Epigenetics in myeloid derived suppressor cells: a sheathed sword towards cancer

Abstract

Myeloid-derived suppressor cells (MDSCs), a heterogeneous population of cells composed of progenitors and precursors to myeloid cells, are deemed to participate in the development of tumor-favoring immunosuppressive microenvironment. Thus, the regulatory strategies targeting MDSCs' expansion, differentiation, accumulation and function could possibly be effective “weapons” in anti-tumor immunotherapies. Epigenetic mechanisms, which involve DNA modification, covalent histone modification and RNA interference, result in the heritable down-regulation or silencing of gene expression without a change in DNA sequences. Epigenetic modification of MDSC's functional plasticity leads to the remodeling of its characteristics, therefore reframing the microenvironment towards countering tumor growth and metastasis. This review summarized the pertinent findings on the DNA methylation, covalent histone modification, microRNAs and small interfering RNAs targeting MDSC in cancer genesis, progression and metastasis. The potentials as well as possible obstacles in translating into anti-cancer therapeutics were also discussed.

Tumor-derived microRNAs induce myeloid suppressor cells and predict immunotherapy resistance in melanoma

“…Major evidence, albeit primarily in murine models, indicates a central role of miR-mediated posttranscriptional regulation in MDSC differentiation and function (40,51). Via in vitro studies on monocyte conditioning, we found that hallmarks of human MDSCs, i.e., downregulation of HLA-DR, secretion of IL-6, TGF-β, and CCL2, and inhibition of T cell proliferation and function (9, 10), can be reconstituted by in vitro cotransfection of the 8 MDSC-miRs; this finding held true even when the requirement was decreased to 4 miRs (miR-146a, miR-100, miR-125b, and miR-155) in some donors (data not shown).…”

Hypothesis: stimulation of trained immunity as adjunctive immunotherapy in cancer

“…MDSCs are a heterogeneous population of cells composed of progenitors and precursors to myeloid cells that exert immunosuppressive effects, subsequently favoring tumor development [14]. The epigenetic programs of MDSCs determine their function, which include DNA and histone modifications as well as modulatory noncoding RNAs [76]. A similar pattern is present when monocytes infiltrate tumors and differentiate into TAMs which promote tumor growth, progression, invasion, and angiogenesis and suppress the antitumoral immune responses [1].…”

Connections between Metabolism and Epigenetic Modification in MDSCs

“…Because epigenetic modifications are reversible and susceptible to environmental factors, they may be a promising direction for clinical medicine [ 69 ]. These epigenetic modifications play an important role in the regulation of cancer cells [ 70 ], immunosuppressive cells [ 71 ], and tumor-associated fibroblasts [ 72 ] in the TME. These cells continuously update and reshape through epigenetic modification in response to a series of signals sent by cancer cells, thereby jointly promoting the occurrence, development, and metastasis of tumors.…”

“…[ 73 ]. In addition to common DNA methylation and histone modification, Non-Coding RNAs also play an important role in epigenetic modification, especially miRNA and siRNA [ 71 ], and emerging studies have recently identified the role of miRNAs in MDSCs amplification, development, migration, and function [ 70 ]. MDSC-related microRNAs (miR-146a, miR-155, miR-125b, miR-100, let-7e, miR-125A, miR-146b, miR-99b) are associated with the resistance of melanoma patients to immunocheckpoint inhibitor therapy.…”

“…MDSC-associated miRNA is not only an indicator of MDSC activity in cancer patients but also a potential blood marker for poor immunotherapy outcomes [ 74 ]. Moreover, artificial siRNAs targeting different MDSCs genes were used to play anti-cancer effects [ 71 ]. Since MDSCs are not a terminally differentiated immune cell population but a heterogeneous mixture of immature myeloid origin cells, they are highly plastic and can be differentiated into DCs or macrophages.…”