PDX Models: A Versatile Tool for Studying the Role of Myeloid-Derived Suppressor Cells in Breast Cancer.

Abstract

The pivotal role of myeloid-derived suppressive cells (MDSCs) in cancer has become increasingly apparent over the past few years. However, to fully understand how MDSCs can promote human tumor progression and to develop strategies to target this cell type, relevant models that closely resemble the clinical complexity of human tumors are needed. Here, we show that mouse MDSCs of both the monocytic (M-MDCS) and the granulocytic (PMN-MDSC) lineages are recruited to human breast cancer patient-derived xenograft (PDX) tumors in mice. Transcriptomic analysis of FACS-sorted MDSC-subpopulations from the PDX tumors demonstrated the expression of several MDSC genes associated with both their mobilization and immunosuppressive function, including S100A8/9, Ptgs2, Stat3, and Cxcr2, confirming the functional identity of these cells. By combining FACS analysis, RNA sequencing, and immune florescence, we show that the extent and type of MDSC infiltration depend on PDX model intrinsic factors such as the expression of chemokines involved in mobilizing and recruiting tumor-promoting MDSCs. Interestingly, MDSCs have been shown to play a prominent role in breast cancer metastasis, and in this context, we demonstrate increased recruitment of MDSCs in spontaneous PDX lung metastases compared to the corresponding primary PDX tumors. We also demonstrate that T cell-induced inflammation enhances the recruitment of MDSC in experimental breast cancer metastases. In conclusion, breast cancer PDX models represent a versatile tool for studying molecular mechanisms that drive myeloid cell recruitment to primary and metastatic tumors and facilitate the development of innovative therapeutic strategies targeting these cells.