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      Doxorubicin pretreatment enhances FAPα/survivin co-targeting DNA vaccine anti-tumor activity primarily through decreasing peripheral MDSCs in the 4T1 murine breast cancer model

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          ABSTRACT

          The tumor microenvironment (TME) provides necessary nutrition for tumor growth and recruits immunosuppressive factors including regulatory T cells and myeloid-derived suppressor cells (MDSCs) to inhibit the anti-tumor immune response induced by immunotherapy. As a main TME component, cancer associated fibroblasts (CAFs) can restrain T cell infiltration and activity through extracellular matrix remodeling. Vaccines targeting fibroblast-activating protein α (FAPα), which is mainly expressed on the CAF surface, can eliminate CAFs in tumors and regulate the TME, enhancing the potency of T cell-mediated anti-tumor effects. However, the anti-tumor effects were not fully realized as the tumor induces a large number of peripheral MDSCs during its growth, rendering the body of mice in an immunosuppressive state and preventing the vaccine from inducing effective anti-tumor immune responses. Here, we developed a dual-targeted DNA vaccine OsFS, targeting tumor matrix antigen FAPα and tumor cell antigen survivin simultaneously, exhibited enhanced antineoplastic effects in an established breast cancer model. Moreover, doxorubicin (Dox) pretreatment to remove the peripheral MDSCs induced to regulate the peripheral immune environment could further facilitate the anti-tumor activity of the vaccine. These results indicated that combination treatment of the tumor cells and the TME dual-targeting vaccine plus Dox could effectively realize the anti-tumor activity of the vaccine by decreasing immunosuppressive factors and inducing more tumor-infiltrating lymphocytes, which may offer important guidance for clinical research regarding the combination of the DNA vaccine with low-dose Dox.

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          Most cited references39

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          The blockade of immune checkpoints in cancer immunotherapy.

          Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
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            Immunological hallmarks of stromal cells in the tumour microenvironment.

            A dynamic and mutualistic interaction between tumour cells and the surrounding stroma promotes the initiation, progression, metastasis and chemoresistance of solid tumours. Far less understood is the relationship between the stroma and tumour-infiltrating leukocytes; however, emerging evidence suggests that the stromal compartment can shape antitumour immunity and responsiveness to immunotherapy. Thus, there is growing interest in elucidating the immunomodulatory roles of the stroma that evolve within the tumour microenvironment. In this Review, we discuss the evidence that stromal determinants interact with leukocytes and influence antitumour immunity, with emphasis on the immunological attributes of stromal cells that may foster their protumorigenic function.
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              Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha.

              The stromal microenvironment of tumors, which is a mixture of hematopoietic and mesenchymal cells, suppresses immune control of tumor growth. A stromal cell type that was first identified in human cancers expresses fibroblast activation protein-α (FAP). We created a transgenic mouse in which FAP-expressing cells can be ablated. Depletion of FAP-expressing cells, which made up only 2% of all tumor cells in established Lewis lung carcinomas, caused rapid hypoxic necrosis of both cancer and stromal cells in immunogenic tumors by a process involving interferon-γ and tumor necrosis factor-α. Depleting FAP-expressing cells in a subcutaneous model of pancreatic ductal adenocarcinoma also permitted immunological control of growth. Therefore, FAP-expressing cells are a nonredundant, immune-suppressive component of the tumor microenvironment.
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                Author and article information

                Journal
                Oncoimmunology
                Oncoimmunology
                KONI
                koni20
                Oncoimmunology
                Taylor & Francis
                2162-4011
                2162-402X
                2020
                16 April 2020
                16 April 2020
                : 9
                : 1
                : 1747350
                Affiliations
                [a ]National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University , Changchun, P. R. China
                [b ]Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, School of Life Sciences, Jilin University , Changchun, P. R. China
                Author notes
                CONTACT Hai-Hong Zhang zhanghh@ 123456jlu.edu.cn
                Xiang-Hui Yu Yuxianghui@ 123456jlu.edu.cn National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University , No. 2699, Street Qianjin, Changchun 130012, P. R. China
                Article
                1747350
                10.1080/2162402X.2020.1747350
                7185204
                32363118
                eacdb950-046d-49b0-8c87-56430b388e5f
                © 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 22 November 2019
                : 25 February 2020
                : 29 February 2020
                Page count
                Figures: 8, References: 56, Pages: 15
                Funding
                Funded by: Key R & D Projects of Science and Technology Department of Jilin Province
                Award ID: 20180201001YY
                Funded by: Major Projects of Science and Technology Innovation
                Award ID: 17YJ002
                Funded by: National Science and Technology Major Project of the Ministry of Science and Technology of China
                Award ID: 2014ZX09304314-001
                Funded by: Jilin Province Science and Technology Development Program
                Award ID: 20160519018JH
                Funded by: Specialized Research Fund for the National Natural Science Foundation of China
                Award ID: 31300765
                Supported by the Key R & D Projects of Science and Technology Department of Jilin Province [no. 20180201001YY], Major Projects of Science and Technology Innovation in Changchun City [no. 17YJ002], the Specialized Research Fund for the National Natural Science Foundation of China [no. 31300765], the Jilin Province Science and Technology Development Program [no. 20160519018JH], and the National Science and Technology Major Project of the Ministry of Science and Technology of China [no. 2014ZX09304314-001].
                Categories
                Original Research

                Immunology
                tumor microenvironment,fibroblast activating protein α,survivin,myeloid-derived suppressor cells,doxorubicin

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