Abstract
Myeloid derived suppressor cells (MDSCs) are a highly heterogeneous population of immature immune cells with immunosuppressive functions that are recruited to the tumor microenvironment (TME). MDSCs promote tumor growth and progression by inhibiting immune effector cell proliferation and function. MDSCs are affected by both novel anti-cancer therapies targeting the immune system to promote anti-tumor immunity, as well as by conventional treatments such as radiotherapy. Following radiotherapy, cytoplasmic double stranded DNA stimulates the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway, resulting in type I interferon production. Effectiveness of radiotherapy and cGAS/STING signaling are closely intertwined: activation of cGAS and STING is key to generate systemic anti-tumor immunity after irradiation. This review focuses on how radiotherapy and cGAS/STING signaling in MDSCs and/or tumor cells impact MDSC recruitment, expansion and function. The influence of conventional and ablative radiotherapy treatment schedules, inflammatory response following radiotherapy, and hypoxia are discussed as MDSC modulators.
Highlights
myeloid derived suppressor cells (MDSC) and the TMEThe tumor microenvironment (TME) is defined as the milieu sur rounding the tumor composed of vessels, soluble factors and multiple cell types, including immune cells and stromal cells such as pericytes and cancer associated fibroblasts [1,2]
The above discussed literature describes an intricate role of RT and cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) signaling in regulating MDSCs and opens up new questions on how RT and cGAS/STING activation could be exploited to target and reprogram MDSCs to increase tumor control and survival (Open ques tions box)
STING signaling after RT could enhance immunosuppression in the TME by recruiting chemokine receptor type 2 (CCR2)+ monocytic MDSC (M-MDSC) via secretion of IFN-β
Summary
The tumor microenvironment (TME) is defined as the milieu sur rounding the tumor composed of vessels, soluble factors and multiple cell types, including immune cells and stromal cells such as pericytes and cancer associated fibroblasts [1,2]. MDSC expansion is driven by multiple different factors In this process, specific cytokines and growth factors (such as tumor necrosis factor (TNF)α [11], granulocyte/macrophage colony-stimulating factor (GM-CSF) [12], vascular endothelial growth factor (VEGF) [13], interleukin (IL)-1β and indoleamine 2,3-dioxygenase (IDO), together with downstream medi ator IL-6 [14,15,16]) play an important role (reviewed in [17]). MDSCs suppress the function of effector cells such as T cells [9,19] and NK cells [20], skew macrophage polarization towards an immunosuppressive M2-like phenotype [21], and promote immunosuppressive Tregs [22,23]
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