline, p = 0.04) and increased at 6 weeks compared to the immediately post-TARE nadir (mean 9.42 vs. 1.62, p = 0.04). IL-10 decreased at 3 weeks (mean 0.36 vs. 1.75, p = 0.025) post-TARE compared to baseline. Increased CD3+T cells (mean 78.24 vs. 60.8, p = 0.002) and decreased CTLA-4+CD4+T cells (mean 2.58 vs. 4.41, p = 0.033) were observed at 3 weeks compared to baseline. Increased Ki-67+ proliferating CD8+T cells at 3 and 6 weeks (mean 7.28 and 9.06, respectively, vs. 3.93 at baseline, p = 0.02 and 0.03) were recorded. CONCLUSION A shift toward a favorable antitumoral cytokinic and immune cells response was observed after TARE. Significant changes were in specialized immune cells subsets playing important roles in the activation of the immune system. These results support trials combining TARE with immunotherapy for patients with CLM.
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Affiliation(s)
- Yuliya Kitsel
- Interventional Oncology/Radiology Service, Memorial Sloan Kettering Cancer Center, 1275 York Avenue; IR Suite H118, New York, NY, 10075, USA
- Department of Imaging Physics, MD Anderson Cancer Center, Houston, TX, USA
| | - Elena N Petre
- Interventional Oncology/Radiology Service, Memorial Sloan Kettering Cancer Center, 1275 York Avenue; IR Suite H118, New York, NY, 10075, USA
| | - Phillip Wong
- Immune Monitoring Core Facility, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Vlasios Sotirchos
- Interventional Oncology/Radiology Service, Memorial Sloan Kettering Cancer Center, 1275 York Avenue; IR Suite H118, New York, NY, 10075, USA
| | - Efsevia Vakiani
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Platon M Dimopoulos
- Interventional Oncology/Radiology Service, Memorial Sloan Kettering Cancer Center, 1275 York Avenue; IR Suite H118, New York, NY, 10075, USA
- General University Hospital of Patras, Rio, Patras, Greece
| | - Karuna Ganesh
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Benoit Rousseau
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Constantinos T Sofocleous
- Interventional Oncology/Radiology Service, Memorial Sloan Kettering Cancer Center, 1275 York Avenue; IR Suite H118, New York, NY, 10075, USA.
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Leland P, Degheidy H, Lea A, Bauer SR, Puri RK, Joshi BH. Identification and characterisation of novel CAR-T cells to target IL13Rα2 positive human glioma in vitro and in vivo. Clin Transl Med 2024; 14:e1664. [PMID: 38685487 PMCID: PMC11058282 DOI: 10.1002/ctm2.1664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Revised: 04/02/2024] [Accepted: 04/04/2024] [Indexed: 05/02/2024] Open
Abstract
BACKGROUND Previously, we discovered that human solid tumours, but not normal human tissues, preferentially overexpress interleukin-13Receptor alpha2, a high binding receptor for IL-13. To develop novel anti-cancer approaches, we constructed a chimeric antigen receptor construct using a high binding and codon optimised scFv-IL-13Rα2 fragment fused with CD3ζ and co-stimulatory cytoplasmic domains of CD28 and 4-1BB. METHODS We developed a scFv clone, designated 14-1, by biopanning the bound scFv phages using huIL-13Rα2Fc chimeric protein and compared its binding with our previously published clone 4-1. We performed bioinformatic analyses for complementary determining regions (CDR) framework and residue analyses of the light and heavy chains. This construct was packaged with helper plasmids to produce CAR-lentivirus and transduced human Jurkat T or activated T cells from peripheral blood mononuclear cells (PBMCs) to produce CAR-T cells and tested for their quality attributes in vitro and in vivo. Serum enzymes including body weight from non-tumour bearing mice were tested for assessing general toxicity of CAR-T cells. RESULTS The binding of 14-1 clone is to IL-13Rα2Fc-chimeric protein is ∼5 times higher than our previous clone 4-1. The 14-1-CAR-T cells grew exponentially in the presence of cytokines and maintained phenotype and biological attributes such as cell viability, potency, migration and T cell activation. Clone 14-1 migrated to IL-13Rα2Fc and cell free supernatants only from IL-13Rα2+ve confluent glioma tumour cells in a chemotaxis assay. scFv-IL-13Rα2-CAR-T cells specifically killed IL-13Rα2+ve but not IL-13Rα2-ve tumour cells in vitro and selectively caused significant release of IFN-γ only from IL-13Rα2+ve co-cultures. These CAR-T cells regressed IL-13Rα2+ve glioma xenografts in vivo without any general toxicity. In contrast, the IL-13Rα2 gene knocked-down U251 and U87 xenografts failed to respond to the CAR-T therapy. CONCLUSION Taken together, we conclude that the novel scFv-IL-13Rα2 CAR-T cell therapy may offer an effective therapeutic option after designing a careful pre-clinical and clinical study.
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Affiliation(s)
- Pamela Leland
- Tumor Vaccine and Biotechnology BranchDivision of Cell Therapy IISilver SpringMarylandUSA
| | - Heba Degheidy
- Cellular and Tissue Therapy Branch, Office of Cellular Therapy & Human Tissues, Office of Therapeutic ProductsCenter for Biologics Evaluation and ResearchU.S. Food and Drug Administration, White OakSilver SpringMarylandUSA
| | - Ashley Lea
- Tumor Vaccine and Biotechnology BranchDivision of Cell Therapy IISilver SpringMarylandUSA
| | - Steven R. Bauer
- Cellular and Tissue Therapy Branch, Office of Cellular Therapy & Human Tissues, Office of Therapeutic ProductsCenter for Biologics Evaluation and ResearchU.S. Food and Drug Administration, White OakSilver SpringMarylandUSA
- Wake Forest Institute for Regenerative MedicineWinston‐SalemNorth CarolinaUSA
| | - Raj K. Puri
- Tumor Vaccine and Biotechnology BranchDivision of Cell Therapy IISilver SpringMarylandUSA
- Iovance Biotherapeutics, Inc.FrederickMarylandUSA
| | - Bharat H. Joshi
- Tumor Vaccine and Biotechnology BranchDivision of Cell Therapy IISilver SpringMarylandUSA
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Xu J, Gan C, Yu S, Yao S, Li W, Cheng H. Analysis of Immune Resistance Mechanisms in TNBC: Dual Effects Inside and Outside the Tumor. Clin Breast Cancer 2024; 24:e91-e102. [PMID: 38016911 DOI: 10.1016/j.clbc.2023.10.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 10/30/2023] [Indexed: 11/30/2023]
Abstract
Triple-negative breast cancer (TNBC) is a unique subtype of breast cancer characterized by the lack of expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. TNBC exhibits a high degree of aggressiveness, metastatic potential, and a poor prognosis. Despite the limited success of conventional treatments, immune checkpoint inhibitors (ICIs) have emerged as promising therapeutics for TNBC. Therefore, understanding the mechanisms underlying innate and acquired resistance to ICIs in TNBC is essential. Numerous studies suggest that intrinsic and extrinsic factors significantly contribute to the development of ICI resistance in TNBC. Intrinsic resistance may result from alterations in tumor-intrinsic signaling pathways, such as dysregulation of interferon (IFN) signaling or other signaling pathways. In contrast, extratumoral mechanisms may develop due to alterations in the tumor microenvironment, changes in T cell-related factors or adaptations within the immune system itself. In this paper, we endeavor to elucidate the underlying mechanisms of immune resistance by systematically examining immune mechanisms, the present state of immunotherapy, and the processes of immune resistance. Nonetheless, enhancing our understanding of the mechanisms underlying intratumoral and extratumoral resistance to ICIs in TNBC is crucial for optimizing patient outcomes in this challenging disease. Persistent efforts to identify novel targets for combination therapies, biomarkers that can predict the response to immunotherapy, and resistance mechanisms will be instrumental in achieving this objective.
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Affiliation(s)
- Jian Xu
- Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; The Second Clinical College of Anhui Medical University, Hefei, Anhui, China
| | - Chen Gan
- Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; The Second Clinical College of Anhui Medical University, Hefei, Anhui, China
| | - Sheng Yu
- Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; The Second Clinical College of Anhui Medical University, Hefei, Anhui, China
| | - Senbang Yao
- Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; The Second Clinical College of Anhui Medical University, Hefei, Anhui, China
| | - Wen Li
- Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; The Second Clinical College of Anhui Medical University, Hefei, Anhui, China
| | - Huaidong Cheng
- Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; Shenzhen Clinical Medical School of Southern Medical University, Shenzhen, Guangdong, China; Department of Oncology, Shenzhen Hospital of Southern Medical University, Shenzhen, Guangdong, China.
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5
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Qin Z, Zhu F, Xie B, Zhang Y, Yuan M, Yang P, Zhang L, Wei J, Zhu Z, Qian Z, Wang Z, Fan L, Xu S, Tan Y, Qian J. Comprehensive analysis of ASB3 as a prognostic biomarker in hepatocellular carcinoma. Transl Oncol 2024; 39:101816. [PMID: 37925796 PMCID: PMC10654593 DOI: 10.1016/j.tranon.2023.101816] [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: 07/15/2023] [Revised: 10/15/2023] [Accepted: 10/22/2023] [Indexed: 11/07/2023] Open
Abstract
BACKGROUND Some reports have indicated a high expression level of ASB3 in various cancers, but its role in hepatocellular carcinoma (HCC) remains elusive. METHODS ASB3 levels and clinical features were obtained from the TCGA database. Meanwhile, the expression levels of ASB3 in tumor and paraneoplastic tissues were further verified by qRT-PCR and Imunohistochemistry (IHC). ASB3-related downstream molecular analysis was carried out with Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Pathways linked to ASB3 expression were identified by means of gene set enrichment analysis (GSEA). Single-sample GSEA (ssGSEA) aided in conducting a correlation analysis of ASB3 with immune infiltration. Functional experiments were performed in HepG2 cells by using the small interfering RNA. RESULTS ASB3 expression was remarkably higher in HCC tissues. Its remarkable precision in forecasting cancer suggests that ASB3 might serve as an unidentified diagnostic and prognostic indicator of HCC. Higher ASB3 expression led to worse overall survival (OS), particularly in various clinical subgroups of HCC. GO/KEGG analysis indicated that critical biological activities, such as the activation of complement systems and humoral immune response, could potentially underlie the progression of HCC. Furthermore, GSEA demonstrated enrichment of certain pathways, including the MAPK, IL17, and fibrinolysis pathways, in samples with elevated ASB3 levels. ASB3 exhibited a substantial association with T helper cells, dendritic cells (DCs), and central memory T (Tcm) cell infiltration level. Cell function experiments confirmed elevated ASB3 levels in HCC cell lines as opposed to hepatic epithelial cell lines. Moreover, the ability of HCC cells to proliferate and invade was remarkably reduced by ASB3 knockdown. CONCLUSION Summarize briefly, we found that ASB3 can be a promising biomarker in HCC.
