Sindbis Virus with Anti-OX40 Overcomes the Immunosuppressive Tumor Microenvironment of Low-Immunogenic Tumors
| Autor: | Cynthia Loomis, Alicia Hurtado, Daniel Meruelo, Silvana Opp, Iris Scherwitzl, Christine Pampeno, Kasthuri Kannan, Minjun Yu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Sindbis virus medicine.medical_treatment anti-OX40 alpha-virus immunotherapy anti-tumor immunity lcsh:RC254-282 Article oncolytic virus anti-OX40 combination therapy 03 medical and health sciences 0302 clinical medicine Immune system Antigen Cancer immunotherapy cancer immunity Sindbis Medicine Pharmacology (medical) Tumor microenvironment biology Effector business.industry Immunotherapy biology.organism_classification lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Oncolytic virus 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research Molecular Medicine business |
| Zdroj: | Molecular Therapy: Oncolytics, Vol 17, Iss, Pp 431-447 (2020) Molecular Therapy Oncolytics |
| ISSN: | 2372-7705 |
| Popis: | Despite remarkable responses to cancer immunotherapy in a subset of patients, many patients remain resistant to therapies. It is now clear that elevated levels of tumor-infiltrating T cells as well as a systemic anti-tumor immune response are requirements for successful immunotherapies. However, the tumor microenvironment imposes an additional resistance mechanism to immunotherapy. We have developed a practical and improved strategy for cancer immunotherapy using an oncolytic virus and anti-OX40. This strategy takes advantage of a preexisting T cell immune repertoire in vivo, removing the need to know about present tumor antigens. We have shown in this study that the replication-deficient oncolytic Sindbis virus vector expressing interleukin-12 (IL-12) (SV.IL12) activates immune-mediated tumor killing by inducing OX40 expression on CD4 T cells, allowing the full potential of the agonistic anti-OX40 antibody. The combination of SV.IL12 with anti-OX40 markedly changes the transcriptome signature and metabolic program of T cells, driving the development of highly activated terminally differentiated effector T cells. These metabolically reprogrammed T cells demonstrate enhanced tumor infiltration capacity as well as anti-tumor activity capable of overcoming the repressive tumor microenvironment. Our findings identify SV.IL12 in combination with anti-OX40 to be a novel and potent therapeutic strategy that can cure multiple types of low-immunogenic solid tumors. Graphical Abstract Despite remarkable responses to cancer immunotherapy, many patients remain resistant to therapies. The harsh tumor microenvironment blocks tumor penetration, impairing the cancer killing functions of the immune system. In this study, the authors show that the combination of an oncolytic virus and anti-OX40 antibody can successfully cure multiple tumors by overcoming this resistance. |
| Databáze: | OpenAIRE |
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