Targeting Myeloid-Derived Suppressor Cells to Bypass Tumor-Induced Immunosuppression

Abstract

The immune system has many sophisticated mechanisms to balance an extensive immune response. Distinct immunosuppressive cells could protect from excessive tissue damage and autoimmune disorders. Tumor cells take an advantage of those immunosuppressive mechanisms and establish a strongly immunosuppressive tumor microenvironment (TME), which inhibits antitumor immune responses, supporting the disease progression. Myeloid-derived suppressor cells (MDSC) play a crucial role in this immunosuppressive TME. Those cells represent a heterogeneous population of immature myeloid cells with a strong immunosuppressive potential. They inhibit an antitumor reactivity of T cells and NK cells. Furthermore, they promote angiogenesis, establish pre-metastatic niches, and recruit other immunosuppressive cells such as regulatory T cells. Accumulating evidences demonstrated that the enrichment and activation of MDSC correlated with tumor progression, recurrence, and negative clinical outcome. In the last few years, various preclinical studies and clinical trials targeting MDSC showed promising results. In this review, we discuss different therapeutic approaches on MDSC targeting to overcome immunosuppressive TME and enhance the efficiency of current tumor immunotherapies.

Keywords: cancer immunotherapy; immunosuppression; myeloid-derived suppressor cells; therapeutic targeting; tumor microenvironment.

Figure 1

Myeloid-derived suppressor cells (MDSC) recruitment and activation during tumor progression. Tumor and immune cells constantly release inflammatory mediators, leading to the dysregulation of normal myelopoiesis and to the conversion of immature myeloid cells (IMC) into MDSC in the bone marrow. The latter cells expand and migrate to the tumor site through the interaction between CCR and respective chemokines (CCL). In the tumor microenvironment, MDSC are activated and strongly inhibit an antitumor reactivity of T cells via various mechanisms.

Figure 2

Strategies for myeloid-derived suppressor cells (MDSC) targeting. The MDSC modulation could be achieved by the inhibition of their immunosuppressive activity (blue box), by the blockade of MDSC recruitment to the tumor site (green box), and by the regulation of myelopoiesis and/or depletion of MDSC (red box). Examples for each therapeutic approach are shown.