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Cancer immunotherapy has proven to increase the survival of patients such as melanoma thereby becoming an integral part if clinical oncology. However, the efficacy of immunotherapy is hampered by immunosuppressive myeloid cells.
Researchers Glenn van Wigcheren and Georgina Flórez-Grau set out to research how myeloid derived suppressor cells (MDSCs) and tolerogenic dendritic cells (tolDCs) mediate immunomodulation of T cells and how is induced in vitro using robust cytokine-stimulated cultures. The research group led by Jolanda de Vries in collaboration with Department of Medical BioSciences (Division of Immunotherapy) published the results in the Journal of Biological Chemistry on September 2023.
They described that in vitro generated MDSCs closely resemble MDSCs isolated from Head and neck squamous cell carcinoma (HNSCC) patients. These MDSCs expressed CD11b, CD33, CD14 and low levels of HLA-DR, CD80, CD83 and CD86. In addition, CD84, a recently proposed marker of murine and human MDSCs, was specifically expressed by both generated and isolated MDSCs. The suppressive machinery expressed by MDSCs consisted of inhibitory molecules such PD-L1 and the secretion of IL-10. The immature and suppressive nature of MDSCs induced in progenitor monocytes was dependent on PI3K-Akt signaling. These results better characterize MDSCs, especially those found in HNSCC patients, and solidify the essential role of PI3K-Akt signaling in the development of M-MDSCs from precursor cells.
The researchers also revealed that in vitro dexamethasone treatment of monocytes induces accumulation of β-catenin and upregulation of Wnt pathway target genes. In addition, antagonism of β-catenin during TolDC generation blocked their ability to induce tolerance among T cells, highlighting its importance. It was found that expression of MerTK, a major suppressive mechanism for dexamethasone-induced TolDCs, tightly followed β-catenin expression. The outcomes of this article open new venues for overcoming or exploiting the immunomodulation by myeloid cells in different therapeutic strategies.
Read the study here
Glenn F. van Wigcheren, Jorge Cuenca-Escalona, Suzan Stelloo, Julia Brake, Eline Peeters, Sophie.K. Horrevorts, Siebren Frölich, Iván Ramos-Tomillero, Yvonne Wesseling-Rozendaal, Carla M.L. van Herpen, Anja van de Stolpe, Michiel Vermeulen, I.Jolanda M. de Vries, Carl G. Figdor, Georgina Flórez-Grau,
Myeloid-derived suppressor cells and tolerogenic dendritic cells are distinctively induced by PI3K and Wnt signaling pathways. J Biol Chem. 2023 Sep 20:105276. doi: 10.1016/j.jbc.2023.105276. Epub ahead of print. PMID: 37739035.
