Activation of myeloid and endothelial cells by CD40L gene therapy supports T-cell expansion and migration into the tumor microenvironment

• Published in: Gene therapy 2017-02, Vol.24 (2), p.92-103
• Main Authors: Eriksson, E, Moreno, R, Milenova, I, Liljenfeldt, L, Dieterich, L C, Christiansson, L, Karlsson, H, Ullenhag, G, Mangsbo, S M, Dimberg, A, Alemany, R, Loskog, A
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/31; 42/44; 631/250/127; 631/250/251; 631/61/201; 631/67/580; 64/60; 692/699/67/1504/1713; 82/79; 96; Adenoviridae; Adenoviruses; Animals; Biomedical and Life Sciences; Biomedicine; Care and treatment; CD40 Ligand - genetics; Cell Biology; Cell Movement - immunology; Cytokines - metabolism; Dendritic cells; Dendritic Cells - immunology; Development and progression; Endothelium, Vascular - immunology; Female; Gene Expression; Gene Therapy; Genetic aspects; Genetic Therapy; Genetic Vectors - administration & dosage; Health aspects; Human Genetics; Humans; Immunologi; Immunology; Immunotherapy; Methods; Mice; Mice, Inbred C57BL; Myeloid Cells - immunology; Nanotechnology; Oncology; Oncolytic Viruses - genetics; Original; original-article; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - therapy; Patient outcomes; T cell receptors; T cells; T-Lymphocytes, Cytotoxic - immunology; Tumor Cells, Cultured; Tumor Microenvironment - immunology; Xenograft Model Antitumor Assays
• ISSN: 0969-7128; 1476-5462; 1476-5462
• DOI: 10.1038/gt.2016.80

CD40 is an interesting target in cancer immunotherapy due to its ability to stimulate T-helper 1 immunity via maturation of dendritic cells and to drive M2 to M1 macrophage differentiation. Pancreatic cancer has a high M2 content that has shown responsive to anti-CD40 agonist therapy and CD40 may thus be a suitable target for immune activation in these patients. In this study, a novel oncolytic adenovirus armed with a trimerized membrane-bound extracellular CD40L (TMZ-CD40L) was evaluated as a treatment of pancreatic cancer. Further, the CD40L mechanisms of action were elucidated in cancer models. The results demonstrated that the virus transferring TMZ-CD40L had oncolytic capacity in pancreatic cancer cells and could control tumor progression. TMZ-CD40L was a potent stimulator of human myeloid cells and T-cell responses. Further, CD40L-mediated stimulation increased tumor-infiltrating T cells in vivo , which may be due to a direct activation of endothelial cells to upregulate receptors for lymphocyte attachment and transmigration. In conclusion, CD40L-mediated gene therapy is an interesting concept for the treatment of tumors with high levels of M2 macrophages, such as pancreatic cancer, and an oncolytic virus as carrier of CD40L may further boost tumor killing and immune activation.