Myeloid-derived suppressor cells: key immunosuppressive regulators and therapeutic targets in hematological malignancies

Abstract

The immunosuppressive tumor microenvironment (TME) supports the development of tumors and limits tumor immunotherapy, including hematological malignancies. Hematological malignancies remain a major public health issue with high morbidity and mortality worldwide. As an important component of immunosuppressive regulators, the phenotypic characteristics and prognostic value of myeloid-derived suppressor cells (MDSCs) have received much attention. A variety of MDSC-targeting therapeutic approaches have produced encouraging outcomes. However, the use of various MDSC-targeted treatment strategies in hematologic malignancies is still difficult due to the heterogeneity of hematologic malignancies and the complexity of the immune system. In this review, we summarize the biological functions of MDSCs and further provide a summary of the phenotypes and suppressive mechanisms of MDSC populations expanded in various types of hematological malignancy contexts. Moreover, we discussed the clinical correlation between MDSCs and the diagnosis of malignant hematological disease, as well as the drugs targeting MDSCs, and focused on summarizing the therapeutic strategies in combination with other immunotherapies, such as various immune checkpoint inhibitors (ICIs), that are under active investigation. We highlight the new direction of targeting MDSCs to improve the therapeutic efficacy of tumors.

Keywords: Hematological malignancies; Immunosuppressive regulator; Immunotherapy; Myeloid-derived suppressor cells; Tumor microenvironment.

Fig. 1

Stages of MDSC differentiation and accumulation. Hematopoietic stem cells (HSCs) differentiate in bone marrow into common myeloid progenitors (CMPs), which can further differentiate through the hematopoietic system. Under physiological conditions, CMPs can differentiate into neutrophils or monocytes and subsequently into MΦs or DCs. However, under pathologic conditions, immature myeloid cells (IMCs) are expanded and converted to immunosuppressive MDSCs, which include monocytic myeloid-derived suppressor cells (M-MDSCs) and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). In tumors, M-MDSCs can further differentiate into tumor-associated macrophages (TAMs) (M1 and M2 phenotypes). Different cytokines are involved in the whole differentiation process. Growth factors such as SCF, G-CSF, GM-CSF, and M-CSF regulate myelopoiesis progression, inducing the expansion of MDSCs. In the presence of proinflammatory cytokines such as IFN-γ, IL-4, IL-6, IL-1β, and CXCL1, IMCs are pathologically activated and then differentiate into M-MDSCs and PMN-MDSCs. Hypoxia in the TME facilitates the expression of hypoxia-inducible factor 1-alpha (HIF-1α), which leads to MDSC recruitment and accumulation. TME, tumor microenvironment

Fig. 2

Immunosuppressive mechanisms and targets of MDSCs. MDSCs inhibit T-cell activity through distinct mechanisms, including loss of the TCR ζ-chain; nitration of the TCR complex; depletion of amino acids necessary for the T-cell response; the production of adenosine, high levels of NO, RNS, Arg1, and chemokines; the presence of immune checkpoint blockade; and impairment of T-cell homing. Moreover, MDSCs promote Treg and macrophage differentiation and increase FOXP3 expression. Additionally, MDSCs suppress NK cells and CD8⁺ T cells. Finally, tumor-infiltrating MDSCs promote the migration of tumor cells by interacting with cancer stem cells (CSCs).

Fig. 3

Therapeutic agents against MDSCs classified by mechanism in hematological malignancy. The main approaches to target MDSCs include [1] depleting MDSCs; [2] blocking MDSC recruitment to the tumor microenvironment (TME); [3] promoting the differentiation of MDSCs into mature myeloid cells; [4] blocking MDSC-mediated immunosuppression