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

Aohan Hou,Wanling Chen,Kaiyu Hou,Yujie Lei,Qiubo Huang

doi:10.3389/fimmu.2020.00783

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.

Highlights

In the last decades, cancer therapy has been transformed by Immunotherapies whose element is the anti-tumor response mediated by cytotoxic T lymphocyte (CTL)
In contrast to vascular endothelial growth factor A (VEGFA) directly suppress T cell proliferation that we mention above, these findings further indicate that lack of DCs and impaired antigen presentation may be a potential mechanism of resistance to Immune checkpoint inhibitors (ICIs), which can be caused by VEGFA-VEGFR1 signaling pathway activation
A research showed the same effect in colon and breast cancer mouse models, where the co-blockade of CTLA-4 and CSF1/colony-stimulating factor 1 receptor (CSF1R) enhanced the beneficial effect by significant reduction in the number of tumor-infiltrating M-Myeloid-derived suppressor cells (MDSCs), not PMN-MDSCs, and reprogramming M-MDSCs that displayed markedly increased expression of MHC class II and reduced expression of the immunosuppressive molecules ARG1 and TGF-β [146]

Summary

Introduction

Cancer therapy has been transformed by Immunotherapies whose element is the anti-tumor response mediated by cytotoxic T lymphocyte (CTL). The highly increased number of TIM-3 expressing CD4+ and CD8+ T cells have been observed in samples from lung cancer patients and murine model with acquired resistance to anti-PD-1 treatment [49].

Results

Conclusion