Modulation of T-cell function by myeloid-derived suppressor cells in hematological malignancies

Abstract

Myeloid-derived suppressor cells (MDSCs) are pathologically activated neutrophils and monocytes that negatively regulate the immune response to cancer and chronic infections. Abnormal myelopoiesis and pathological activation of myeloid cells generate this heterogeneous population of myeloid-derived suppressor cells. They are characterized by their distinct transcription, phenotypic, biochemical, and functional features. In the tumor microenvironment (TME), myeloid-derived suppressor cells represent an important class of immunosuppressive cells that correlate with tumor burden, stage, and a poor prognosis. Myeloid-derived suppressor cells exert a strong immunosuppressive effect on T-cells (and a broad range of other immune cells), by blocking lymphocyte homing, increasing production of reactive oxygen and nitrogen species, promoting secretion of various cytokines, chemokines, and immune regulatory molecules, stimulation of other immunosuppressive cells, depletion of various metabolites, and upregulation of immune checkpoint molecules. Additionally, the heterogeneity of myeloid-derived suppressor cells in cancer makes their identification challenging. Overall, they serve as a major obstacle for many cancer immunotherapies and targeting them could be a favorable strategy to improve the effectiveness of immunotherapeutic interventions. However, in hematological malignancies, particularly B-cell malignancies, the clinical outcomes of targeting these myeloid-derived suppressor cells is a field that is still to be explored. This review summarizes the complex biology of myeloid-derived suppressor cells with an emphasis on the immunosuppressive pathways used by myeloid-derived suppressor cells to modulate T-cell function in hematological malignancies. In addition, we describe the challenges, therapeutic strategies, and clinical relevance of targeting myeloid-derived suppressor cells in these diseases.

Keywords: hematological malignancies; immunosuppression; myeloid-derived suppressor cells; t cells; tumor microenvironment.

FIGURE 1

MDSCs suppressive mechanism targets both innate and adaptive immunity 1. Targeting T cell and NK cell function by TGFβ/IL10 induced inhibition. Also, MDSCs release ROS, H₂O₂ and peroxynitrite which dysregulate the TCR Z chain inhibiting T-cell/MDSC interaction 2. MDSCs maintain a pre-metastatic niche inhibiting T-cell migration, 3. MDSCs interact with Tregs via CCL4/5 and CD40 that recruitments them to the TME, 4. MDSCs induce a M2 macrophage phenotype by secretion of IL-10, thereby promoting immune escape for tumor cells. Furthermore, secretion of factors like IL-10 and TGF-b, and reduction of L-arginine by MDSCs induce Treg polarization. (iNOS-Inducible nitric oxide synthase, Arg- Arginase, PD-L1- Programmed death-ligand 1, TGFβ- Transforming growth factor beta, IL-10- Interleukin 10, 1L-6- Interleukin 6,CCL-2- C-C Motif Chemokine Ligand 2, CCL4- C-C Motif Chemokine Ligand 2, ADAM17-a disintegrin and metalloprotease domain).

FIGURE 2

Role of MDSCs in hematological malignancies and Hematopoietic stem cell transplantation. MDSCs have a favorable role in that they suppress T cell activity thereby preventing GVHD after HSCT (Left side of figure). In contrast, the unfavorable expansion of MDSCs promotes tumor growth by increasing angiogenesis, creating a pre-metastatic niche, suppressing T-cell activity and recruiting Tregs in the TME (Right side of figure).