Abstract
Both anti-tumoral and pro-tumoral effects of mesenchymal stem cells (MSCs) in preclinical treatment of ovarian cancer have been controversially demonstrated. In this study, we profiled the phenotypes of mouse compact bone-derived MSCs (CB-MSCs) and bone marrow-derived MSCs (BM-MSCs) and found that CB-MSCs expressed lower CD90 compared to BM-MSCs. We examined gene expression of immune regulating cytokines of CB-MSCs in 2D and 3D culture and under stimulation with TLR4 agonist LPS or immune activator VIC-008. Our data showed that when CB-MSCs were cultured in simulated in vivo 3D condition, CD90 expression was further decreased. Moreover, gene expressions of immune activating cytokines IL-12, IL-21, IFNγ and a pro-inflammatory cytokine CXCL10 in CB-MSCs were increased in 3D culture whereas gene expression of anti-inflammatory cytokines IL-10 and CCL5 were downregulated. Stimulation of CB-MSCs by LPS or VIC-008 presented similar profile of the cytokine gene expressions to that in 3D culture which might benefit the anti-tumor efficacy of CD90low MSCs. The anti-tumor effects of CD90low CB-MSCs alone or in combination with VIC-008 were evaluated in a syngeneic orthotopic mouse model of ovarian cancer. Treatment that combines CB-MSCs and VIC-008 significantly decreased tumor growth and prolonged mouse survival. This was associated with the increase of activated anti-tumoral CD4+ and CD8+ T cells and the decrease of Treg cells in the tumor microenvironment. Taken together, our study demonstrates the synergistic anti-tumoral efficacy by application of CB-MSCs combined with immune activator VIC-008 and provides new insight into CD90low MSCs as a new anti-tumor arsenal.
Highlights
Ovarian cancer is a life-threatening tumor in women as its diagnosis often occurs at a late stage [1]
Decreased expression of CD90 was reported to be associated with a loss of human mesenchymal stem cells (MSCs) immunosuppressive activity [31], low CD90 expression observed in compact bone-derived MSCs (CB-MSCs) might indicate a loss of immunosuppressive function, which might be helpful in the cancer immunotherapy
Within CD29+stem cell antigen-1 (Sca-1)+ population, CD90 expression is still low in CB-MSCs, but higher in Bone marrow derived mesenchymal www.oncotarget.com stem/stromal cells (BM-MSCs) (Figure 2A, 2B)
Summary
Ovarian cancer is a life-threatening tumor in women as its diagnosis often occurs at a late stage [1]. Unmodified MSCs are seldom used to treat ovarian cancer since several studies have suggested that MSCs might promote tumor growth [7, 8]. More emerging studies demonstrated the capability of MSCs in keeping immunity in balance [9]. In some circumstances, they could even promote immune priming. MSCs supported the survival of B cells through undetermined factors [14] and prevented T cells apoptosis through the secretion of IL-7 [15]. These studies suggest that MSCs may have the anti-tumor potential in tumor immunotherapy
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