Targeting Myeloid-Derived Suppressor Cell, a Promising Strategy to Overcome Resistance to Immune Checkpoint Inhibitors

Abstract

Immune checkpoint inhibitors (ICIs) are starting to transform the treatment for patients with advanced cancer. The extensive application of these antibodies for various cancer obtains exciting anti-tumor immune response by activating T cells. Although the encouraging clinical benefit in patients receiving these immunostimulatory agents are observed, numbers of patients still derive limited response or even none for reasons unknown, sometimes at the cost of adverse reactions. Myeloid-derived suppressor cells (MDSCs) is a heterogeneous immature population of myeloid cells partly influencing the efficacy of immunotherapies. These cells not only directly suppress T cell but mediate a potently immunosuppressive network within tumor microenvironment to attenuate the anti-tumor response. The crosstalk between MDSCs and immune cells/non-immune cells generates several positive feedbacks to negatively modulate the tumor microenvironment. As such, the recruitment of immunosuppressive cells, upregulation of immune checkpoints, angiogenesis and hypoxia are induced and contributing to the acquired resistance to ICIs. Targeting MDSCs could be a potential therapy to overcome the limitation. In this review, we focus on the role of MDSCs in resistance to ICIs and summarize the therapeutic strategies targeting them to enhance ICIs efficiency in cancer patients.

Keywords: cytotoxic T-lymphocyte-associated protein 4 (CTLA-4); immune checkpoint inhibitor (ICI); myeloid derived suppressive cells (MDSCs); program death-1 (PD-1); program death-1 ligand 1 (PD-L1).

FIGURE 1

Myeloid-derived suppressor cells suppress T cell function and directly result in the resistance to immune checkpoint inhibitors. In bone marrow, hematopoietic stem cells (HSCs) give rise to common myeloid precursors (CMPs), which then differentiate into MDSCs during tumor progression. The accumulation of MDSCs in tumor site, blood and lymphoid organs, such as the spleen, can be observed when cancer patients are resistance to ICIs. Immune suppression by MDSC is mainly antigen specific, contact dependent, and utilizes several major pathways: (1) Production of reactive nitrogen and oxygen species, such as nitric oxide (NO), reactive oxygen species (ROS), and peroxynitrite (PNT). (2) Elimination of key nutrition factors for T cells from the microenvironment (L-arginine, Ltryptophan, and L-cysteine). (3) Disruption of homing and trafficking of T cells (through the expression of ADAM17, the nitration of CCL2). (4) Production of immunosuppressive eytokines (TGF-3 and IL-10). (5) Upregulation of immune checkpoint, such as PD-Ll, galectin-9, and VISTA. (6) Release of immune regulatory molecules, such as adenosine and VEGFA.

FIGURE 2

The MDSCs accumulation derived a potent immune suppressive network within TME leading to resistance to ICIs. The accumulation of MDSCs is observed in various tumor type after ICIs treatment and can be a promising predictive marker. Besides the direct suppression of T cell function, MDSCs participate in crosstalk between not only immune cells, but immune cells and non-immune cells. Within TME, such crosstalk generates positive feedback loops to reinforce the suppressive immune network, which is an amplifier to extend the intrinsic immune regulation function of MDSCs and to augment their pro-tumorigenic effects. More immune suppressive cells are recruited and induced with various immune checkpoints expression. Finally, TME has been reprogrammed into limited anti-tumor immune response induced by ICIs, companied with increased level of tumor angiogenesis and hypoxia which enhanced the network.