Immune suppressive activity of myeloid-derived suppressor cells in cancer requires inactivation of the type I interferon pathway

Abstract

Myeloid-derived suppressor cells (MDSC) are pathologically activated neutrophils and monocytes with potent immune suppressive activity. These cells play an important role in accelerating tumor progression and undermining the efficacy of anti-cancer therapies. The natural mechanisms limiting MDSC activity are not well understood. Here, we present evidence that type I interferons (IFN1) receptor signaling serves as a universal mechanism that restricts acquisition of suppressive activity by these cells. Downregulation of the IFNAR1 chain of this receptor is found in MDSC from cancer patients and mouse tumor models. The decrease in IFNAR1 depends on the activation of the p38 protein kinase and is required for activation of the immune suppressive phenotype. Whereas deletion of IFNAR1 is not sufficient to convert neutrophils and monocytes to MDSC, genetic stabilization of IFNAR1 in tumor bearing mice undermines suppressive activity of MDSC and has potent antitumor effect. Stabilizing IFNAR1 using inhibitor of p38 combined with the interferon induction therapy elicits a robust anti-tumor effect. Thus, negative regulatory mechanisms of MDSC function can be exploited therapeutically.

MDSC in Mice and Men: Mechanisms of Immunosuppression in Cancer

“…These tissues offer the greatest yields of up to 10 7 to 10 8 cells [17]. It is also possible to isolate MDSCs from lymph nodes (by mechanical disruption), the liver (using Percoll), tumors (by mechanical and enzymatic disruption) or peripheral blood (by cardiac puncture) [18][19][20][21]. However, it might be necessary to combine the blood of several mice to achieve MDSC yields with which experiments can be performed.…”

Myeloid-Derived Suppressor Cells Mediate T Cell Dysfunction in Nonhuman Primate TB Granulomas

“…Recent studies have established myeloid-derived suppressor cells (MDSCs) as an innate immune population comprised of immature myeloid cells and myeloid progenitors with very potent immunosuppressive potential. MDSCs represent a unique population of myeloid cells that deviate from their regular fate to differentiate into macrophages, granulocytes, or dendritic cells (DCs) under physiological conditions like aging ( 6 ) or pathological conditions like chronic inflammation ( 7 – 11 ) or cancer ( 12 – 15 ). They are usually classified into monocytic MDSCs (M-MDSCs) or polymorphonuclear MDSCs (PMN-MDSCs) based on their nuclear organization and expression of key surface receptors.…”

“…The magnitude of suppressive effects of MDSCs on TILs has a direct correlation with proximal localization and physical engagement ( 22 ). Apart from cancer, transplantation, and inflammatory pathologies, where these cells are extensively studied ( 12 – 15 ), MDSCs have been recently reported to be abundant in the blood ( 7 , 23 , 24 ), pleural effusions ( 7 ), and bronchoalveolar lavage (BAL) fluid ( 23 ) of active TB (ATB) patients. MDSCs could potently impair adaptive immunity by killing DCs ( 25 ) or inhibiting T cell functions ( 7 , 9 , 10 , 22 , 25 – 35 ).…”

Tumor immune microenvironment of primary colorectal adenocarcinomas metastasizing to the liver or lungs

“…MDSCs constitute pathologically activated neutrophils and monocytes with potent immunosuppressive properties. 24 TANs are an important component of the TIME and can enhance tumorpromoting inflammation via angiogenesis and extracellular matrix remodeling. 25 On the other hand, isolated CPM was significantly associated with innate immune responses, antimicrobial humoral responses, and immune system processes.…”