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Affiliation(s)
- Zhongqiang Qin
- Department of Interventional Radiology, The First Affiliated Hospital of Bengbu Medical College, No 287 Changhuai Road, Longzihu District, Bengbu, Anhui Province 233000, China
| | - Fangquan Zhu
- Department of Cancer Center, Lu'an Hospital of Anhui Medical University, Lu'an, China
| | - Bo Xie
- Department of Interventional Radiology, The First Affiliated Hospital of Bengbu Medical College, No 287 Changhuai Road, Longzihu District, Bengbu, Anhui Province 233000, China
| | - Yang Zhang
- Department of Interventional Radiology, The First Affiliated Hospital of Bengbu Medical College, No 287 Changhuai Road, Longzihu District, Bengbu, Anhui Province 233000, China
| | - Mu Yuan
- Department of Interventional Radiology, The First Affiliated Hospital of Bengbu Medical College, No 287 Changhuai Road, Longzihu District, Bengbu, Anhui Province 233000, China
| | - Peipei Yang
- Department of Interventional Radiology, The First Affiliated Hospital of Bengbu Medical College, No 287 Changhuai Road, Longzihu District, Bengbu, Anhui Province 233000, China
| | - Lan Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Jianzhu Wei
- Department of Interventional Radiology, The First Affiliated Hospital of Bengbu Medical College, No 287 Changhuai Road, Longzihu District, Bengbu, Anhui Province 233000, China
| | - Ziyi Zhu
- Department of Interventional Radiology, The First Affiliated Hospital of Bengbu Medical College, No 287 Changhuai Road, Longzihu District, Bengbu, Anhui Province 233000, China
| | - Zhen Qian
- Department of Interventional Radiology, The First Affiliated Hospital of Bengbu Medical College, No 287 Changhuai Road, Longzihu District, Bengbu, Anhui Province 233000, China
| | - Zhaoying Wang
- Department of Interventional Radiology, The First Affiliated Hospital of Bengbu Medical College, No 287 Changhuai Road, Longzihu District, Bengbu, Anhui Province 233000, China
| | - Longfei Fan
- Department of Interventional Radiology, The First Affiliated Hospital of Bengbu Medical College, No 287 Changhuai Road, Longzihu District, Bengbu, Anhui Province 233000, China
| | - Shuaishuai Xu
- Department of Interventional Radiology, The First Affiliated Hospital of Bengbu Medical College, No 287 Changhuai Road, Longzihu District, Bengbu, Anhui Province 233000, China
| | - Yulin Tan
- Department of Interventional Radiology, The First Affiliated Hospital of Bengbu Medical College, No 287 Changhuai Road, Longzihu District, Bengbu, Anhui Province 233000, China
| | - Jingyu Qian
- Department of Interventional Radiology, The First Affiliated Hospital of Bengbu Medical College, No 287 Changhuai Road, Longzihu District, Bengbu, Anhui Province 233000, China
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Xiao Y, Zhou H, Chen Y, Liu L, Wu Q, Li H, Lin P, Li J, Wu J, Tang L. A novel anoikis-related gene prognostic signature and its correlation with the immune microenvironment in colorectal cancer. Front Genet 2023; 14:1186862. [PMID: 37323657 PMCID: PMC10265740 DOI: 10.3389/fgene.2023.1186862] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 05/15/2023] [Indexed: 06/17/2023] Open
Abstract
Background: Anoikis is a type of apoptosis associated with cell detachment. Resistance to anoikis is a focal point of tumor metastasis. This study aimed to explore the relationship among anoikis-related genes (ARGs), immune infiltration, and prognosis in colorectal cancer (CRC). Methods: The transcriptome profile and clinical data on patients with CRC were retrieved from The Cancer Genome Atlas and Gene Expression Omnibus databases. Patients were divided into two clusters based on the expression of ARGs. Differences between the two ARG molecular subtypes were analyzed in terms of prognosis, functional enrichment, gene mutation frequency, and immune cell infiltration. An ARG-related prognostic signature for predicting overall survival in patients with CRC was developed and validated using absolute value convergence and selection operator (LASSO) regression analysis. The correlation between the signature risk score and clinicopathological features, immune cell infiltration, immune typing, and immunotherapy response was analyzed. The risk score combined with clinicopathological characteristics was used to construct a nomogram to assess CRC patients' prognosis. Results: Overall, 151 ARGs were differentially expressed in CRC. Two ARG subtypes, namely, ARG-high and ARG-low groups, were identified and correlated with CRC prognosis. The gene mutation frequency and immune, stromal, and ESTIMATE scores of the ARG-high group were higher than those of the ARG-low group. Moreover, CD8, natural killer cells, M1 macrophages, human leukocyte antigen (HLA), and immune checkpoint-related genes were significantly increased in the ARG-high group. An optimized 25-gene CRC prognostic signature was successfully constructed, and its prognostic predictive ability was validated. The high-risk score was correlated with T, N, M, and TNM stages. Risk scores were negatively correlated with dendritic cells, eosinophils, and CD4 cells, and significantly positively correlated with regulatory T cells. Patients in the high-risk group were more likely to exhibit immune unresponsiveness. Finally, the nomogram model was constructed and showed good prognostic predictive power. Conclusion: ARGs are associated with clinicopathological features and the prognosis of CRC, and play important roles in the immune microenvironment. Herein, we underpinned the usefulness of ARGs in CRC to develop more effective immunotherapy techniques.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Junxin Wu
- *Correspondence: Lirui Tang, ; Junxin Wu,
| | - Lirui Tang
- *Correspondence: Lirui Tang, ; Junxin Wu,
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Faeq MH, Al-Haideri M, Mohammad TAM, Gharebakhshi F, Marofi F, Tahmasebi S, Modaresahmadi S. CAR-modified immune cells as a rapidly evolving approach in the context of cancer immunotherapies. Med Oncol 2023; 40:155. [PMID: 37083979 PMCID: PMC10119530 DOI: 10.1007/s12032-023-02019-4] [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: 03/06/2023] [Accepted: 03/28/2023] [Indexed: 04/22/2023]
Abstract
Nowadays, one of the main challenges clinicians face is malignancies. Through the progression of technology in recent years, tumor nature and tumor microenvironment (TME) can be better understood. Because of immune system involvement in tumorigenesis and immune cell dysfunction in the tumor microenvironment, clinicians encounter significant challenges in patient treatment and normal function recovery. The tumor microenvironment can stop the development of tumor antigen-specific helper and cytotoxic T cells in the tumor invasion process. Tumors stimulate the production of proinflammatory and immunosuppressive factors and cells that inhibit immune responses. Despite the more successful outcomes, the current cancer therapeutic approaches, including surgery, chemotherapy, and radiotherapy, have not been effective enough for tumor eradication. Hence, developing new treatment strategies such as monoclonal antibodies, adaptive cell therapies, cancer vaccines, checkpoint inhibitors, and cytokines helps improve cancer treatment. Among adoptive cell therapies, the interaction between the immune system and malignancies and using molecular biology led to the development of chimeric antigen receptor (CAR) T cell therapy. CAR-modified immune cells are one of the modern cancer therapeutic methods with encouraging outcomes in most hematological and solid cancers. The current study aimed to discuss the structure, formation, subtypes, and application of CAR immune cells in hematologic malignancies and solid tumors.
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Affiliation(s)
- Mohammed Hikmat Faeq
- Student of General Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maysoon Al-Haideri
- Department of Physiotherapy, Cihan University-Erbil, Kurdistan Region, Erbil, Iraq
| | - Talar Ahmad Merza Mohammad
- Department of Pharmacology, College of Pharmacy, Hawler Medical University, Kurdistan Region, Erbil, Iraq
| | - Farshad Gharebakhshi
- Department of Radiology, School of Medicine, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Faroogh Marofi
- Department of Hematology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Safa Tahmasebi
- Student Research Committee, Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Shadan Modaresahmadi
- Department of Immunology and Biotechnology, Texas Tech University Health Siences Center, Abilene, TX, USA
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8
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Lei Y, Lin L, Cheng S, Shao Q, Ding C, Zuo R, Chen W, Liao Q, Liu G. Acute inflammatory reaction during anti-angiogenesis therapy combined with immunotherapy as a possible indicator of the therapeutic effect: Three case reports and literature review. Front Oncol 2023; 13:1072480. [PMID: 37124541 PMCID: PMC10140593 DOI: 10.3389/fonc.2023.1072480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 03/27/2023] [Indexed: 05/02/2023] Open
Abstract
The posterior line treatment of unresectable advanced or metastatic gastrointestinal (GI) tumors has always been a challenging point. In particular, for patients with microsatellite stable (MSS)/mismatch repair proficient (pMMR) 0GI tumors, the difficulty of treatment is exacerbated due to their insensitivity to immune drugs. Accordingly, finding a new comprehensive therapy to improve the treatment effect is urgent. In this study, we report the treatment histories of three patients with MSS/pMMR GI tumors who achieved satisfactory effects by using a comprehensive treatment regimen of apatinib combined with camrelizumab and TAS-102 after the failure of first- or second-line regimens. The specific contents of the treatment plan were as follows: apatinib (500 mg/d) was administered orally for 10 days, followed by camrelizumab (200 mg, ivgtt, day 1, 14 days/cycle) and TAS-102 (20 mg, oral, days 1-21, 28 days/cycle). Apatinib (500 mg/d) was maintained during treatment. Subsequently, we discuss the possible mechanism of this combination and review the relevant literature, and introduce clinical trials on anti-angiogenesis therapy combined with immunotherapy.
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Affiliation(s)
- Yihui Lei
- The School of Clinical Medical, Fujian Medical University, Fuzhou, Fujian, China
| | - Li Lin
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Shuyu Cheng
- Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China
| | - Qiming Shao
- The School of Clinical Medical, Fujian Medical University, Fuzhou, Fujian, China
| | - Chenchun Ding
- Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China
| | - Renjie Zuo
- Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China
| | - Weiping Chen
- The School of Clinical Medical, Fujian Medical University, Fuzhou, Fujian, China
| | - Quan Liao
- Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China
| | - Guoyan Liu
- The School of Clinical Medical, Fujian Medical University, Fuzhou, Fujian, China
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China
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Yuan S, Chen W, Yang J, Zheng Y, Ye W, Xie H, Dong L, Xie J. Tumor‑associated macrophage‑derived exosomes promote EGFR‑TKI resistance in non‑small cell lung cancer by regulating the AKT, ERK1/2 and STAT3 signaling pathways. Oncol Lett 2022; 24:356. [PMID: 36168315 PMCID: PMC9478622 DOI: 10.3892/ol.2022.13476] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 07/13/2022] [Indexed: 11/06/2022] Open
Abstract
The evolutionary properties of organisms lead to the issue of targeted drug resistance. Numerous clinical trials have shown that tumor-associated macrophages (TAMs) in patients with lung cancer adversely affect the clinical efficacy of epithelial growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, the mechanism by which TAMs influence the tumor cell response to TKIs remains unclear. The aim of the present study was to investigate the influence of TAM-derived exosomes on the sensitivity of PC9 and HCC827 lung adenocarcinoma cells to the EGFR inhibitor gefitinib. Multiple cytokines were used to induce the differentiation of THP-1 human leukemia monocytes into macrophages in vitro. The obtained cells were identified as TAMs by cytomorphology and flow cytometry. Exosomes were extracted from the TAM culture supernatants and identified using electron microscopy and nanoparticle tracking analysis. Flow cytometry was used to examine the apoptosis of lung adenocarcinoma cells when treated with gefitinib and/or TAM-derived exosomes. In addition, western blotting was used to detect the expression of the key proteins of the AKT, ERK1/2 and STAT3 signaling pathways. TAM-derived exosomes were successfully obtained. The TAM-derived exosomes were shown to affect the proliferation and apoptosis of lung adenocarcinoma cells. Furthermore, the killing effect of gefitinib on the tumor cells was attenuated. The mechanism underlying the effects of the TAM-derived exosomes may be associated with reactivation of the AKT, ERK1/2 and STAT3 signaling pathways. In conclusion, the findings indicate that TAM-derived exosomes promote resistance to gefitinib in non-small cell lung cancer (NSCLC), and the mechanism may be associated with reactivation of the AKT, ERK1/2 and STAT3 signaling pathways. This study may serve as a reference in the exploration of alternative strategies for NSCLC following the development of resistance to EGFR-targeted drugs.
