Effect of laminin environments and tumor factors on the biology of myeloid dendritic cells

Abstract

Dendritic cells (DCs) are immune cells that surveil the organism for infections or malignancies and activate specific T lymphocytes initiating specific immune responses. Contrariwise, DCs have been show to participate in the development of diseases, among them some types of cancer by inducing angiogenesis or immunosuppression. The ultimate fate of DC functions regarding their role in disease or health is prompted by signals from the microenvironment. We have previously shown that the interaction of DCs with various extracellular matrix components modifies the immune properties and angiogenic potential of these cells. The objective of the current studies was to investigate the angiogenic and immune profile of murine myeloid DCs upon interaction with laminin environments, with a particular emphasis on ovarian cancer. Our results show that murine ovarian tumors produce several types of laminins, as determined by PCR analysis, and also that tumor-associated DCs, both from ascites or solid tumors express adhesion molecules capable of interacting with these molecules as determined by flow cytometry and PCR analysis. Further, we established that DCs cultured on laminin upregulate both AKT and MEK signaling pathways, and that long-term culture on laminin surfaces decreases the immunological capacities of these cells when compared to the same cells cultured on synthetic substrates. In addition, we observed that tumor conditioned media was able to modify the metabolic status of these cells, and also reprogram the development of DCs from bone marrow precursors towards the generation of myeloid-derived suppressor cells. Overall, these studies demonstrate that the interaction between soluble factors and extracellular matrix components of the ovarian cancer microenvironment shape the biology of DCs and thus help them become co-conspirators of tumor growth.

Keywords: Bone marrow precursors; Dendritic cells; Laminin; Myeloid-derived suppressor cells; Ovarian cancer.