Nature communications, 2017-11, Vol.8 (1), p.1447-10, Article 1447
2017
Details
- Autor(en) / Beteiligte
- Titel
- Intratumoral CD40 activation and checkpoint blockade induces T cell-mediated eradication of melanoma in the brain
- Ist Teil von
- Nature communications, 2017-11, Vol.8 (1), p.1447-10, Article 1447
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2017
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- CD40 agonists bind the CD40 molecule on antigen-presenting cells and activate them to prime tumor-specific CD8 T cell responses. Here, we study the antitumor activity and mechanism of action of a nonreplicating adenovirus encoding a chimeric, membrane-bound CD40 ligand (ISF35). Intratumoral administration of ISF35 in subcutaneous B16 melanomas generates tumor-specific, CD8 T cells that express PD-1 and suppress tumor growth. Combination therapy of ISF35 with systemic anti-PD-1 generates greater antitumor activity than each respective monotherapy. Triple combination of ISF35, anti-PD-1, and anti-CTLA-4 results in complete eradication of injected and noninjected subcutaneous tumors, as well as melanoma tumors in the brain. Therapeutic efficacy is associated with increases in the systemic level of tumor-specific CD8 T cells, and an increased ratio of intratumoral CD8 T cells to CD4 Tregs. These results provide a proof of concept of systemic antitumor activity after intratumoral CD40 triggering with ISF35 in combination with checkpoint blockade for multifocal cancer, including the brain.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-017-01572-7Titel-ID: cdi_doaj_primary_oai_doaj_org_article_91b84c7ca48048a5926a4f18a85bbaa3
- Format
- –
- Schlagworte
- Adenoviridae - genetics, Animals, Anticancer properties, Antigen-presenting cells, Antitumor activity, Brain, Brain - pathology, Brain Neoplasms - immunology, Brain Neoplasms - therapy, Brain tumors, Cancer, CD4 antigen, CD4-CD8 Ratio, CD40 antigen, CD40 Antigens - agonists, CD40 Antigens - metabolism, CD40 Ligand - genetics, CD40 Ligand - immunology, CD8 antigen, CD8-Positive T-Lymphocytes - immunology, Cell activation, Cell Line, Tumor, CTLA-4 Antigen - antagonists & inhibitors, CTLA-4 protein, Enzyme Activation, Female, Immune checkpoint, Immunotherapy - methods, Lymphocytes, Lymphocytes T, Melanoma, Melanoma, Experimental - immunology, Melanoma, Experimental - therapy, Mice, Mice, Inbred C57BL, Mice, Knockout, PD-1 protein, Programmed Cell Death 1 Receptor - antagonists & inhibitors, Programmed Cell Death 1 Receptor - biosynthesis, T cell receptors, Tumors