دورية أكاديمية
IFNα and 5-Aza-2'-deoxycytidine combined with a dendritic-cell targeting DNA vaccine alter tumor immune cell infiltration in the B16F10 melanoma model.
| العنوان: | IFNα and 5-Aza-2'-deoxycytidine combined with a dendritic-cell targeting DNA vaccine alter tumor immune cell infiltration in the B16F10 melanoma model. |
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| المؤلفون: | Gordy JT; Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States., Sandhu AK; Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States., Fessler K; Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States., Luo K; Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States., Kapoor AR; Division of Infectious Diseases, Center for Tuberculosis Research, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United States., Ayeh SK; Division of Infectious Diseases, Center for Tuberculosis Research, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United States., Hui Y; Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States., Schill C; Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States., Chen F; Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States., Wang T; Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States., Karanika S; Division of Infectious Diseases, Center for Tuberculosis Research, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United States., Sunshine JC; The Departments of Dermatology, Pathology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States., Karakousis PC; Division of Infectious Diseases, Center for Tuberculosis Research, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United States., Markham RB; Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States. |
| المصدر: | Frontiers in immunology [Front Immunol] 2023 Jan 19; Vol. 13, pp. 1074644. Date of Electronic Publication: 2023 Jan 19 (Print Publication: 2022). |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101560960 Publication Model: eCollection Cited Medium: Internet ISSN: 1664-3224 (Electronic) Linking ISSN: 16643224 NLM ISO Abbreviation: Front Immunol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: [Lausanne : Frontiers Research Foundation] |
| مواضيع طبية MeSH: | Melanoma* , Vaccines, DNA* , Cancer Vaccines*, Animals ; Mice ; Decitabine/pharmacology ; Interferon-alpha ; RNA, Messenger ; Tumor Microenvironment |
| مستخلص: | Introduction: DNA vaccines containing a fusion of the gene encoding chemokine MIP-3α (CCL20), the ligand for CCR6 on immature dendritic cells (DCs), to melanoma-associated antigen genes have enhanced anti-tumor immunity and efficacy compared to those lacking the chemokine gene. Previous work has shown that type-I interferon (IFNα or IFN) and 5-Aza-2'-deoxycytidine (5Aza) significantly enhance the therapeutic benefit of DNA vaccines as measured by reduced tumor burden and improved mouse survival. Methods: Here, we explored mouse intratumoral immune correlates underlying the therapeutic benefit of this combination regimen (vaccine, IFN, and 5Aza) as compared to vaccine alone and IFN and 5Aza without vaccine, focusing on chemokine mRNA expression by qRT-PCR and inflammatory cellular infiltration into the tumor microenvironment (TME) by flow cytometry and immunohistochemistry (IHC). Results: The combination group significantly upregulated intratumoral mRNA expression of key immune infiltration chemokines XCL1 and CXCL10. Flow cytometric analyses of tumor suspensions exhibited greater tumor infiltration of CD8+ DCs, CCR7+ DCs, and NK cells in the combination group, as well as reduced levels of myeloid-derived suppressor cells (MDSCs) in vaccinated groups. The mice receiving combination therapy also had greater proportions of effector/memory T-cells (Tem), in addition to showing an enhanced infiltration of Tem and central memory CD8+ T-cells, (Tcm). Tem and Tcm populations both correlated with smaller tumor size. Immunohistochemical analysis of tumors confirmed that CD8+ cells were more abundant overall and especially in the tumor parenchyma with combination therapy. Discussion: Efficient targeting of antigen to immature DCs with a chemokine-fusion vaccine offers a potential alternative approach to classic and dendritic cell-based vaccines. Combining this approach with IFNα and 5Aza treatments significantly improved vaccine efficacy. This treatment creates an environment of increased inflammatory chemokines that facilitates the trafficking of CD8+ DCs, NK cells, and CD8+ T-cells, especially memory cells, while reducing the number of MDSCs. Importantly, in the combination group, CD8+ cells were more able to penetrate the tumor mass in addition to being more numerous. Further analysis of the pathways engaged by our combination therapy is expected to provide additional insights into melanoma pathogenesis and facilitate the development of novel treatment strategies. Competing Interests: Authors RM and JG are inventors on a patent 11419928 for the vaccine that has been issued to Johns Hopkins University. The remaining authors declare that the research was conducted in the absence of any further commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Gordy, Sandhu, Fessler, Luo, Kapoor, Ayeh, Hui, Schill, Chen, Wang, Karanika, Sunshine, Karakousis and Markham.) |
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| معلومات مُعتمدة: | T32 AI007291 United States AI NIAID NIH HHS; P30 CA006973 United States CA NCI NIH HHS; K24 AI143447 United States AI NIAID NIH HHS; R01 AI148710 United States AI NIAID NIH HHS |
| فهرسة مساهمة: | Keywords: 5-Aza-2’-deoxycitidine; B16F10 melanoma; CCL20; CD8+ T-cells; chemokine; dendritic cell; interferon; vaccine |
| المشرفين على المادة: | 776B62CQ27 (Decitabine) 0 (Interferon-alpha) 0 (RNA, Messenger) 0 (Vaccines, DNA) 0 (Cancer Vaccines) |
| تواريخ الأحداث: | Date Created: 20230206 Date Completed: 20230208 Latest Revision: 20230422 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC9892704 |
| DOI: | 10.3389/fimmu.2022.1074644 |
| PMID: | 36741387 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1664-3224 |
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| DOI: | 10.3389/fimmu.2022.1074644 |