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Affiliation(s)
- Shiyang Yuan
- Department of Critical Care Medicine, Nanping First Hospital Affiliated to Fujian Medical University, Nanping, Fujian 353000, P.R. China
| | - Wenjun Chen
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Jian Yang
- Department of Critical Care Medicine, Nanping First Hospital Affiliated to Fujian Medical University, Nanping, Fujian 353000, P.R. China
| | - Yuanhai Zheng
- Department of Critical Care Medicine, Nanping First Hospital Affiliated to Fujian Medical University, Nanping, Fujian 353000, P.R. China
| | - Wen Ye
- Department of Critical Care Medicine, Nanping First Hospital Affiliated to Fujian Medical University, Nanping, Fujian 353000, P.R. China
| | - Hui Xie
- Department of Critical Care Medicine, Nanping First Hospital Affiliated to Fujian Medical University, Nanping, Fujian 353000, P.R. China
| | - Lie Dong
- Department of Respiratory and Critical Care Medicine, Nanping First Hospital Affiliated to Fujian Medical University, Nanping, Fujian 353000, P.R. China
| | - Junping Xie
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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10
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Current Knowledge of Immunosuppression as a Risk Factor for Skin Cancer Development. Crit Rev Oncol Hematol 2022; 177:103754. [DOI: 10.1016/j.critrevonc.2022.103754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 06/27/2022] [Accepted: 07/02/2022] [Indexed: 11/23/2022] Open
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11
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Nanomedicine for Immunotherapy Targeting Hematological Malignancies: Current Approaches and Perspective. NANOMATERIALS 2021; 11:nano11112792. [PMID: 34835555 PMCID: PMC8619332 DOI: 10.3390/nano11112792] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/04/2021] [Accepted: 10/18/2021] [Indexed: 12/12/2022]
Abstract
Conventional chemotherapy has partial therapeutic effects against hematological malignancies and is correlated with serious side effects and great risk of relapse. Recently, immunotherapeutic drugs have provided encouraging results in the treatment of hematological malignancies. Several immunotherapeutic antibodies and cell therapeutics are in dynamic development such as immune checkpoint blockades and CAR-T treatment. However, numerous problems restrain the therapeutic effectiveness of tumor immunotherapy as an insufficient anti-tumor immune response, the interference of an immune-suppressive bone marrow, or tumoral milieu with the discharge of immunosuppressive components, access of myeloid-derived suppressor cells, monocyte intrusion, macrophage modifications, all factors facilitating the tumor to escape the anti-cancer immune response, finally reducing the efficiency of the immunotherapy. Nanotechnology can be employed to overcome each of these aspects, therefore having the possibility to successfully produce anti-cancer immune responses. Here, we review recent findings on the use of biomaterial-based nanoparticles in hematological malignancies immunotherapy. In the future, a deeper understanding of tumor immunology and of the implications of nanomedicine will allow nanoparticles to revolutionize tumor immunotherapy, and nanomedicine approaches will reveal their great potential for clinical translation.
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12
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Short Review on Advances in Hydrogel-Based Drug Delivery Strategies for Cancer Immunotherapy. Tissue Eng Regen Med 2021; 19:263-280. [PMID: 34596839 DOI: 10.1007/s13770-021-00369-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 06/10/2021] [Accepted: 06/16/2021] [Indexed: 12/20/2022] Open
Abstract
Cancer immunotherapy has become the new paradigm of cancer treatment. The introduction and discovery of various therapeutic agents have also accelerated the application of immunotherapy in clinical trials. However, despite the significant potency and demonstrated advantages of cancer immunotherapy, its clinical application to patients faces several safety and efficacy issues, including autoimmune reactions, cytokine release syndrome, and vascular leak syndrome-related issues. In addressing these problems, biomaterials traditionally used for tissue engineering and drug delivery are attracting attention. Among them, hydrogels can be easily injected into tumors with drugs, and they can minimize side effects by retaining immune therapeutics at the tumor site for a long time. This article reviews the status of functional hydrogels for effective cancer immunotherapy. First, we describe the basic mechanisms of cancer immunotherapy and the advantages of using hydrogels to apply these mechanisms. Next, we summarize recent advances in the development of functional hydrogels designed to locally release various immunotherapeutic agents, including cytokines, cancer immune vaccines, immune checkpoint inhibitors, and chimeric antigen receptor-T cells. Finally, we briefly discuss the current problems and possible prospects of hydrogels for effective cancer immunotherapy.
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13
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Exploration of prognostic index based on immune-related genes in patients with liver hepatocellular carcinoma. Biosci Rep 2021; 40:225490. [PMID: 32579175 PMCID: PMC7327182 DOI: 10.1042/bsr20194240] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Revised: 06/23/2020] [Accepted: 06/24/2020] [Indexed: 02/08/2023] Open
Abstract
The present study aimed to screen the immune-related genes (IRGs) in patients with liver hepatocellular carcinoma (LIHC) and construct a synthetic index for indicating the prognostic outcomes. The bioinformatic analysis was performed on the data of 374 cancer tissues and 50 normal tissues, which were downloaded from TCGA database. We observed that 17 differentially expressed IRGs were significantly associated with survival in LIHC patients. These LIHC-specific IRGs were validated with function analysis and molecular characteristics. Cox analysis was applied for constructing a RiskScore for predicting the survival. The RiskScore involved six IRGs and corresponding coefficients, which was calculated with the following formula: RiskScore = [Expression level of FABP5 *(0.064)] + [Expression level of TRAF3 * (0.198)] + [Expression level of CSPG5 * (0.416)] + [Expression level of IL17D * (0.197)] + [Expression level of STC2 * (0.036)] + [Expression level of BRD8 * (0.140)]. The RiskScore was positively associated with the poor survival, which was verified with the dataset from ICGC database. Further analysis revealed that the RiskScore was independent of any other clinical feature, while it was linked with the infiltration levels of six types of immune cells. Our study reported the survival-associated IRGs in LIHC and then constructed IRGs-based RiskScore as prognostic indicator for screening patients with high risk of short survival. Both the screened IRGs and IRGs-based RiskScore were clinically significant, which may be informative for promoting the individualized immunotherapy against LIHC.
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14
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Capillo G, Zaccone G, Cupello C, Fernandes JMO, Viswanath K, Kuciel M, Zuwala K, Guerrera MC, Aragona M, Icardo JM, Lauriano ER. Expression of acetylcholine, its contribution to regulation of immune function and O 2 sensing and phylogenetic interpretations of the African butterfly fish Pantodon buchholzi (Osteoglossiformes, Pantodontidae). FISH & SHELLFISH IMMUNOLOGY 2021; 111:189-200. [PMID: 33588082 DOI: 10.1016/j.fsi.2021.02.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 02/02/2021] [Accepted: 02/08/2021] [Indexed: 06/12/2023]
Abstract
Acetylcholine (Ach) is the main neurotransmitter in the neuronal cholinergic system and also works as a signaling molecule in non-neuronal cells and tissues. The diversity of signaling pathways mediated by Ach provides a basis for understanding the biology of the cholinergic epithelial cells and immune cells in the gill of the species studied. NECs in the gill were not found surprisingly, but specialized cells showing the morphological, histochemical and ultrastructural characteristics of eosinophils were located in the gill filaments and respiratory lamellae. Much remains unknown about the interaction between the nerves and eosinophils that modulate both the release of acetylcholine and its nicotinic and muscarinic receptors including the role of acetylcholine in the mechanisms of O2 chemosensing. In this study we report for the first time the expression of Ach in the pavement cells of the gill lamellae in fish, the mast cells associated with eosinophils and nerve interaction for both immune cell types, in the gill of the extant butterfly fish Pantodon buchholzi. Multiple roles have been hypothesized for Ach and alpha nAChR in the gills. Among these there are the possible involvement of the pavement cells of the gill lamellae as O2 chemosensitive cells, the interaction of Ach positive mast cells with eosinophils and interaction of eosinophils with nerve terminals. This could be related to the use of the vesicular acetylcholine transporter (VAChT) and the alpha 2 subunit of the acetylcholine nicotinic receptor (alpha 2 nAChR). These data demonstrate the presence of Ach multiple sites of neuronal and non-neuronal release and reception within the gill and its ancestral signaling that arose during the evolutionary history of this conservative fish species.
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Affiliation(s)
- Gioele Capillo
- Department of Veterinary Sciences, University of Messina, Polo Universitario Dell'Annunziata, I-98168, Messina, Italy
| | - Giacomo Zaccone
- Department of Veterinary Sciences, University of Messina, Polo Universitario Dell'Annunziata, I-98168, Messina, Italy.
| | - Camila Cupello
- Departamento de Zoologia, Instituto de Biologia-IBRAG, Universidade de Estado Do Rio de Janeiro, Rua Sao Francisco Xavier, 524, 20550-900, Rio de Janeiro, Brazil
| | | | - Kiron Viswanath
- Faculty of Biosciences and Aquaculture, Nord University, 8026, Bodø, Norway
| | - Michal Kuciel
- Poison Information Centre, Department of Toxicology and Environmental Disease, Faculty of Medicine, Jagiellonian University, Kopernika 15, 30-501, Cracow, Poland
| | - Krystyna Zuwala
- Department of Comparative Anatomy, Faculty of Biology, Institute of Zoology and Biomedical Research, Jagellonian University, Cracow, Poland
| | - Maria Cristina Guerrera
- Department of Veterinary Sciences, University of Messina, Polo Universitario Dell'Annunziata, I-98168, Messina, Italy
| | - Marialuisa Aragona
- Department of Veterinary Sciences, University of Messina, Polo Universitario Dell'Annunziata, I-98168, Messina, Italy
| | - Jose Manuel Icardo
- Department of Anatomy and Cell Biology, Poligono de Cazona, Faculty of Medicine, University of Cantabria, Santander, Spain
| | - Eugenia Rita Lauriano
- Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Messina, Italy
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15
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Optimal combination treatment regimens of vaccine and radiotherapy augment tumor-bearing host immunity. Commun Biol 2021; 4:78. [PMID: 33469123 PMCID: PMC7815836 DOI: 10.1038/s42003-020-01598-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 12/14/2020] [Indexed: 01/29/2023] Open
Abstract
A major obstacle to immunotherapy is insufficient infiltration of effector immune cells into the tumor microenvironment. Radiotherapy greatly reduces tumor burden but relapses often occur. Here we show that the immunosuppressive tumor microenvironment was gradually established by recruiting Tregs after radiation. Despite tumors being controlled after depletion of Tregs in the irradiated area, improvement of mice survival remained poor. A much better antitumor effect was achieved with vaccination followed by radiation than other treatments. Vaccination followed by radiation recruited more effector T cells in tumor regions, which responded to high levels of chemokines. Sequential combination of vaccination and radiotherapy could elicit distinct host immune responses. Our study demonstrated that optimal combination of irradiation and vaccination is required to achieve effective antitumor immune responses. We propose a combination regimen that could be easily translated into the clinic and offer an opportunity for rational combination therapies design in cancer treatment.
