To kill two birds with one stone : targeting myeloid cells in cancers

Cancer progression is often accompanied by chronic inflammation and severe impairment of the immune system. In recent years, therapies eliciting tumor-specific immunity have resulted in striking tumor control and survival benefits in cancer patients. However, establishment of effective and durable immune responses is hampered by various tumor-dependent mechanisms. Besides the direct suppression mediated by tumor cells, a number of immune cell types, including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), ‘M2-biased’ tumor-associated macrophages (TAMs) and regulatory dendritic cells, occur in the periphery and tumor microenvironment. These cells conduct potent inhibition of anti-tumor immunity and are associated with poor prognosis in patients. Studies included in this thesis aim to elucidate the molecular machinery that tumor cells utilize to induce suppressive functions from healthy myeloid cells (Study I, II and IV) and how the resulted suppressive myeloid cells could limit functions of T cells (Study I), natural killer (NK) cells (Study II) and differentiation of the immune-stimulating dendritic cells (DCs) (Study III). Finally, we tested the role of a myeloid-specific chemical inhibitor in antagonizing the induction of these suppressive myeloid cells in vitro. In a transgenic murine model developing highly aggressive spontaneous tumors, treatment with the inhibitor elicited robust control of established tumors and potentiated the anti-tumor effects of checkpoint blocking antibodies (Study IV). In summary, this thesis provides mechanistic insights for the induction of suppressive myeloid cells and demonstrates the therapeutic potential of targeting these cells for the treatment of solid tumors.

List of scientific papers

I. Mao Y., Poschke I., Wennerberg E., Picode Coaña Y., Hansson J., Masucci G., Lundqvist A., Kiessling R., Melanoma-educated CD14+ cells acquire a myeloid-derived suppressor cell phenotype and are potent inhibitors of T cells via COX-2/PGE2-dependent mechanisms, Cancer Research 73 (13): 3877-87, 2013.
https://doi.org/10.1158/0008-5472.CAN-12-4115

II. Mao Y., Sarhan D., Steven A., Seliger B., Kiessling R., Lundqvist A., Inhibition of tumor-derived prostaglandin-E2 blocks the induction of myeloid-derived suppressor cells and recovers natural killer cell activity, Clinical Cancer Research, 2014 Aug 1;;20(15):4096-106.
https://doi.org/10.1158/1078-0432.CCR-14-0635

III. Poschke I., Mao Y., Adamson L., Salazar-Onfray F., Masucci G., Kiessling R., Myeloid-derived suppressor cells impair the quality of dendritic cell vaccine, Cancer immunology, immunotherapy : CII 2012;;61(6):827-38.
https://doi.org/10.1007/s00262-011-1143-y

IV. Mao Y., Eissler N., LeBlanc K., Johnsen J.I., Kogner P., Kiessling R., Targeting CSF-1R potentiates checkpoint inhibitors to control spontaneous neuroblastoma growth through modulating suppressive myeloid cells. [Manuscript]