Heterologous arenavirus vector prime-boost overrules self-tolerance for efficient tumor-specific CD8 T cell attack
| Autor: | Ilena Vincenti, Sabine Hoepner, Alfred Zippelius, Ursula Berka, Stephanie Darbre, Magdalena A. Krzyzaniak, Stephan Günther, Nicole Kirchhammer, Carsten Magnus, Romy Kerber, Daniel D. Pinschewer, Weldy V. Bonilla, Josipa Raguz, Sarah Schmidt, Min Lu, Klaus Orlinger, Anna-Friederike Marx, Sandra M. Kallert, Mindaugas Pauzuolis, Doron Merkler |
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| Rok vydání: | 2021 |
| Předmět: |
medicine.medical_treatment
Genetic Vectors Guinea Pigs Immunization Secondary Gene Expression pre-existing immunity Heterologous CD8 T cells Immunodominance ddc:616.07 Lymphocytic choriomeningitis Cancer Vaccines Article General Biochemistry Genetics and Molecular Biology Mice therapeutic tumor vaccine medicine Alarmins Animals Lymphocytic choriomeningitis virus Cytotoxic T cell Vector (molecular biology) arenavirus Pichinde virus Phylogeny tumor control Arenavirus biology Vaccination anti-vector immunity Immunotherapy Mastocytoma biology.organism_classification medicine.disease Antibodies Neutralizing Survival Analysis Virology viral genealogy Mice Inbred C57BL CTL Self Tolerance Female Genetic Engineering T-Lymphocytes Cytotoxic |
| Zdroj: | Cell Reports Medicine Cell Reports. Medicine, Vol. 2, No 3 (2021) P. 100209 |
| ISSN: | 2666-3791 |
| Popis: | Summary Therapeutic vaccination regimens inducing clinically effective tumor-specific CD8+ T lymphocyte (CTL) responses are an unmet medical need. We engineer two distantly related arenaviruses, Pichinde virus and lymphocytic choriomeningitis virus, for therapeutic cancer vaccination. In mice, life-replicating vector formats of these two viruses delivering a self-antigen in a heterologous prime-boost regimen induce tumor-specific CTL responses up to 50% of the circulating CD8 T cell pool. This CTL attack eliminates established solid tumors in a significant proportion of animals, accompanied by protection against tumor rechallenge. The magnitude of CTL responses is alarmin driven and requires combining two genealogically distantly related arenaviruses. Vector-neutralizing antibodies do not inhibit booster immunizations by the same vector or by closely related vectors. Rather, CTL immunodominance hierarchies favor vector backbone-targeted responses at the expense of self-reactive CTLs. These findings establish an arenavirus-based immunotherapy regimen that allows reshuffling of immunodominance hierarchies and breaking self-directed tolerance for efficient tumor control. Graphical abstract Highlights Engineered arenaviruses induce potent tumor self-specific CD8 T cell (CTL) response Combinations of distantly but not closely related arenavirus vectors eliminate tumors Vector backbone-targeted CTL responses compete against tumor self-reactive CTLs Optimized vector combinations reshuffle immunodominance to break self-tolerance Therapeutic tumor vaccination should break self-tolerance. Assessing combinations of engineered arenavirus vectors, Bonilla et al. find that distantly related vector combinations reshuffle T cell immunodominance hierarchies to break self-tolerance and eliminate established solid tumors, whereas closely related vectors interfere because of immunodominance of anti-vector CD8 T cells rather than antibodies. |
| Databáze: | OpenAIRE |
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