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16
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Zeng Z, Yang B, Liao Z. Progress and prospects of immune checkpoint inhibitors in advanced gastric cancer. Future Oncol 2021; 17:1553-1569. [PMID: 33397136 DOI: 10.2217/fon-2020-0829] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Gastric cancer, a digestive malignancy, is the sixth most frequent cancer and the second leading cause of tumor-related deaths worldwide. The emergence and advancement of immunotherapeutic agents has brought significant survival benefits for patients with gastric cancer and increasingly challenged the conventional therapy pattern involving chemotherapy and target drugs. Furthermore, these breakthroughs have paved the way for immunotherapy, especially with immune checkpoint inhibitors, which act by blocking specific signaling pathways, in particular the CTLA4 pathway and the PD-1/PD-L1 pathway. In this review, we summarize the current trials of immune checkpoint inhibitors in GC and their predictive biomarkers, and discuss their present limitations.
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Affiliation(s)
- Zhu Zeng
- Department of Abdominal Oncology, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China
| | - Biao Yang
- Department of Gastroenterology, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China
| | - Zhengyin Liao
- Department of Abdominal Oncology, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China
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17
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Ashrafizadeh M, Farhood B, Eleojo Musa A, Taeb S, Najafi M. The interactions and communications in tumor resistance to radiotherapy: Therapy perspectives. Int Immunopharmacol 2020; 87:106807. [PMID: 32683299 DOI: 10.1016/j.intimp.2020.106807] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Revised: 06/26/2020] [Accepted: 07/10/2020] [Indexed: 12/24/2022]
Abstract
Tumor microenvironment (TME) includes a wide range of cell types including cancer cells, cells which are involved in stromal structure and immune cells (tumor suppressor and tumor promoting cells). These cells have several interactions with each other that are mainly regulated via the release of intercellular mediators. Radiotherapy can modulate these interactions via shifting secretions into inflammatory or anti-inflammatory responses. Radiotherapy also can trigger resistance of cancer (stem) cells via activation of stromal cells. The main mechanisms of tumor resistance to radiotherapy is the exhaustion of anti-tumor immunity via suppression of CD4+ T cells and apoptosis of cytotoxic CD8+ T lymphocytes (CTLs). Cancer-associated fibroblasts (CAFs), mesenchymal-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) are the main suppressor of anti-tumor immunity via the release of several chemokines, cytokines and immune suppressors. In this review, we explain the main cellular and molecular interactions and secretions in TME following radiotherapy. Furthermore, the main signaling pathways and intercellular connections that can be targeted to improve therapeutic efficiency of radiotherapy will be discussed.
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Affiliation(s)
- Milad Ashrafizadeh
- Department of Basic Science, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Bagher Farhood
- Department of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Ahmed Eleojo Musa
- Department of Medical Physics, Tehran University of Medical Sciences (International Campus), Tehran, Iran
| | - Shahram Taeb
- Ionizing and Non-Ionizing Radiation Protection Research Center (INIRPRC), Shiraz University of Medical Sciences, Shiraz, Iran
| | - Masoud Najafi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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18
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Tubin S, Yan W, Mourad WF, Fossati P, Khan MK. The future of radiation-induced abscopal response: beyond conventional radiotherapy approaches. Future Oncol 2020; 16:1137-1151. [PMID: 32338046 DOI: 10.2217/fon-2020-0063] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Advances in the immunological pharmaceuticals, such as checkpoint inhibitors and agonists, have positive implications for the future of the radiotherapy abscopal response. A once rare phenomenon, whereby distant nonirradiated tumor sites regressed after radiotherapy alone, may become more common when combined with the immune modulating agents. Radiotherapy can increase neoantigen expression, increased tumor PD-L1 expression, increase MHC class I expression, reverse exhausted CD8 T cells and increase tumor-infiltrating tumors within the tumor microenvironment. These changes in the tumor and the tumor microenvironment after radiotherapy could potentiate responses to anti-CTL-4, anti-PD-L1/PD-1 and other immunotherapy agents. Thus, advances in checkpoint inhibitors have increased interest in re-evaluation of the role of conventional radiotherapy approaches on the immune system. We reviewed newer nonconventional approaches such as SBRT-PATHY, GRID, FLASH, carbon ion and proton therapy and their role in eliciting immune responses. We believe that combining these novel radiation methods may enhance the outcome with the newly US FDA approved immune modulating agents.
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Affiliation(s)
- Slavisa Tubin
- MedAustron Center for Ion Therapy and Research, Marie Curie Strasse 5, A-2700 Wiener Neustadt, Austria
| | - Weisi Yan
- Department of Radiation Oncology, Thomas Jefferson University, 11th St, Philadelphia, PA 19107, USA
| | - Waleed F Mourad
- Department of Radiation Medicine, Markey Cancer Center, University of Kentucky, Medical Center, MN 150 - Lexington, KY 40536-0298, USA
| | - Piero Fossati
- MedAustron Center for Ion Therapy and Research, Marie Curie Strasse 5, A-2700 Wiener Neustadt, Austria
| | - Mohammad K Khan
- Department of Radiation Oncology, Emory University School of Medicine, Winship Cancer Institute, 1365-C Clifton Road, Atlanta, GA 30322, USA
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19
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Cao P, Sun Z, Feng C, Zhang J, Zhang F, Wang W, Zhao Y. Myeloid-derived suppressor cells in transplantation tolerance induction. Int Immunopharmacol 2020; 83:106421. [PMID: 32217462 DOI: 10.1016/j.intimp.2020.106421] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 02/29/2020] [Accepted: 03/16/2020] [Indexed: 02/06/2023]
Abstract
Myeloid-derived suppressor cells (MDSCs) are a group of heterogeneous cells derived from bone marrow. These cells are developed from immature myeloid cells and have strong negative immunomodulatory effects. In the context of pathology (such as tumor, autoimmune disease, trauma, and burns), MDSCs accumulate around tumor and inflammatory tissues, where their main role is to inhibit the function of effector T cells and promote the recruitment of regulatory T cells. MDSCs can be used in organ transplantation to regulate the immune responses that participate in rejection of the transplanted organ. This effect is achieved by increasing the production of MDSCs in vivo or transfusion of MDSCs induced in vitro to establish immune tolerance and prolong the survival of the graft. In this review, we discuss the efficacy of MDSCs in a variety of transplantation studies as well as the induction of immune tolerance to prevent transplant rejection through the use of common clinical immunosuppressants combined with MDSCs.
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Affiliation(s)
- Peng Cao
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Zejia Sun
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Chang Feng
- Transplantation Biology Research Division, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing 100101, China
| | - Jiandong Zhang
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Feilong Zhang
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Wei Wang
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China.
| | - Yong Zhao
- Transplantation Biology Research Division, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing 100101, China
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20
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Bi S, Huang W, Chen S, Huang C, Li C, Guo Z, Yang J, Zhu J, Song L, Yu R. Cordyceps militaris polysaccharide converts immunosuppressive macrophages into M1-like phenotype and activates T lymphocytes by inhibiting the PD-L1/PD-1 axis between TAMs and T lymphocytes. Int J Biol Macromol 2020; 150:261-280. [PMID: 32044366 DOI: 10.1016/j.ijbiomac.2020.02.050] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 01/31/2020] [Accepted: 02/06/2020] [Indexed: 01/13/2023]
Abstract
Tumour-associated macrophages (TAMs) inhibit the killing effect of T lymphocytes on tumour cells through the immunocheckpoint programmed death ligand-1 (PD-L1)/programmed death-1 (PD-1) axis. TAMs-targeted therapy is a promising approach that could be used to reverse the immunosuppressive tumour microenvironment. Here, we further report CMPB90-1, a novel natural polysaccharide from Cordyceps militaris, could function as an anti-tumour modulator that resets TAMs from a tumour-promoting M2 phenotype to a tumour-killing M1 phenotype. This process involves reversing the functional inhibition of T lymphocytes by inhibiting the PD-L1/PD-1 axis between TAMs and T lymphocytes. Mechanistically, the membrane receptor of CMPB90-1 binding to M2 macrophages was identified by tandem mass spectrometry. CMPB90-1 converts immunosuppressive TAMs via binding to toll-like receptor 2 (TLR2), which causes the release of Ca2+ and the activation of p38, Akt and NF-κB, or ERK. This process then leads to the polarization of TAMs from M2 phenotype to the M1 phenotype. In vivo experiment shows that CMPB90-1 is able to polarize TAMs into the M1 phenotype and has anti-tumour effects with improved safety. Additionally, the anti-tumour effects of CMPB90-1 in vivo depend on the phenotypic conversion of TAMs. The results demonstrated that CMPB90-1 could be developed as a potential immune-oncology treatment reagent.
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Affiliation(s)
- Sixue Bi
- Department of Pharmacology, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China
| | - Weijuan Huang
- Biotechnological Institute of Chinese Materia Medica, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China
| | - Shan Chen
- Department of Natural Products Chemistry, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China
| | - Chunhua Huang
- Department of Natural Products Chemistry, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China
| | - Chunlei Li
- Department of Pharmacology, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China
| | - Zhongyi Guo
- Biotechnological Institute of Chinese Materia Medica, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China
| | - Jianing Yang
- Department of Pharmacology, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China
| | - Jianhua Zhu
- Department of Natural Products Chemistry, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
| | - Liyan Song
- Department of Pharmacology, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
| | - Rongmin Yu
- Biotechnological Institute of Chinese Materia Medica, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China; Department of Natural Products Chemistry, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
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21
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Emerging Prospects for Nanoparticle-Enabled Cancer Immunotherapy. J Immunol Res 2020; 2020:9624532. [PMID: 32377541 PMCID: PMC7199570 DOI: 10.1155/2020/9624532] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Revised: 10/30/2019] [Accepted: 11/02/2019] [Indexed: 12/18/2022] Open
Abstract
One of the standards for cancer treatment is cancer immunotherapy which treats both primary and metastasized tumors. Although cancer immunotherapeutics show better outcomes as compared with conventional approaches of cancer treatment, the currently used cancer immunotherapeutics have limited application in delivering cancer antigens to immune cells. Conversely, in solid tumors, tumor microenvironment suppresses the immune system leading to the evasion of anticancer immunity. Some promising attempts have been made to overcome these drawbacks by using different approaches, for instance, the use of biomaterial-based nanoparticles. Accordingly, various studies involving the application of nanoparticles in cancer immunotherapy have been discussed in this review article. This review not only describes the modes of cancer immunotherapy to reveal the importance of nanoparticles in this modality but also narrates nanoparticle-mediated delivery of cancer antigens and therapeutic supplements. Moreover, the impact of nanoparticles on the immunosuppressive behavior of tumor environment has been discussed. The last part of this review deals with cancer immunotherapy using a combination of traditional interventional oncology approach and image-guided local immunotherapy against cancer. According to recent studies, cancer therapy can potentially be improved through nanoparticle-based immunotherapy. In addition, drawbacks associated with the currently used cancer immunotherapeutics can be fixed by using nanoparticles.
