Targeting Myeloid-derived Suppressor Cells

Introduction

Myeloid-derived suppressor cells (MDSCs) are a group of myeloid-derived natural immune cells with inhibitory functions and contribute to an immunologically permissive microenvironment for cancer cells. Immature MDSCs can differentiate into multiple mature myeloid cells such as mature granulocytes, macrophages, or dendritic cells. TME not only affects the function of MDSCs but also changes the pattern of MDSCs differentiation. Activated MDSCs are also related to aspects of tumor progression. The presence of MDSCs in the TME might decrease the efficacy of immunotherapies and are responsible for the poor prognosis of chemotherapy. MDSCs can cause tumor immune tolerance by inhibiting both natural immunity and T cell adaptive immunity. Therefore, targeting MDSCs is a promising approach to reshape TME and improve immunotherapies.

Fig.1 Differentiation and accumulation of MDSCs in the TME.^1,3

Roles of MDSCs in TME

• Immunosuppressive Functions

MDSCs can suppress both innate and adaptive immune responses. T-cell activation is suppressed by MDSC-mediated deprivation of L-arginine and cysteine from the TME, production of reactive oxygen species (ROS) and peroxynitrite, downregulation of L-selectin, and the induction of T regulatory (Treg) cells through MDSCs IL-10 and TGF-β production. MDSCs may make up a substantial fraction of the tumor-infiltrating macrophage pool, therefore, MDSCs may be the precursors of tumor-associated macrophages (TAMs). And both populations appear to play fundamental roles in shaping the immunosuppressive environment in solid tumors. MDSCs also suppress natural killer (NK) cell cytotoxicity via the production of ROS/ nitric oxide (NO) and suppress IFN-γ production and inhibit M1 macrophages. Moreover, MDSCs inhibit antitumor responses through the interaction of immune checkpoint molecules.

• Nonimmune Activities

MDSCs promote tumor progression also through non-immune activities. MDSCs actively participate in tumor metastasis by inducing EMT, increasing the invasiveness and stemness of tumor cells, and stimulating angiogenesis, including the secretion of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and matrix metalloproteinase (MMP)-9.

Fig.2 Functions of MDSCs in the TME.^2,3

Targeting MDSCs in Reshaping TME

MDSCs play crucial roles in shaping immunosuppressive TME and their accumulation is a major obstacle for tumor immunotherapy. Therefore, MDSCs have been explored as an important immunotherapeutic target to enhance anticancer responses.

• Blockage of MDSCs recruitment

MDSCs are actively recruited to primary and metastatic tumor sites by chemokines produced by the tumor with little specificity. Targeting chemokine receptors on MDSCs could be applied to prevent the migration and accumulation of MDSCs in the TME. For example, treatments targeting cyclooxygenase 2 (COX-2)/PGE2 signaling and CSF-1R/CSF-1 might prevent MDSCs recruitment to the tumor site to retard tumor growth and improve T-cell activity.

• Depletion and Maturation of MDSCs

Regulation of the maturation and differentiation of MDSCs will be potential strategies to reshape the immunosuppressive TME. Multiple agents such as RUNX1, all-trans retinoic acid (ATRA), IL-12, CCL5, drive MDSCs differentiation into mature myeloid cells. MDSCs could also be depleted with HSP90 (heat shock protein 90) inhibitors.

• Abrogation of MDSCs immunosuppression

Blockade of MDSCs immunosuppressive mechanisms represents the major therapeutic approach to re-establishing T-cells activity and immunotherapy success. For example, MDSCs upregulated the expression of immune suppressive factors such as ROS, inducible nitric oxide synthase (iNOS) and arginase1 (ARG1) to reduce T cells antitumor activity. Thus, those factors above become important therapeutic targets.

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References

1. Wang, Yufei, et al. "Metabolic regulation of myeloid-derived suppressor cell function in cancer." Cells 9.4 (2020): 1011.
2. Mabuchi, Seiji, Tomoyuki Sasano, and Naoko Komura. "Targeting myeloid-derived suppressor cells in ovarian cancer." Cells 10.2 (2021): 329.
3. Distributed under Open Access license CC BY 4.0, without modification.