Abstract
It is generally accepted that the success of immunotherapy depends on the presence of tumor-specific CD8⁺ cytotoxic T cells and the modulation of the tumor environment. In this study, we validated mRNA encoding soluble factors as a tool to modulate the tumor microenvironment to potentiate infiltration of tumor-specific T cells. Intratumoral delivery of mRNA encoding a fusion protein consisting of interferon-β and the ectodomain of the transforming growth factor-β receptor II, referred to as Fβ², showed therapeutic potential. The treatment efficacy was dependent on CD8⁺ T cells and could be improved through blockade of PD-1/PD-L1 interactions. In vitro studies revealed that administration of Fβ² to tumor cells resulted in a reduced proliferation and increased expression of MHC I but also PD-L1. Importantly, Fβ² enhanced the antigen presenting capacity of dendritic cells, whilst reducing the suppressive activity of myeloid-derived suppressor cells. In conclusion, these data suggest that intratumoral delivery of mRNA encoding soluble proteins, such as Fβ², can modulate the tumor microenvironment, leading to effective antitumor T cell responses, which can be further potentiated through combination therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Breast Neoplasms / genetics
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Breast Neoplasms / immunology
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Breast Neoplasms / therapy
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CD8-Positive T-Lymphocytes / immunology
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Cell Line, Tumor
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Dendritic Cells / immunology
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Female
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Genetic Therapy / methods
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HEK293 Cells
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Humans
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Immunotherapy / methods
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Injections, Intralesional
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Interferon-beta / biosynthesis
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Interferon-beta / genetics*
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Interferon-beta / immunology
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Lung Neoplasms / genetics
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Lung Neoplasms / immunology
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Lung Neoplasms / therapy
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Lymphoma, T-Cell / genetics
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Lymphoma, T-Cell / immunology
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Lymphoma, T-Cell / therapy
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Melanoma, Experimental / genetics
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Melanoma, Experimental / immunology
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Melanoma, Experimental / therapy
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Mice
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Mice, Inbred C57BL
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Myeloid Cells / immunology
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Neoplasms / genetics
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Neoplasms / immunology*
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Neoplasms / therapy*
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Protein Biosynthesis
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Protein Serine-Threonine Kinases / biosynthesis
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Protein Serine-Threonine Kinases / genetics*
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Protein Serine-Threonine Kinases / immunology
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RNA, Messenger / administration & dosage*
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RNA, Messenger / genetics
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / biosynthesis
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Receptors, Transforming Growth Factor beta / genetics*
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Receptors, Transforming Growth Factor beta / immunology
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Recombinant Fusion Proteins / biosynthesis
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / immunology
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Tumor Microenvironment / immunology
Substances
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RNA, Messenger
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Receptors, Transforming Growth Factor beta
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Recombinant Fusion Proteins
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Interferon-beta
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type II