Recombinant
| Autor: | Weiwen, Deng, Victor, Lira, Thomas E, Hudson, Edward E, Lemmens, William G, Hanson, Ruben, Flores, Gonzalo, Barajas, George E, Katibah, Anthony L, Desbien, Peter, Lauer, Meredith L, Leong, Daniel A, Portnoy, Thomas W, Dubensky |
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| Rok vydání: | 2018 |
| Předmět: |
Mice
Inbred BALB C Macrophages Vaccination Drug Evaluation Preclinical CD8-Positive T-Lymphocytes Biological Sciences Vaccines Attenuated Cancer Vaccines Listeria monocytogenes Xenograft Model Antitumor Assays Mice Inbred C57BL Mice Treatment Outcome Immunology and Inflammation Antigens Neoplasm Cell Line Tumor Neoplasms CD8+ T Tumor Microenvironment Vaccines DNA Animals Humans Female cancer vaccine |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 |
| Popis: | Significance The development of therapeutic cancer vaccines using recombinant microorganisms has been pursued for many decades. However, the underlying mechanisms of therapeutic cancer vaccines remain unclear. Here we compare recombinant Listeria-based cancer vaccines to synthetic long peptide and adenovirus delivery systems for tumor antigens, and describe immunologic correlates of antitumor efficacy of Listeria-based cancer vaccines. Our results show that the profound antitumor efficacy requires tumor microenvironment (TME) remodeling that depends on tumor-specific CD8+ T cells induced by live-attenuated double-deleted Listeria monocytogenes expressing cognate tumor antigens. Together, this work highlights the importance of cognate tumor antigen expression by cancer vaccines and pinpoints the relationship between induced tumor antigen-specific immunity and the TME. Agents that remodel the tumor microenvironment (TME), prime functional tumor-specific T cells, and block inhibitory signaling pathways are essential components of effective immunotherapy. We are evaluating live-attenuated, double-deleted Listeria monocytogenes expressing tumor antigens (LADD-Ag) in the clinic. Here we show in numerous mouse models that while treatment with nonrecombinant LADD induced some changes in the TME, no antitumor efficacy was observed, even when combined with immune checkpoint blockade. In contrast, LADD-Ag promoted tumor rejection by priming tumor-specific KLRG1+PD1loCD62L− CD8+ T cells. These IFNγ-producing effector CD8+ T cells infiltrated the tumor and converted the tumor from an immunosuppressive to an inflamed microenvironment that was characterized by a decrease in regulatory T cells (Treg) levels, a proinflammatory cytokine milieu, and the shift of M2 macrophages to an inducible nitric oxide synthase (iNOS)+CD206− M1 phenotype. Remarkably, these LADD-Ag–induced tumor-specific T cells persisted for more than 2 months after primary tumor challenge and rapidly controlled secondary tumor challenge. Our results indicate that the striking antitumor efficacy observed in mice with LADD-based immunotherapy stems from TME remodeling which is a direct consequence of eliciting potent, systemic tumor-specific CD8+ T cells. |
| Databáze: | OpenAIRE |
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