Therapeutic prospects of targeting myeloid‐derived suppressor cells and immune checkpoints in cancer

Abstract

Immune evasion is a characteristic of most human malignancies and is induced via various mechanisms. Immunosuppressive cells, including myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg), are key mediators in assisting tumors to escape immune surveillance. Expansion of MDSC, Treg and elevated levels of immune checkpoints (IC) are frequently detected in the tumor microenvironment and periphery of cancer patients. Various therapeutic agents have been shown to target MDSC and to block IC for inducing anti-tumor immunity and reversal of tumor immune escape. Importantly, some recent studies have shown that MDSC targeting improves the efficacy of IC blockade in cancer therapy. However, there is a pressing need to improve our understanding of the distinct role of these cells to develop combination therapy that attacks tumor cells from all frontiers to improve cancer therapeutics. Herein, we discuss the role of MDSC in cancer progression, interactions with IC in the context of anti-cancer immunity and the current therapeutic strategies to target MDSC and block IC in cancer.

Immune Checkpoints in Circulating and Tumor-Infiltrating CD4+ T Cell Subsets in Colorectal Cancer Patients

“…Predictive biomarkers for successful IC inhibition with clinical benefits are a necessity in such instances. Expression of ICs and their ligands in the TME have been proposed as such predictive biomarkers (66), and better understanding of the immune components can therefore assist in identifying robust biomarkers for response to therapy and also assist in targeted-therapies, tailor made on individual patient basis.…”

Transcriptomic profiling disclosed the role of DNA methylation and histone modifications in tumor-infiltrating myeloid-derived suppressor cell subsets in colorectal cancer

“…In inflammation-related cancers, myelopoiesis is disrupted and leads to accumulation of a heterogeneous population of myeloid cells, halted at varying stages of maturation/differentiation and with a potent immunosuppressive activity, referred to as myeloid-derived suppressor cells (MDSCs) [3,4]. MDSCs express myeloid markers but lack expression of MHC class II molecule, HLA-DR, and are mainly divided into three phenotypically distinct subpopulations; CD33 + HLA-DR −/low CD14 − CD15 − early-stage, or immature MDSCs (e-MDSC/I-MDSC), which consist of immature myeloid progenitors; CD33 + HLA-DR −/low CD14 + CD15 − monocytic MDSCs (M-MDSCs), which represent suppressive monocytes; and CD33 + HLA-DR −/low CD14 − CD15 + polymorphonuclear or granulocytic MDSCs (PMN-MDSCs or G-MDSCs), which are phenotypically distinct from mature neutrophils and possess strong suppressive activity [3,[5][6][7].…”

“…MDSCs have been implicated in the pathogenesis of cancer [5,8], where they act as potent suppressors of T cell-mediated responses against tumor cells within the tumor microenvironment (TME) [8] and lymphoid organs [9]. MDSCs enhance the progression of various types of tumors by promoting immune suppression, cancerassociated fibroblasts (CAF) activation, angiogenesis, and tumor growth and metastasis [10] via the expression of co-inhibitory receptors, such as PD-L1, and the release of a vast array of molecules, such as arginase-1, inducible nitric oxide synthase (iNOS), nitric oxide (NO), and reactive oxygen/nitrogen species (ROS/RNS) [11,12].…”

RNA-Seq Analysis of Colorectal Tumor-Infiltrating Myeloid-Derived Suppressor Cell Subsets Revealed Gene Signatures of Poor Prognosis

“…as CD33 + HLA-DR -/low CD14 + CD15 -, and polymorphonuclear MDSCs (PMN-MDSCs) identified as CD33 + HLA-DR -/low CD14 -CD15 + (1,3,4). Myelopoiesis is disrupted in inflammationrelated cancers (5), such as colorectal cancer (CRC), leading to increased number of MDSCs in the circulation and tumor tissues (1,2).…”