Immunosuppression mediated by myeloid-derived suppressor cells (MDSCs) during tumour progression

Abstract

Under steady-state conditions, bone marrow-derived immature myeloid cells (IMC) differentiate into granulocytes, macrophages and dendritic cells (DCs). This differentiation is impaired under chronic inflammatory conditions, which are typical for tumour progression, leading to the accumulation of IMCs. These cells are capable of inducing strong immunosuppressive effects through the expression of various cytokines and immune regulatory molecules, inhibition of lymphocyte homing, stimulation of other immunosuppressive cells, depletion of metabolites critical for T cell functions, expression of ectoenzymes regulating adenosine metabolism, and the production of reactive species. IMCs are therefore designated as myeloid-derived suppressor cells (MDSCs), and have been shown to accumulate in tumour-bearing mice and cancer patients. MDSCs are considered to be a strong contributor to the immunosuppressive tumour microenvironment and thus an obstacle for many cancer immunotherapies. Consequently, numerous studies are focused on the characterisation of MDSC origin and their relationship to other myeloid cell populations, their immunosuppressive capacity, and possible ways to inhibit MDSC function with different approaches being evaluated in clinical trials. This review analyses the current state of knowledge on the origin and function of MDSCs in cancer, with a special emphasis on the immunosuppressive pathways pursued by MDSCs to inhibit T cell functions, resulting in tumour progression. In addition, we describe therapeutic strategies and clinical benefits of MDSC targeting in cancer.

Decoding the Role of Interleukin-30 in the Crosstalk between Cancer and Myeloid Cells

“…Activated myeloid cells are the primary cellular source and one of the targets of IL-30, which can also be produced by cancer cells, especially, in aggressive tumors, as observed in the breast and prostate. This review briefly reports on the immunobiology of IL-30 and related cytokines, by comparing mouse and human counterparts, and then focuses on the mechanisms whereby IL-30 amplifies intratumoral myeloid cell infiltrate and triggers a vicious cycle that worsens immunosuppression in the tumor microenvironment (TME) and constitutes a real threat for a successful immunotherapeutic strategy.Cells 2020, 9, 615 2 of 14 of reactive oxygen species (ROS), nitric oxide (NO), and ectoenzymes, which regulate the adenosine metabolism; expression of immune checkpoint molecules [10,11]; depletion of metabolites critical for lymphocyte functions [12,13]; and through their secretion of growth, angio-lymph-angiogenic factors and inflammatory mediators [13], that are crucial for tissue remodeling and tumor development.Recent insights into this inflammatory milieu, specifically in breast (BC) and prostate (PC) cancers, have unveiled a role for the novel immunoregulatory mediator Interleukin(IL)-30/IL-27p28 [14] in the TME and in the intricate relationship between cancer and myeloid cells, which orchestrates tumor-promoting events with evident clinical implications [15,16].…”

“…Cells 2020, 9, 615 2 of 14 of reactive oxygen species (ROS), nitric oxide (NO), and ectoenzymes, which regulate the adenosine metabolism; expression of immune checkpoint molecules [10,11]; depletion of metabolites critical for lymphocyte functions [12,13]; and through their secretion of growth, angio-lymph-angiogenic factors and inflammatory mediators [13], that are crucial for tissue remodeling and tumor development.…”

Tissue‐specific tumor microenvironments influence responses to immunotherapies

“…Given the immunosuppressive effects of MDSCs, multiple strategies are under investigation to reverse their influence in the TME . Agents such as all‐ trans retinoic acid (ATRA) to differentiate MDSCs to mature myeloid cells, humanised IgG4 mAb targeting Semaphorin 4D…”

“…Given the immunosuppressive effects of MDSCs, multiple strategies are under investigation to reverse their influence in the TME. 47,48 Agents such as all-trans retinoic acid (ATRA) 49 to differentiate MDSCs to mature myeloid cells, humanised IgG4 mAb targeting Semaphorin 4D. 50,51 to inhibit MDSC expansion and gemcitabine 52,53 to deplete MDSCs have demonstrated antitumor activity in preclinical studies and are currently being tested in clinical trials for synergistic effects with checkpoint inhibitors.…”

Modulation of the functions of myeloid‐derived suppressor cells : a new strategy of hydrogen sulfide anti‐cancer effects

“…Tumour progression is strongly sustained by immunosuppressive cells such as the MDSCs. These cells, by inhibiting cytotoxic T cell proliferation and activation, induce failure of the anti-tumour immune response and lead to chemoresistance (Groth et al, 2019). Thus, we hypothesized that the anti-tumour effect displayed by DATS was related not only to its pro-apoptotic effect on B16F10 cells ( Figure S1) but also to its ability to modify the immune cell and monocytic (mo, Ly6C high Ly6G − ) subsets (Bronte et al, 2016).…”