Reciprocal Cellular Cross-Talk within the Tumor Microenvironment Promotes Oncolytic Virus Activity

Signalling between cancer cells and the normal stromal cells that support them is known to negatively impact the activity of a variety of chemically based anti-cancer therapies^1-4. In this regard, we have recently shown that, in the case of oncolytic virus based therapeutics, crosstalk between cancer- associated fibroblasts (CAFs) and cancer cells leads to enhanced infectivity. TGFβ produced by tumor cells re-programs supporting cancer-associated fibroblasts dampening their steady state level of anti-viral transcripts and rendering them sensitive to virus infection. We found that in turn, CAFs produce high levels of fibroblast growth factor 2 (FGF-2) initiating a signaling cascade in cancer cells that leads to a decrease in RIG-I expression and impedes the ability of the malignant cell to sense and respond to an invading virus therapeutic. In pancreatic cancer patient explants, the expression of FGF-2 correlated with susceptibility to infection with oncolytic viruses and resistant patient samples could be sensitized by the addition of FGF-2 in vitro and in vivo.

1-Chung, A.S., et al. An interleukin-17-mediated paracrine network promotes tumor resistance to anti-angiogenic therapy. Nature medicine 19, 1114-1123 (2013).

2-Nakasone, E.S., et al. Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance. Cancer cell 21, 488-503 (2012).

3-Straussman, R., et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487, 500-504 (2012).

4-Sun, Y., et al. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nature medicine 18, 1359-1368 (2012).