Abstract 3662: Activation of CD40 while inhibiting IL6/STAT3 using oncolytic viruses induces mature DCs with high cytokine production but blocks PDL1 expression

Abstract

Abstract The tumor microenvironment (TME) consists of tumor cells and stroma, including fibroblasts, blood vessels, immune cells and extracellular matrix. The TME supports tumor progression, metastasis as well as resistance to cancer therapeutics. In pancreatic cancer, the TME is dense due to overproduction of collagen and the tumor is infiltrated with suppressive myeloid cells such as M2 macrophages and myeloid suppressor cells. One key regulator of myeloid cells is CD40, a receptor expressed on a variety of cell types. CD40/CD40L signaling results in production of cytokines and chemokines by myeloid cells but also endothelial and epithelial cells to alert the immune system of immediate danger. 4-1BB is expressed by lymphocytes and dendritic cells (DCs). Stimulation via 4-1BBL drives lymphocyte expansion and regulates memory formation. IL6 signaling leads to STAT3 phosphorylation in myeloid cells and tumor cells leading to suppressive phenotypes, tumor proliferation, and angiogenesis. Further, STAT3 signaling enhances production of TGFb, which in turn leads to overexpression of collagen. We have constructed a family of oncolytic adenoviruses (LOAd) activating the CD40, 4-1BB and/or inhibiting IL6 signaling. The LOAd viruses (-, 700, 703, 713) were investigated for their capacity to activate human monocyte-derived DCs as well as their effect on pancreatic tumor cells and stroma (fibroblastic stellate cells, endothelial cells) using flow cytometry, MTS assay and ProSeek Proteomics. The LOAd viruses expressing a trimerized CD40L, 4-1BBL and/or a scFv IL6R showed efficient oncolysis of tumor cells but primary stellate cells were unaffected. However, stellate cells reduced tumor-promoting factors such as FGF5, PlGF, amphiregulin, Gal3, TGFb and collagen type I. Dendritic cells increased costimulators, cytokines as well as chemokines but PDL1 was not expressed when IL6/STAT3 was blocked. Infected endothelial cells upregulated receptors important for lymphocyte transmigration (ICAM, VCAM and E-Selectin). Taken together, our data demonstrates that it is possible to utilize oncolytic adenoviruses to spark immune activation at the same time changing biological processes via STAT3 blockade and/or CD40/4-1BB pathway activation to reduce factors that promotes tumor progression. Citation Format: Emma Eriksson, Ioanna Milenova, Jessica Wenthe, Anna Dimberg, Rafael Moreno, Gustav Ullenhag, Ramon Alemany, Angelica Loskog. Activation of CD40 while inhibiting IL6/STAT3 using oncolytic viruses induces mature DCs with high cytokine production but blocks PDL1 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3662. doi:10.1158/1538-7445.AM2017-3662