POLARIZATION OF HUMAN ADIPOSE-DERIVED MESENCHYMAL STROMAL CELLS BY TOLL-LIKE RECEPTOR PRIMING

 Mesenchymal stromal cells (MSC) are a multipotent stromal population of interest as cancer therapeutics for their inherent tropism towards cancer sites. This renders them a potential cellular vehicle for delivering anti-tumor therapies. A limitation to their broader use is a plasticity in their biological roles, which depending on the context, may potentiate opposite roles in tumor modulation. Therefore, strategies to “guide” these cells towards a desired functional role are of high interest in the field of cancer therapeutics. In this dissertation, the functional polarization paradigm via stimulation with toll-like receptor ligands (poly I:C or LPS), previously described in bone-marrow derived MSC (BM-MSC), was evaluated in MSC sourced from adipose tissues (ASC). ASC provide several advantages over BM-MSC, such as the relative ease of acquisition of clinically relevant cellular doses via in vitro expansion. Findings in our studies in prostate cancer models in vitro suggested that a generation of phenotypically and functionally distinct ASC populations could be achieved via differential pre-stimulation approaches on ASC. We observed significant effects on the migratory and immunomodulatory capability of ASC, demonstrated via in vitro assays. Upon administration of these cells in vivo in a mouse model of prostate cancer, poly I:C-primed (or pre-conditioned) ASC were found to accelerate tumor growth progression. While unprimed and LPS-primed ASC did not exert a significant effect on tumor growth at the macroscopic level, gene expression analyses suggested that all treatments promoted distinct modulatory effects in the tumor microenvironment, including altered modulation of angiogenesis, and immune response processes, however, only in the case of poly I:C-primed ASC these effects translated to a significant effect in the tumor growth rate in the mouse model examined.