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22
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Majumdar S, Saha S. Systems Immunology Approach in Understanding the Association of Allergy and Cancer. SYSTEMS AND SYNTHETIC IMMUNOLOGY 2020:53-72. [DOI: 10.1007/978-981-15-3350-1_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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23
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Lauret Marie Joseph E, Laheurte C, Jary M, Boullerot L, Asgarov K, Gravelin E, Bouard A, Rangan L, Dosset M, Borg C, Adotévi O. Immunoregulation and Clinical Implications of ANGPT2/TIE2 + M-MDSC Signature in Non-Small Cell Lung Cancer. Cancer Immunol Res 2019; 8:268-279. [PMID: 31871121 DOI: 10.1158/2326-6066.cir-19-0326] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 10/04/2019] [Accepted: 12/18/2019] [Indexed: 11/16/2022]
Abstract
Myeloid-derived suppressor cells (MDSC) promote immunosuppression and are a target in the field of immuno-oncology. Accumulation of MDSCs is associated with poor prognosis and resistance to immunotherapy for several cancers. Here, we describe an accumulation of a subset of circulating monocytic MDSCs (M-MDSC) overexpressing TIE2, the receptor for angiopoietin-2 (ANGPT2), in patients with non-small cell lung cancer (NSCLC). Greater numbers of circulating TIE2+ M-MDSCs were detected in patients with NSCLC compared with healthy subjects, and this accumulation correlated with ANGPT2 concentration in blood. The presence of an ANGPT2-rich environment was associated with impairment of preexisting T-cell responses against tumor-associated antigens (TAA) in patients with NSCLC. We demonstrated that ANGPT2 sensitizes TIE2+ M-MDSCs such that these cells suppress TAA-specific T cells. In patients with NSCLC, upregulation of the ANGPT2/TIE2+ M-MDSC signature in blood was associated with a poor prognosis. Our results identify the ANGPT2/TIE2+ M-MDSC axis as a participant in tumor immune evasion that should be taken into account in future cancer immunotherapy.
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Affiliation(s)
| | - Caroline Laheurte
- Université Bourgogne Franche-Comté, INSERM, EFS, BFC, UMR1098, RIGHT, Besançon, France.,Etablissement Français du Sang Bourgogne Franche-Comté, Plateforme de Biomonitoring, Besançon, France.,INSERM CIC-1431, CHU Besançon, Besançon, France
| | - Marine Jary
- Université Bourgogne Franche-Comté, INSERM, EFS, BFC, UMR1098, RIGHT, Besançon, France.,Service d'Oncologie médicale, CHU Besançon, Besançon, France
| | - Laura Boullerot
- Université Bourgogne Franche-Comté, INSERM, EFS, BFC, UMR1098, RIGHT, Besançon, France.,INSERM CIC-1431, CHU Besançon, Besançon, France
| | - Kamal Asgarov
- Université Bourgogne Franche-Comté, INSERM, EFS, BFC, UMR1098, RIGHT, Besançon, France
| | - Eléonore Gravelin
- Université Bourgogne Franche-Comté, INSERM, EFS, BFC, UMR1098, RIGHT, Besançon, France.,INSERM CIC-1431, CHU Besançon, Besançon, France
| | - Adeline Bouard
- Université Bourgogne Franche-Comté, INSERM, EFS, BFC, UMR1098, RIGHT, Besançon, France
| | - Laurie Rangan
- Université Bourgogne Franche-Comté, INSERM, EFS, BFC, UMR1098, RIGHT, Besançon, France
| | - Magalie Dosset
- Université Bourgogne Franche-Comté, INSERM, EFS, BFC, UMR1098, RIGHT, Besançon, France
| | - Christophe Borg
- Université Bourgogne Franche-Comté, INSERM, EFS, BFC, UMR1098, RIGHT, Besançon, France.,INSERM CIC-1431, CHU Besançon, Besançon, France.,Service d'Oncologie médicale, CHU Besançon, Besançon, France
| | - Olivier Adotévi
- Université Bourgogne Franche-Comté, INSERM, EFS, BFC, UMR1098, RIGHT, Besançon, France. .,Etablissement Français du Sang Bourgogne Franche-Comté, Plateforme de Biomonitoring, Besançon, France.,INSERM CIC-1431, CHU Besançon, Besançon, France.,Service d'Oncologie médicale, CHU Besançon, Besançon, France
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24
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Gonzalez Badillo FE, Zisi Tegou F, Abreu MM, Masina R, Sha D, Najjar M, Wright SH, Bayer AL, Korpos É, Pugliese A, Molano RD, Tomei AA. CCL21 Expression in β-Cells Induces Antigen-Expressing Stromal Cell Networks in the Pancreas and Prevents Autoimmune Diabetes in Mice. Diabetes 2019; 68:1990-2003. [PMID: 31371518 PMCID: PMC6754241 DOI: 10.2337/db19-0239] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 07/21/2019] [Indexed: 12/31/2022]
Abstract
Tumors induce tolerance toward their antigens by producing the chemokine CCL21, leading to the formation of tertiary lymphoid organs (TLOs). Ins2-CCL21 transgenic, nonobese diabetic (NOD) mice express CCL21 in pancreatic β-cells and do not develop autoimmune diabetes. We investigated by which mechanisms CCL21 expression prevented diabetes. Ins2-CCL21 mice develop TLOs by 4 weeks of age, consisting of naive CD4+ T cells compartmentalized within networks of CD45-gp38+CD31- fibroblastic reticular cell (FRC)-like cells. Importantly, 12-week-old Ins2-CCL21 TLOs contained FRC-like cells with higher contractility, regulatory, and anti-inflammatory properties and enhanced expression of β-cell autoantigens compared with nontransgenic NOD TLOs found in inflamed islets. Consistently, transgenic mice harbored fewer autoreactive T cells and a higher proportion of regulatory T cells in the islets. Using adoptive transfer and islet transplantation models, we demonstrate that TLO formation in Ins2-CCL21 transgenic islets is critical for the regulation of autoimmunity, and although the effect is systemic, the induction is mediated locally likely by lymphocyte trafficking through TLOs. Overall, our findings suggest that CCL21 promotes TLOs that differ from inflammatory TLOs found in type 1 diabetic islets in that they resemble lymph nodes, contain FRC-like cells expressing β-cell autoantigens, and are able to induce systemic and antigen-specific tolerance leading to diabetes prevention.
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Affiliation(s)
- Freddy E Gonzalez Badillo
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
- Department of Biomedical Engineering, University of Miami, Miami, FL
| | - Flavia Zisi Tegou
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
- Department of Biomedical Engineering, University of Miami, Miami, FL
| | - Maria M Abreu
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
| | - Riccardo Masina
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
| | - Divya Sha
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
| | - Mejdi Najjar
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
| | - Shane H Wright
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
| | - Allison L Bayer
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL
| | - Éva Korpos
- Institute of Physiological Chemistry and Pathobiochemistry and Cells in Motion, Cluster of Excellence, University of Muenster, Muenster, Germany
| | - Alberto Pugliese
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL
| | - R Damaris Molano
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
| | - Alice A Tomei
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
- Department of Biomedical Engineering, University of Miami, Miami, FL
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL
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25
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Song L, Ma S, Chen L, Miao L, Tao M, Liu H. Long-term prognostic significance of interleukin-17-producing T cells in patients with non-small cell lung cancer. Cancer Sci 2019; 110:2100-2109. [PMID: 31100180 PMCID: PMC6609818 DOI: 10.1111/cas.14068] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 05/01/2019] [Accepted: 05/01/2019] [Indexed: 12/16/2022] Open
Abstract
The presence of interleukin (IL)‐17‐producing T cells has recently been reported in non‐small cell lung cancer (NSCLC) patients. However, the long‐term prognostic significance of these populations in NSCLC patients remains unknown. In the present study, we collected peripheral blood from 82 NSCLC patients and 22 normal healthy donors (NC). Percentages of IL‐17‐producing CD4+T (Th17), CD8+T (Tc17) and γδT cells (γδT17) were measured to determine their association with clinical outcomes and overall survival (OS) in NSCLC. All NSCLC patients were followed up until July 2018. Median follow‐up time was 13.5 months (range 1‐87 months). The 3‐ and 5‐year survival rate was 27% and 19.6%, respectively. We found that Th17 cells and γδT17 cells were significantly increased, whereas Tc17 cells were markedly decreased in patients with NSCLC compared with those in NC. In addition, Th17 cells were significantly positively associated with T helper type 1 cells (Th1), whereas γδT17 cells were significantly negatively associated with γδT + interferon (IFN)‐γ+ cells. High percentages of peripheral Tc17 cells were significantly associated with favorable 5‐year OS (P = .025), especially in patients with early TNM stage (P = .016). Furthermore, high percentages of peripheral Th17 cells were positively associated with favorable 5‐year OS in patients with late TNM stage (P = .002). However, no significant association was observed between γδT17 cells and OS, regardless of the TNM stage. In conclusion, our findings suggest that enhanced Th17 and reduced Tc17 cells in the peripheral blood could be a significant predictor of a favorable prognosis for NSCLC patients.
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Affiliation(s)
- Li Song
- Department of Oncology, Department of Clinical Pharmacology, The First Affiliated Hospital of Soochow University, Suzhou, China.,College of Pharmaceutical Sciences, Soochow University, Suzhou, China.,Department of Oncology, Affiliated Tumor Hospital of Nantong University, Nantong, China
| | - Shoubao Ma
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.,Department of Hematology, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Longpei Chen
- Department of Oncology, Shanghai Changhai Hospital, Shanghai, China
| | - Liyan Miao
- Department of Oncology, Department of Clinical Pharmacology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Min Tao
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China.,PREMED Key Laboratory for Precision Medicine, Soochow University, Suzhou, China
| | - Haiyan Liu
- Immunology Programme, Life Sciences Institute and Department of Microbiology and Immunology, National University of Singapore, Singapore
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26
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Yuan S, Dong Y, Peng L, Yang M, Niu L, Liu Z, Xie J. Tumor-associated macrophages affect the biological behavior of lung adenocarcinoma A549 cells through the PI3K/AKT signaling pathway. Oncol Lett 2019; 18:1840-1846. [PMID: 31423252 PMCID: PMC6607053 DOI: 10.3892/ol.2019.10483] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Accepted: 05/02/2019] [Indexed: 12/24/2022] Open
Abstract
Tumor associated macrophages (TAMs) are a major type of inflammatory cell in a tumor microenvironment. Previous evidence has suggested that TAMs promote tumorigenesis, growth, invasion and metastasis, thereby affecting tumor metabolism. The mechanisms through which they affect the invasion and metastasis of lung cancer cells remain unclear. The present study investigated the effects and molecular mechanisms of TAMs on the proliferation, invasion and migration of lung adenocarcinoma A549 cells. Human mononuclear leukemia THP-1 cells were induced into TAMs. The morphological changes that occurred during the induction of the THP-1 cells were examined with a light microscope. Successful TAM formation was confirmed via flow cytometry. Proliferation, invasion and migration of the lung adenocarcinoma A549 cells were detected by EDU proliferation, scratch wound and Transwell invasion and migration assays, respectively. The expression levels of key proteins involved in the PI3K/AKT signaling pathway were detected by western blot analysis. It was identified that treatment with interleukin (IL)-4, IL-13 and Phorbol-12-myristate-13-acetate successfully induced THP-1 to form TAMs. The indirect coculture model of TAMs was established by Transwell chamber detection, and the proliferation, invasion and migration ability of lung adenocarcinoma A549 cells were enhanced. Western blot analysis indicated that the expression levels of phosphorylated (p)-PI3K and p-AKT proteins were significantly upregulated in the TAMs coculture group compared with that of the blank control group. In summary, the present study demonstrated that TAMs may promote the proliferation, invasion and migration of lung adenocarcinoma A549 cells in vitro, perhaps through the activation of the PI3K/AKT signaling pathway.
