Contribution of Mesenchymal Stem Cells from Obese Adipose Tissue to PD-L1 Over-Expression and Breast Cancer Progression through Pathogenic Th17 Cell Activation

Simple Summary: Obesity is a risk factor for cancer, including breast cancer (BC). Our study proposes a novel mechanism by which it could contribute to BC progression due to interactions between mesenchymal stem cells from obese adipose tissue (ob-ASC) with infiltrating immune cells and the promotion of pathogenic cells double-secreting IL-17/IFN gamma. Indeed, we demonstrated herein that the inflammatory environment mediated by the interaction of MSCs with immune cells enhanced (i) pro-inflammatory cytokine and neo-angiogenic factor secretion, (ii) metalloproteinase and (iii) immune checkpoint (ICP) over-expression, and (iv) cell migration in human breast cancer cells lines (BCCL). Moreover, (v) using neutralizing antibodies, we demonstrated the differential effects of IL-17A or IFN gamma on BCCL pro-inflammatory cytokine over-expression or ICP upregulation, respectively, and the potentiating effects on BCCL migration. Finally, (vi) ICP overexpression was likely to depend on the obese status of MSCs. Therefore, our results suggest that the activation of pathogenic Th17 cells by ob-ASC could contribute to BC aggressiveness. Background: Obesity is a well-known risk factor for cancer. We have previously reported the role of adipose-tissue-derived mesenchymal stem cells from obese individuals (ob-ASC) in the promotion of pathogenic Th17 cells and immune check point (ICP) upregulation. Thus, we postulated herein that this mechanism could contribute to breast cancer (BC) aggressiveness. Methods: Conditioning medium (CM) from mitogen-activated ob-ASC and immune cell co-cultures were added to two human breast cancer cell line (BCCL) cultures. Expressions of pro-inflammatory cytokines, angiogenesis markers, metalloproteinases, and PD-L1 (a major ICP) were measured at the mRNA and/or protein levels. BCCL migration was explored in wound healing assays. Anti-cytokine neutralizing antibodies (Ab) were added to co-cultures. Results: CM from ob-ASC/MNC co-cultures increased IL-1 beta, IL-8, IL-6, VEGF-A, MMP-9, and PD-L1 expressions in both BCCLs and accelerated their migration. The use of Abs demonstrated differential effects for IL-17A and IFN gamma on BCCL pro-inflammatory cytokine over-expression or PD-L1 upregulation, respectively, but potentiating effects on BCCL migration. Finally, co-cultures with ob-ASC, but not lean ASC, enhanced PD-L1 expression. Conclusions: Our results demonstrate increased inflammation and ICP markers and accelerated BCCL migration following the activation of pathogenic Th17 cells by ob-ASC, which could represent a new mechanism linking obesity with BC progression.

Automated summary

Obesity increases the risk of cancer, including breast cancer. This study proposes a new mechanism in which mesenchymal stem cells from obese adipose tissue (ob-ASC) interact with immune cells, leading to inflammation and the activation of pathogenic cells double-secreting IL-17/IFN gamma. This interaction promotes breast cancer progression by enhancing cytokine secretion, angiogenic factor secretion, metalloproteinase expression, immune checkpoint overexpression, and cell migration in breast cancer cells.