Reciprocal cellular cross-talk within the tumor microenvironment promotes oncolytic virus activity

Abstract

Tumors are complex ecosystems composed of networks of interacting 'normal' and malignant cells. It is well recognized that cytokine-mediated cross-talk between normal stromal cells, including cancer-associated fibroblasts (CAFs), vascular endothelial cells, immune cells, and cancer cells, influences all aspects of tumor biology. Here we demonstrate that the cross-talk between CAFs and cancer cells leads to enhanced growth of oncolytic virus (OV)-based therapeutics. Transforming growth factor-β (TGF-β) produced by tumor cells reprogrammed CAFs, dampened their steady-state level of antiviral transcripts and rendered them sensitive to virus infection. In turn, CAFs produced high levels of fibroblast growth factor 2 (FGF2), initiating a signaling cascade in cancer cells that reduced retinoic acid-inducible gene I (RIG-I) expression and impeded the ability of malignant cells to detect and respond to virus. In xenografts derived from individuals with pancreatic cancer, the expression of FGF2 correlated with the susceptibility of the cancer cells to OV infection, and local application of FGF2 to resistant tumor samples sensitized them to virotherapy both in vitro and in vivo. An OV engineered to express FGF2 was safe in tumor-bearing mice, showed improved therapeutic efficacy compared to parental virus and merits consideration for clinical testing.

Lysyl oxidase activates cancer stromal cells and promotes gastric cancer progression: quantum dot-based identification of biomarkers in cancer stromal cells

“…10 There is a critical need to deal with the tumor progression no longer as a cancer cell autonomous event but as a continuing process, which relies upon these complex networks of both the immediate microenvironment (cellcell or cell-matrix interactions) and the extended TME (eg, vascularization). 11,12 Beyond question, the morphological, biochemical and biophysical properties of extended TME are significantly different among normal tissues and cancer tissues. The continuous change in cancer stroma in different clinical stages was called stromal activation, which was parallel to cancer cell growth and invasion.…”

All that glitters is not gold: the need to consider desirable and undesirable immune aspects of oncolytic virus therapy

“…On one hand, it provides an infection-vulnerable niche that promotes replication of the virus. 4 On the other hand, it hampers the establishment of OV-driven antitumor immune responses and represents a major hurdle in the development of a clinically meaningful anticancer immunity. Thus, the strategic management of cancer-associated immunosuppression during all stages of OVbased oncotherapy is of utmost importance.…”

The Interaction Between Human Papillomaviruses and the Stromal Microenvironment

“…Cancer cells and CAFs are relatively sensitive to virus infection, in part because the TGFβ1 and FGF produced by these cells can inhibit IFN production 241 . EGF and HGF can also suppress the antiviral activity of IFNα and IFNβ 242 .…”