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Affiliation(s)
- Shiyang Yuan
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yaling Dong
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Laishui Peng
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Mei Yang
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Linxia Niu
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Zhiwen Liu
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Junping Xie
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immunosuppressive cells of the myeloid lineage upregulated by mediators of inflammation, such as IL-2, granulocyte colony-stimulating factor, and S100A8/A9. These cells have been studied extensively by tumor biologists. Because of their robust immunosuppressive potential, MDSCs have stirred recent interest among transplant immunologists as well. MDSCs inhibit T-cell responses through, among other mechanisms, the activity of arginase-1 and inducible nitric oxide synthase, and the expansion of T regulatory cells. In the context of transplantation, MDSCs have been studied in several animal models, and to a lesser degree in humans. Here, we will review the immunosuppressive qualities of this important cell type and discuss the relevant studies of MDSCs in transplantation. It may be possible to exploit the immunosuppressive capacity of MDSCs for the benefit of transplant patients.
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28
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Huang H, Zhang M, Yao S, Zhang M, Peng J. Immune modulation of a lipid-soluble extract of Pinellia pedatisecta Schott in the tumor microenvironment of an HPV + tumor-burdened mouse model. JOURNAL OF ETHNOPHARMACOLOGY 2018; 225:103-115. [PMID: 29783020 DOI: 10.1016/j.jep.2018.04.037] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 04/21/2018] [Accepted: 04/25/2018] [Indexed: 06/08/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Pinellia pedatisecta Schott extract (PE), a traditional Chinese medicine, has been used to reduce swelling, dry dampness and suppress cervical tumors. AIMS To evaluate the roles of PE in the regulation of anti-tumor effects and the cellular immune response in the tumor microenvironment. METHODS The immune microenvironment of HPV+TC-1 tumors was examined by immunohistochemistry, real-time PCR and flow cytometry. RESULTS Our study demonstrated that PE in vitro could significantly increase the percentage of apoptosis and necrosis in HPV+TC-1 cells and block the cell cycle phase. In vivo treatment with PE eradicated established subcutaneous HPV+TC-1 tumors in wild-type C57BL/6 mice by infiltrating CD8+ T cells and CD4+ T cells and by directly suppressing tumor growth and resistance to avascular necrosis. The key factors in the canonical Wnt signaling pathway in the experimental group (PE+mDC+naive CD4+T cells) were challenged, and the levels of beta-catenin, C-myc, cyclin D1 and PPAR1 were significantly enhanced at the 5th day. In particular, the subset proportion of Th1 cells (characterized by IFNγ production and the transcription factor Tbet) increased significantly, and both Th2 cells (characterized by IL-4 production and the transcription factor GATA3) and Th17 cells (characterized by IL-17 production and the transcription factor RoRγt) decreased profoundly. CONCLUSIONS These findings linked the anti-tumor properties of PE with the immune microenvironment to present a reliable basis for the future practical application of PE in cervical cancer as a novel and pharmacologically safe immunotherapy strategy.
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Affiliation(s)
- Haixia Huang
- Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai 200032
| | - Mingxing Zhang
- Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai 200032
| | - Sheng Yao
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai201203, P.R. China
| | - Meng Zhang
- Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai 200032
| | - Jing Peng
- Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai 200032
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29
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Park W, Heo YJ, Han DK. New opportunities for nanoparticles in cancer immunotherapy. Biomater Res 2018; 22:24. [PMID: 30275967 PMCID: PMC6158870 DOI: 10.1186/s40824-018-0133-y] [Citation(s) in RCA: 117] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 08/24/2018] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Recently, cancer immunotherapy has become standard for cancer treatment. Immunotherapy not only treats primary tumors, but also prevents metastasis and recurrence, representing a major advantage over conventional cancer treatments. However, existing cancer immunotherapies have limited clinical benefits because cancer antigens are often not effectively delivered to immune cells. Furthermore, unlike lymphoma, solid tumors evade anti-cancer immunity by forming an immune-suppressive tumor microenvironment (TME). One approach for overcoming these limitations of cancer immunotherapy involves nanoparticles based on biomaterials. MAIN BODY Here, we review in detail recent trends in the use of nanoparticles in cancer immunotherapy. First, to illustrate the unmet needs for nanoparticles in this field, we describe the mechanisms underlying cancer immunotherapy. We then explain the role of nanoparticles in the delivery of cancer antigens and adjuvants. Next, we discuss how nanoparticles can be helpful within the immune-suppressive TME. Finally, we summarize current and future uses of nanoparticles with image-guided interventional techniques in cancer immunotherapy. CONCLUSION Recently developed approaches for using nanoparticles in cancer immunotherapy have enormous potential for improving cancer treatment. Cancer immunotherapy based on nanoparticles is anticipated not only to overcome the limitations of existing immunotherapy, but also to generate synergistic effects via cooperation between nanoparticles and immune cells.
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Affiliation(s)
- Wooram Park
- Department of Biomedical Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi 13488 Republic of Korea
| | - Young-Jae Heo
- Department of Biomedical Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi 13488 Republic of Korea
| | - Dong Keun Han
- Department of Biomedical Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi 13488 Republic of Korea
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30
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Osada T, Hartman ZC, Wei J, Lei G, Hobeika AC, Gwin WR, Diniz MA, Spector N, Clay TM, Chen W, Morse MA, Lyerly HK. Polyfunctional anti-human epidermal growth factor receptor 3 (anti-HER3) antibodies induced by HER3 vaccines have multiple mechanisms of antitumor activity against therapy resistant and triple negative breast cancers. Breast Cancer Res 2018; 20:90. [PMID: 30092835 PMCID: PMC6085609 DOI: 10.1186/s13058-018-1023-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2018] [Accepted: 07/18/2018] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Upregulation of human epidermal growth factor receptor 3 (HER3) is a major mechanism of acquired resistance to therapies targeting its heterodimerization partners epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), but also exposes HER3 as a target for immune attack. We generated an adenovirus encoding full length human HER3 (Ad-HER3) to serve as a cancer vaccine. Previously we reported the anti-tumor efficacy and function of the T cell response to this vaccine. We now provide a detailed assessment of the antitumor efficacy and functional mechanisms of the HER3 vaccine-induced antibodies (HER3-VIAs) in serum from mice immunized with Ad-HER3. METHODS Serum containing HER3-VIA was tested in complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) assays and for its effect on HER3 internalization and degradation, downstream signaling of HER3 heterodimers and growth of metastatic HER2+ (BT474M1), HER2 therapy-resistant (rBT474), and triple negative (MDA-MB-468) breast cancers. RESULTS HER3-VIAs mediated CDC and ADCC, HER3 internalization, interruption of HER3 heterodimer-driven tumor signaling pathways, and anti-proliferative effects against HER2+ tumor cells in vitro and significant antitumor effects against metastatic HER2+ BT474M1, treatment refractory HER2+ rBT474 and triple negative MDA-MB-468 in vivo. CONCLUSIONS In addition to the T cell anti-tumor response induced by Ad-HER3, the HER3-VIAs provide additional functions to eliminate tumors in which HER3 signaling mediates aggressive behavior or acquired resistance to HER2-targeted therapy. These data support clinical studies of vaccination against HER3 prior to or concomitantly with other therapies to prevent outgrowth of therapy-resistant HER2+ and triple negative clones.
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Affiliation(s)
- Takuya Osada
- Division of Surgical Sciences, Department of Surgery, Duke University Medical Center, MSRB Research Drive, Box 2714, Durham, NC, 27710, USA
| | - Zachary C Hartman
- Division of Surgical Sciences, Department of Surgery, Duke University Medical Center, MSRB Research Drive, Box 2714, Durham, NC, 27710, USA
| | - Junping Wei
- Division of Surgical Sciences, Department of Surgery, Duke University Medical Center, MSRB Research Drive, Box 2714, Durham, NC, 27710, USA
| | - Gangjun Lei
- Division of Surgical Sciences, Department of Surgery, Duke University Medical Center, MSRB Research Drive, Box 2714, Durham, NC, 27710, USA
| | - Amy C Hobeika
- Division of Surgical Sciences, Department of Surgery, Duke University Medical Center, MSRB Research Drive, Box 2714, Durham, NC, 27710, USA
| | - William R Gwin
- Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Marcio A Diniz
- Biostatistics and Bioinformatics Research Center, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Neil Spector
- Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Timothy M Clay
- Cell and Gene Therapy Discovery Research, PTS, GlaxoSmithKline, Collegeville, PA, USA
- Division of General Surgery, Department of Surgery, Duke University Medical Center, Durham, NC, USA
| | - Wei Chen
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Michael A Morse
- Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - H Kim Lyerly
- Division of Surgical Sciences, Department of Surgery, Duke University Medical Center, MSRB Research Drive, Box 2714, Durham, NC, 27710, USA.
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31
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Rajendrakumar SK, Uthaman S, Cho CS, Park IK. Nanoparticle-Based Phototriggered Cancer Immunotherapy and Its Domino Effect in the Tumor Microenvironment. Biomacromolecules 2018; 19:1869-1887. [DOI: 10.1021/acs.biomac.8b00460] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Santhosh Kalash Rajendrakumar
- Department of Biomedical Science and BK21 PLUS Center for Creative Biomedical Scientists at Chonnam National University, Chonnam National University Medical School, Gwangju 61469, South Korea
| | - Saji Uthaman
- Department of Polymer Science and Engineering, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, South Korea
| | - Chong-Su Cho
- Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 08826, South Korea
| | - In-Kyu Park
- Department of Biomedical Science and BK21 PLUS Center for Creative Biomedical Scientists at Chonnam National University, Chonnam National University Medical School, Gwangju 61469, South Korea
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32
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Zekri ARN, El Deeb S, Bahnassy AA, Badr AM, Abdellateif MS, Esmat G, Salama H, Mohanad M, El-dien AE, Rabah S, Abd Elkader A. Role of relevant immune-modulators and cytokines in hepatocellular carcinoma and premalignant hepatic lesions. World J Gastroenterol 2018; 24:1228-1238. [PMID: 29568203 PMCID: PMC5859225 DOI: 10.3748/wjg.v24.i11.1228] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2017] [Revised: 12/24/2017] [Accepted: 01/16/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To assess the levels of different immune modulators in patients with hepatocellular carcinoma (HCC), in relation to other hepatic diseases.
