Myeloid-derived suppressor cells-a new therapeutic target to overcome resistance to cancer immunotherapy

Abstract

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that accumulate during pathologic conditions, such as cancer. Patients diagnosed with advanced metastatic cancers have an average survival of 12-24 mo, a survival time that hasn't changed significantly in the past 30 yr. Despite some encouraging improvements in response rates and overall survival in patients receiving immunotherapies, such as immune checkpoint inhibitors, most patients will ultimately progress. MDSCs contribute to immunotherapeutic resistance by actively inhibiting antitumor T cell proliferation and cytotoxic activity as well as by promoting expansion of protumorigenic T regulatory cells, thereby, dampening the host immune responses against the tumor. In addition, MDSCs promote angiogenesis, tumor invasion, and metastasis. Thus, MDSCs are potential therapeutic targets in cases of multiple cancers. This review focuses on the phenotypic and functional characteristics of MDSCs and provides an overview of the mono- and combinatorial-therapeutic strategies that target MDSCs with an objective of enhancing the efficacy of cancer immunotherapies.

Keywords: MDSC; MIF; PFKFB3; immune checkpoint inhibitors; immune suppression; tumor immunology.

Figure 1

Overview of MDSC immunosuppressive mechanisms. Under steady‐state conditions, hematopoietic stem cells (HSCs) located in the bone marrow give rise to common myeloid precursors (CMPs), which then differentiate into mature myeloid cells. During tumor progression, CMPs give rise to MDSCs, which subsequently accumulate in blood and in lymphoid organs, such as the spleen. Immunosuppressive MDSCs suppress the immune system by distinct mechanisms, including induction of T_reg proliferation; production of high levels of ARG1 that depletes T cells of l‐arginine; production of high levels of ROS and nitrogen species (RNS; peroxynitrate) that lead to nitration and nitrosylation of TCR, CD8, and chemokine C(X)CRs receptors; promotion of angiogenesis; and blockade of the migration of naive CD62L⁺ T cells to lymphoid organs, which results in diminished expansion of effector T cells ADAM17, ADAM disintegrin, and metallopeptidase domain 17 and S100A8 and S100A9—S100 calcium‐binding proteins.

Figure 2

Molecular pathways involved in the maintenance of the MDSC suppressive function. A wide variety of proinflammatory factors are involved in the induction of the suppressive function in MDSCs. Several of those pathways promote the suppressive function of both M‐MDSCs and PMN‐MDSCs (e.g., IL‐4/IL‐13–mediated STAT6 signaling and TNF‐α–induced NF‐κB activation), whereas others are more specific to maintaining the suppressive properties of either PMN‐MDSC or the M‐MDSC subsets (e.g., MIF‐cyclooxygenase 2‐PGE₂ signaling in M‐MDSCs). The STAT1 pathway has been hypothesized to have contrasting roles by inducing the M‐MDSC suppressive activity but inhibiting the activity of PMN‐MDSCs.

Figure 3

MIF inhibition induces a DC phenotype in MDSCs derived from a patient with melanoma. (A) Aberrant accumulation of MDSCs in patients with late‐stage melanoma (stage III/IV) may represent an essential mechanism of immediate and/or acquired resistance to IPI and/or nivolumab (NIVO) immune checkpoint inhibitors. (B) Therapeutic targeting of MIF with 4‐IPP, a highly efficacious and orally bioavailable, small‐molecule MIF antagonist, attenuates MDSC immune suppression derived from patients with melanoma. Importantly, 4‐IPP induces a functional MDSC → DC‐like differentiation and thus, can attenuate the MDSC‐mediated resistance to immunotherapies.