Cancer progression is as sociated with a profound alteration in “emergency” myelopoiesis, leading to recruitment of mostly immunosuppressive cells such as myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM). In response to saturating amounts of tumor-induced colony-stimulating factors (CSFs), myeloid progenitors divide more frequently to sustain the hematopoietic output necessary to promote emergency myelopoiesis. Despite the knowledge about the involvement of cytokines and transcription factors in emergency myelopoiesis, the molecular mechanisms by which the cytokines induce transcriptional events regulating cancer-driven myelopoiesis remain largely unclear. Our preliminary data show that G protein signaling modulator-3 (GPSM3) is upregulated selectively in MDSC, either from tumor -bearing hosts or generated from bone marrow myeloid progenitors by the cytokines G-CSF, GM - CSF and IL-6. GPSM3-deficient myeloid progenitors display a reduced capacity to differentiate into granulocytes /monocytes following G-CSF /GM - CSF stimulation. Decreased accumulation of MDSC in GPSM3-deficient tumor - bearing hosts is linked with an altered expression in the key transcriptional mediators of myeloid progenitor commitment and differentiation to the granulocytic /monocytic lineage. Moreover, the immunoregulatory activity of both tumor - induced and cytokine -induced MDSC is dependent on GPSM3. These results have led to the novel hypothesis that GPSM3 is a master regulator of cancer-associated myelopoiesis and key driver of the differentiation of MDSCs for both immune suppression and tumor promotion. In this proposal, we will characterize further the phenotype and function of MDSC in the tumor microenvironment, and explore the signaling pathways implicated by GPSM3 in regulating MDSC differentiation and activation using both gain-of - function and loss -of - function approaches.
|Effective start/end date||3/7/17 → 2/28/23|
- National Cancer Institute (5R01CA208354-05)
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