METHODS Eighty-eight patients were included in the current study and represented patients with HCC (20), liver cirrhosis (28) and chronic hepatitis (CH; 25), and normal controls (NC; 15). Peripheral blood was isolated for immunophenotyping of active myeloid dendritic cells (mDCs; CD1c and CD40), mature inactive myeloid cells (CD1c and HLA), active plasmacytoid cells (pDCs; CD303 and CD40), mature inactive pDCs (CD30 and HLA), active natural killer (NK) cells (CD56 and CD161), active NK cells (CD56 and CD314) and inactive NK cells (CD56 and CD158) was done by flow cytometry. Serum levels of interleukin (IL)-2, IL-10, IL-12, IL-1β, interferon (IFN)-α, IFN-γ and tumor necrosis factor (TNF)-αR2 were assessed by ELISA.
RESULTS Active mDCs (CD1C+/CD40+) and inactive mDCs (CD1c+/HLA+) were significantly decreased in HCC patients in relation to NC (P < 0.001). CD40+ expression on active pDCs was decreased in HCC patients (P < 0.001), and its level was not significantly changed among other groups. Inactive pDCs (CD303+/HLA+), inactive NKs (CD56+/CD158+) and active NKs (CD56+/CD161+) were not statistically changed among the four groups studied; however, the latter was increased in CH (P < 0.05). NKG2D was statistically decreased in HCC, CH and cirrhosis (P < 0.001), and it was not expressed in 63% (12/20) of HCC patients. There was significant decrease of IL-2, IFN-α and IFN-γ (P < 0.001), and a significant increase in IL-10, IL-1β, and TNF-αR2 (P <0.01, P < 0.001 and P < 0.001; respectively) in HCC patients. There was inverted correlation between IL-12 and IL-1β in HCC (r = -0.565, P < 0.01), with a strong correlation between pDCs (CD303+/CD40+) and NKs (CD56+/CD161+; r = 0.512, P < 0.05) as well as inactive mDCs (CD1c+/HLA+) and inactive NK cells (CD56+/CD158+; r = 0.945, P < 0.001).
CONCLUSION NKG2D, CD40, IL-2 and IL-10 are important modulators in the development and progression of HCC.
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Affiliation(s)
- Abdel-Rahman N Zekri
- Molecular Virology and Immunology Unit, Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo 11976, Egypt
| | - Somaya El Deeb
- Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt
| | - Abeer A Bahnassy
- Department of Pathology, National Cancer Institute, Cairo University, Cairo 11976, Egypt
| | - Abeer M Badr
- Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt
| | - Mona S Abdellateif
- Medical Biochemistry and Molecular Biology, Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo 11976, Egypt
| | - Gamal Esmat
- Department of Hepatology and Tropical Medicine, Faculty of Medicine, Cairo University, Cairo 11441, Egypt
| | - Hosny Salama
- Department of Hepatology and Tropical Medicine, Faculty of Medicine, Cairo University, Cairo 11441, Egypt
| | - Marwa Mohanad
- Department of Biochemistry, Misr University for Science and Technology, 6th October 12945, Giza Governorate, Egypt
| | - Ahmed Esam El-dien
- Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt
| | - Shimaa Rabah
- Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt
| | - Assmaa Abd Elkader
- Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt
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Shao L, Zhang B, Wang L, Wu L, Kan Q, Fan K. MMP-9-cleaved osteopontin isoform mediates tumor immune escape by inducing expansion of myeloid-derived suppressor cells. Biochem Biophys Res Commun 2017; 493:1478-1484. [DOI: 10.1016/j.bbrc.2017.10.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 10/02/2017] [Indexed: 10/18/2022]
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Formulation of the bivalent prostate cancer vaccine with surgifoam elicits antigen-specific effector T cells in PSA-transgenic mice. Vaccine 2017; 35:5794-5798. [PMID: 28939158 DOI: 10.1016/j.vaccine.2017.09.037] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 08/07/2017] [Accepted: 09/12/2017] [Indexed: 11/24/2022]
Abstract
We previously developed and characterized an adenoviral-based prostate cancer vaccine for simultaneous targeting of prostate-specific antigen (PSA) and prostate stem cell antigen (PSCA). We also demonstrated that immunization of mice with the bivalent vaccine (Ad5-PSA+PSCA) inhibited the growth of established prostate tumors. However, there are multiple challenges hindering the success of immunological therapies in the clinic. One of the prime concerns has been to overcome the immunological tolerance and maintenance of long-term effector T cells. In this study, we further characterized the use of the bivalent vaccine (Ad5-PSA+PSCA) in a transgenic mouse model expressing human PSA in the mouse prostate. We demonstrated the expression of PSA analyzed at the mRNA level (by RT-PCR) and protein level (by immunohistochemistry) in the prostate lobes harvested from the PSA-transgenic (PSA-Tg) mice. We established that the administration of the bivalent vaccine in surgifoam to the PSA-Tg mice induces strong PSA-specific effector CD8+ T cells as measured by IFN-γ secretion and in vitro cytotoxic T-cell assay. Furthermore, the use of surgifoam with Ad5-PSA+PSCA vaccine allows multiple boosting vaccinations with a significant increase in antigen-specific CD8+ T cells. These observations suggest that the formulation of the bivalent prostate cancer vaccine (Ad5-PSA+PSCA) with surgifoam bypasses the neutralizing antibody response, thus allowing multiple boosting. This formulation is also helpful for inducing an antigen-specific immune response in the presence of self-antigen, and maintains long-term effector CD8+ T cells.
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Zhou J, Yao Y, Shen Q, Li G, Hu L, Zhang X. Demethylating agent decitabine disrupts tumor-induced immune tolerance by depleting myeloid-derived suppressor cells. J Cancer Res Clin Oncol 2017; 143:1371-1380. [PMID: 28321548 DOI: 10.1007/s00432-017-2394-6] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2016] [Accepted: 03/12/2017] [Indexed: 12/30/2022]
Abstract
PURPOSE The immunoregulatory effect of demethylating agent decitabine (DAC) has been recognized recently. However, little is known about its impact on immune tolerance. In this study, we aimed to determine the impact of DAC on the immune tolerance induced by tumor cells. METHODS The effects of DAC on immune cells in vivo were measured by flow cytometry. Myeloid-derived suppressor cells (MDSCs) were sorted using magnetic beads and cultured in vitro. The mixed lymphocyte reaction was used to determine the immunoregulatory effect of DAC in vitro. An adoptive transfusion mouse model was established to evaluate the effect in vivo. RESULTS We found that DAC treatment significantly depleted MDSCs in vivo by inducing MDSCs apoptosis. When given at a low dose, the immune effector cells were less affected by the treatment, except for MDSCs. The mixed lymphocyte reaction in vitro showed that T-cell responses were enhanced when MDSCs were depleted. Supplementation of MDSCs would attenuate this T-cell activation effect. Using an adoptive transfusion mouse model, we further demonstrated in vivo that DAC treatment could induce autologous anti-tumor immune response by depleting MDSCs. CONCLUSIONS This study is the first to illustrate DAC's immunoregulatory effect on immune tolerance. The disruption of immune tolerance is due to MDSCs depletion that induces an autologous immune response in vivo. By depleting MDSCs, DAC treatment removes one of the obstacles affecting anti-tumor immune activation and warrants further experimental and clinical studies to explore its potential utility in combination with various anti-tumor immunotherapies in the future.
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Affiliation(s)
- Jihao Zhou
- Department of Hematology, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, 1017 Dongmen North Road, Shenzhen, 518020, Guangdong Province, People's Republic of China
| | - Yushi Yao
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
| | - Qi Shen
- Department of Hematology, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, 1017 Dongmen North Road, Shenzhen, 518020, Guangdong Province, People's Republic of China
| | - Guoqiang Li
- Department of Hematology, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, 1017 Dongmen North Road, Shenzhen, 518020, Guangdong Province, People's Republic of China
| | - Lina Hu
- Department of Hematology, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, 1017 Dongmen North Road, Shenzhen, 518020, Guangdong Province, People's Republic of China
| | - Xinyou Zhang
- Department of Hematology, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, 1017 Dongmen North Road, Shenzhen, 518020, Guangdong Province, People's Republic of China.
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Zhang H, Li Z, Wang L, Tian G, Tian J, Yang Z, Cao G, Zhou H, Zhao L, Wu Z, Yin Z. Critical Role of Myeloid-Derived Suppressor Cells in Tumor-Induced Liver Immune Suppression through Inhibition of NKT Cell Function. Front Immunol 2017; 8:129. [PMID: 28243237 PMCID: PMC5303828 DOI: 10.3389/fimmu.2017.00129] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Accepted: 01/25/2017] [Indexed: 12/27/2022] Open
Abstract
Metastasis followed by the tumor development is the primary cause of death for cancer patients. However, the underlying molecular mechanisms of how the growth of tumor resulted in the immune suppression, especially at the blood-enriched organ such as liver, were largely unknown. In this report, we studied the liver immune response of tumor-bearing (TB) mice using concanavalin A (Con A)-induced hepatitis model. We demonstrated that TB mice displayed an immune suppression phenotype, with attenuated alanine aminotransferase levels and liver damage upon Con A treatment. We also elucidated that large amounts of myeloid-derived suppressor cells (MDSCs) being influx into the liver in TB mice and these MDSCs were essential for liver immune suppression through both depletion and reconstitution approaches. We further determined that these MDSCs selectively suppressed the IFN-γ production deriving from NKT cells through membrane-bound transforming growth factor β (TGF-β). Finally, we defined a tumor-derived TGF-β-triggered CXCL1/2/5- and CXCR2-dependent recruitment of MDSC into the liver. In summary, our results defined a novel mechanism of liver immune suppression triggered by growing living tumor and provided possible therapeutic targets against these MDSCs.
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Affiliation(s)
- Hongru Zhang
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University , Tianjin , China
| | - Zheng Li
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China; Shenzhou Space Biotechnology Group, Beijing, China
| | - Li Wang
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University , Tianjin , China
| | - Gaofei Tian
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University , Tianjin , China
| | - Jun Tian
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University , Tianjin , China
| | - Zishan Yang
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University , Tianjin , China
| | - Guangchao Cao
- The First Affiliate Hospital, Biomedical Translational Research Institute, Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan University , Guangzhou , China
| | - Hong Zhou
- Department of Immunology, Nanjing Medical University , Nanjing , China
| | - Liqing Zhao
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University , Tianjin , China
| | - Zhenzhou Wu
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University , Tianjin , China
| | - Zhinan Yin
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China; The First Affiliate Hospital, Biomedical Translational Research Institute, Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan University, Guangzhou, China; Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, Sichuan, China
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Eckert F, Gaipl U, Niedermann G, Hettich M, Schilbach K, Huber S, Zips D. Beyond checkpoint inhibition - Immunotherapeutical strategies in combination with radiation. Clin Transl Radiat Oncol 2017; 2:29-35. [PMID: 29657997 PMCID: PMC5893529 DOI: 10.1016/j.ctro.2016.12.006] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Revised: 12/22/2016] [Accepted: 12/22/2016] [Indexed: 12/20/2022] Open
Abstract
The revival of cancer immunotherapy has taken place with the clinical success of immune checkpoint inhibition. However, the spectrum of immunotherapeutic approaches is much broader encompassing T cell engaging strategies, tumour-specific vaccination, antibodies or immunocytokines. This review focuses on the immunological effects of irradiation and the evidence available on combination strategies with immunotherapy. The available data suggest great potential of combined treatments, yet also poses questions about dose, fractionation, timing and most promising multimodal strategies.
