Myeloid-derived suppressor cells and tolerogenic dendritic cells are distinctively induced by PI3K and Wnt signaling pathways

• Published in: The Journal of biological chemistry Vol. 299; no. 11; p. 105276
• Main Authors: van Wigcheren, Glenn F., Cuenca-Escalona, Jorge, Stelloo, Suzan, Brake, Julia, Peeters, Eline, Horrevorts, Sophie.K., Frölich, Siebren, Ramos-Tomillero, Iván, Wesseling-Rozendaal, Yvonne, van Herpen, Carla M.L., van de Stolpe, Anja, Vermeulen, Michiel, de Vries, I. Jolanda M., Figdor, Carl G., Flórez-Grau, Georgina
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2023; American Society for Biochemistry and Molecular Biology
• Subjects: Dendritic Cells - immunology; Humans; immune tolerance; Immunomodulation - immunology; immunosuppression; Immunotherapy; MDSC; Myeloid-Derived Suppressor Cells - immunology; Neoplasms - immunology; Neoplasms - therapy; Phosphatidylinositol 3-Kinases - immunology; Proto-Oncogene Proteins c-akt - immunology; Signal Transduction - immunology; TolDC; Tumor Cells, Cultured; Wnt Signaling Pathway - immunology; HH; MDSC; TolDC; M-MDSC; MoDC; DEG; GO; immunosuppression; PBMC; immune tolerance; HNSCC; immunotherapy; ROS; HD; DC
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1016/j.jbc.2023.105276

Imbalanced immune responses are a prominent hallmark of cancer and autoimmunity. Overactive as well as suppressed immunological activity is evidenced to promote disease. This immunological disbalance is often driven through disrupted immunomodulation by innate myeloid immune cells. Myeloid cells can be overly suppressive, inhibiting protective immune responses or be inactive not controlling autoreactive immune cells. Understanding the mechanisms that induce and drive suppressive myeloid cells, such as myeloid-derived suppressor cells (MDSCs) and tolerogenic dendritic cells (TolDCs), can facilitate the development of immune-restoring therapeutic approaches in patients. MDSCs are a major barrier for effective cancer immunotherapy by suppressing antitumor immune responses in cancer patients. TolDCs are administered to patients to promote immune tolerance with the intent to control autoimmune disease. Here, we investigated the development and suppressive/tolerogenic activity of human MDSCs and TolDCs derived from monocytes to gain insight into signaling pathways that drive immunosuppression in these different myeloid subsets. Moreover, human monocyte-derived MDSCs (M-MDSCs) generated in vitro were compared to M-MDSCs isolated from head-and-neck squamous cell carcinoma patients. PI3K-AKT signaling was identified as being crucial for the induction of human M-MDSCs. PI3K inhibition prevented the downregulation of HLA-DR, the upregulation of reactive oxygen species and MerTK, and subsequent suppressive activity of M-MDSCs towards T cells. In addition, we show for the first time that the suppressive activity of dexamethasone-induced TolDCs is induced by β-catenin–dependent Wnt signaling. The identification of PI3K-AKT and Wnt signal transduction pathways as respective inducers of the immunomodulatory capacity of M-MDSCs and TolDCs provides opportunities to overcome suppressive myeloid cells in cancer patients and optimize therapeutic application of TolDCs in patients with autoimmune diseases. Lastly, the observed similarities between generated- and patient-derived M-MDSCs support the use of in vitro–generated M-MDSCs as powerful model to investigate the functionality of human MDSCs.