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Key Words
- Bispecific antibodies
- CAR, chimeric antigen receptor
- CAR-T-cells
- CDN, cyclic dinucleotides
- CTL, cytotoxic T lymphocyte
- CTLA-4, cytotoxic T-lymphocyte-associated protein 4
- GM-CSF, granulocyte-monocyte colony stimulating factor
- IR, irradiation
- Immunocytokines
- Immunotherapy
- PD-1, Programmed cell death protein 1 receptor
- PD-L1, PD-1 ligand
- Radiotherapy
- TCR, T cell receptor
- Treg, regulatory T cells
- Vaccination
- bsAb, bispecific antibody
- scFv, single chain variable fragment
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Affiliation(s)
- F. Eckert
- Department of Radiation Oncology, Universitaetsklinikum Tuebingen, Eberhard-Karls-University Tuebingen, Tuebingen, Germany
| | - U.S. Gaipl
- Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - G. Niedermann
- Department of Radiation Oncology, Medical Center – University of Freiburg, Freiburg, Germany
| | - M. Hettich
- Department of Radiation Oncology, Medical Center – University of Freiburg, Freiburg, Germany
| | - K. Schilbach
- Department of General Pediatrics/Pediatric Oncology, Universitaetsklinikum Tuebingen, Eberhard-Karls-University Tuebingen, Tuebingen, Germany
| | - S.M. Huber
- Department of Radiation Oncology, Universitaetsklinikum Tuebingen, Eberhard-Karls-University Tuebingen, Tuebingen, Germany
| | - D. Zips
- Department of Radiation Oncology, Universitaetsklinikum Tuebingen, Eberhard-Karls-University Tuebingen, Tuebingen, Germany
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Immunosuppression Induced by Chronic Inflammation and the Progression to Oral Squamous Cell Carcinoma. Mediators Inflamm 2016; 2016:5715719. [PMID: 28053372 PMCID: PMC5178366 DOI: 10.1155/2016/5715719] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Accepted: 11/10/2016] [Indexed: 12/17/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC) is an aggressive, invasive malignancy of epithelial origin. The progression from premalignant lesions—oral leukoplakia (OLK) and oral lichen planus (OLP)—to OSCC involves complex inflammatory processes that have not been elucidated. We investigated the roles of inflammatory mediators and infiltrating immunocytes in the pathogenic progression of OLK and OLP to OSCC. The occurrence of regulatory T-cells (Tregs) and tumor-associated macrophages (TAMs) and the expression of anti-inflammatory cytokines and proinflammatory cytokines were investigated in OLK, OLP, and OSCC tissues. Immunohistochemical staining of CD4, FOXP3, CD68, TGF-β1, IL-10, IL-4, IFN-γ, and MCP-1 showed that the occurrence of Tregs and TAMs increased in parallel with disease progression in OLK and OSCC. IL-10 gradually increased during the early stages of OLK and in OSCC. Infiltrating IL-4+ macrophages were seen with increasing frequency in OLK tissue during the progression of oral dysplasia. Fewer TGF-β1+ macrophages were seen in OSCC than in OLK and OLP. The expression of IFN-γ decreased gradually with the OLK development and had the lowest expression in OSCC. MCP-1 expression did not change significantly during the development of OSCC. The results suggested that the immunosuppression induced by chronic inflammation promotes tumorigenesis in OSCC, rather than initiating it.
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Yannelli JR, Wouda R, Masterson TJ, Avdiushko MG, Cohen DA. Development of an autologous canine cancer vaccine system for resectable malignant tumors in dogs. Vet Immunol Immunopathol 2016; 182:95-100. [PMID: 27863558 DOI: 10.1016/j.vetimm.2016.10.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Revised: 10/19/2016] [Accepted: 10/20/2016] [Indexed: 12/12/2022]
Abstract
While conventional therapies exist for canine cancer, immunotherapies need to be further explored and applied to the canine setting. We have developed an autologous cancer vaccine (K9-ACV), which is available for all dogs with resectable disease. K9-ACV was evaluated for safety and immunogenicity for a variety of cancer types in a cohort of companion dogs under veterinary care. The autologous vaccine was prepared by enzymatic digestion of solid tumor biopsies. The resultant single cell suspensions were then UV-irradiated resulting in immunogenic cell death of the tumor cells. Following sterility and endotoxin testing, the tumor cells were admixed with CpG ODN adjuvant and shipped to the participating veterinary clinics. The treating veterinarians then vaccinated each patient with three intradermal injections (10 million cells per dose) at 30-day intervals (one prime and two boost injections). In a cohort of 20 dogs completing the study, 17 dogs (85%) developed an augmented IgG response to autologous tumor antigens as demonstrated using western blot analysis of pre- and post-peripheral blood samples. We also report several dogs have lived beyond expected survival time based on previously published data. In summary, K9-ACV is an additional option to be considered for the treatment of dogs with resectable cancer.
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Affiliation(s)
- J R Yannelli
- University of Kentucky, College of Medicine, Dept. of Microbiology, Immunology and Molecular Genetics, Lexington, KY 40536, United States.
| | - R Wouda
- Kansas State University, College of Veterinary Medicine, Dept of Clinical Sciences, Manhattan, KS 66506, United States
| | - T J Masterson
- Medivet Biologics, LLC, Nicholasville, KY 40356, United States
| | - M G Avdiushko
- University of Kentucky, College of Medicine, Dept. of Microbiology, Immunology and Molecular Genetics, Lexington, KY 40536, United States
| | - D A Cohen
- University of Kentucky, College of Medicine, Dept. of Microbiology, Immunology and Molecular Genetics, Lexington, KY 40536, United States
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Lu C, Redd PS, Lee JR, Savage N, Liu K. The expression profiles and regulation of PD-L1 in tumor-induced myeloid-derived suppressor cells. Oncoimmunology 2016; 5:e1247135. [PMID: 28123883 DOI: 10.1080/2162402x.2016.1247135] [Citation(s) in RCA: 177] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 09/27/2016] [Accepted: 10/05/2016] [Indexed: 12/22/2022] Open
Abstract
Programmed death-ligand 1 (PD-L1) is an inhibitory ligand that binds to PD-1 to suppress T cell activation. PD-L1 is constitutively expressed and inducible in tumor cells, but the expression profiles and regulatory mechanism of PD-L1 in myeloid-derived suppressor cells (MDSCs) are largely unknown. We report that PD-L1 is abundantly expressed in tumor-infiltrating leukocytes in human patients with both microsatellite instable and microsatellite stable colon cancer. About 60% CD11b+CD33+HLA-DR- MDSCs from peripheral blood of human colon cancer patients are PD-L1+. PD-L1+ MDSCs are also significantly higher in tumor-bearing mice than in tumor-free mice. Interestingly, the highest PD-L1+ MDSCs were observed in the tumor microenvironment in which 56-71% tumor-infiltrating MDSCs are PD-L1+in vivo. In contrast, PD-L1+ MDSCs are significantly less in secondary lymphoid organs and peripheral blood as compared to the tumor tissues, whereas bone marrow MDSCs are essentially PD-L1- in tumor-bearing mice. IFNγ is highly expressed in cells of the tumor tissues and IFNγ neutralization significantly decreased PD-L1+ MDSCs in the tumor microenvironment in vivo. However, IFNγ-activated pSTAT1 does not bind to the cd274 promoter in MDSCs. Instead, pSTAT1 activates expression of IRF1, IRF5, IRF7 and IRF8 in MDSCs, and only pSTAT1-activated IRF1 binds to a unique IRF-binding sequence element in vitro and chromatin in vivo in the cd274 promoter to activate PD-L1 transcription. Our data determine that PD-L1 is highly expressed in tumor-infiltrating MDSCs and in a lesser degree in lymphoid organs, and the pSTAT1-IRF1 axis regulates PD-L1 expression in MDSCs.
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Affiliation(s)
- Chunwan Lu
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA
| | - Priscilla S Redd
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA; Georgia Cancer Center, Augusta University, Augusta, GA, USA
| | - Jeffrey R Lee
- Charlie Norwood VA Medical Center, Augusta, GA, USA; Pathology, Medical College of Georgia, Augusta, GA, USA
| | - Natasha Savage
- Pathology, Medical College of Georgia , Augusta, GA, USA
| | - Kebin Liu
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA; Georgia Cancer Center, Augusta University, Augusta, GA, USA
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Kondo Y, Ohno T, Nishii N, Harada K, Yagita H, Azuma M. Differential contribution of three immune checkpoint (VISTA, CTLA-4, PD-1) pathways to antitumor responses against squamous cell carcinoma. Oral Oncol 2016; 57:54-60. [DOI: 10.1016/j.oraloncology.2016.04.005] [Citation(s) in RCA: 97] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Revised: 03/16/2016] [Accepted: 04/12/2016] [Indexed: 01/07/2023]
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De Vlaeminck Y, González-Rascón A, Goyvaerts C, Breckpot K. Cancer-Associated Myeloid Regulatory Cells. Front Immunol 2016; 7:113. [PMID: 27065074 PMCID: PMC4810015 DOI: 10.3389/fimmu.2016.00113] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 03/14/2016] [Indexed: 12/25/2022] Open
Abstract
Myeloid cells are critically involved in the pathophysiology of cancers. In the tumor microenvironment (TME), they comprise tumor-associated macrophages (TAMs), neutrophils (TANs), dendritic cells, and myeloid-derived suppressor cells, which are further subdivided into a monocytic subset and a granulocytic subset. Some of these myeloid cells, in particular TAMs and TANs, are divided into type 1 or type 2 cells, according to the paradigm of T helper type 1 or type 2 cells. Type 1-activated cells are generally characterized as cells that aid tumor rejection, while all other myeloid cells are shown to favor tumor progression. Moreover, these cells are often at the basis of resistance to various therapies. Much research has been devoted to study the biology of myeloid cells. This endeavor has proven to be challenging, as the markers used to categorize myeloid cells in the TME are not restricted to particular subsets. Also from a functional and metabolic point of view, myeloid cells share many features. Finally, myeloid cells are endowed with a certain level of plasticity, which further complicates studying them outside their environment. In this article, we challenge the exclusive use of cell markers to unambiguously identify myeloid cell subsets in the TME. We further propose to divide myeloid cells into myeloid regulatory or stimulatory cells according to their pro- or antitumor function, because we contend that for therapeutic purposes it is not targeting the cell subsets but rather targeting their protumor traits; hence, myeloid regulatory cells will push antitumor immunotherapy to the next level.
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Affiliation(s)
- Yannick De Vlaeminck
- Laboratory of Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel , Brussels , Belgium
| | - Anna González-Rascón
- Laboratory of Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel, Brussels, Belgium; Centro de Investigación en Alimentación y Desarrollo, Hermosillo, Mexico
| | - Cleo Goyvaerts
- Laboratory of Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel , Brussels , Belgium
| | - Karine Breckpot
- Laboratory of Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel , Brussels , Belgium
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