Myeloid-Derived Suppressor Cells Hinder the Anti-Cancer Activity of Immune Checkpoint Inhibitors

Abstract

Immune checkpoint inhibitors (ICI) used for cancer immunotherapy were shown to boost the existing anti-tumor immune response by preventing the inhibition of T cells by tumor cells. Antibodies targeting two negative immune checkpoint pathways, namely cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death-ligand 1 (PD-L1), have been approved first for patients with melanoma, squamous non-small cell lung cancer (NSCLC), and renal cell carcinoma. Clinical trials are ongoing to verify the efficiency of these antibodies for other cancer types and to evaluate strategies to block other checkpoint molecules. However, a number of patients do not respond to this treatment possibly due to profound immunosuppression, which is mediated partly by myeloid-derived suppressor cells (MDSC). This heterogeneous population of immature myeloid cells can strongly inhibit anti-tumor activities of T and NK cells and stimulate regulatory T cells (Treg), leading to tumor progression. Moreover, MDSC can contribute to patient resistance to immune checkpoint inhibition. Accumulating evidence demonstrates that the frequency and immunosuppressive function of MDSC in cancer patients can be used as a predictive marker for therapy response. This review focuses on the role of MDSC in immune checkpoint inhibition and provides an analysis of combination strategies for MDSC targeting together with ICI to improve their therapeutic efficiency in cancer patients.

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

“…Inside the tumor, immune cells are confronted with a suppressive milieu. The TME harbors an assortment of cell types that down modulate the immune response, including stromal cells, fibroblasts, regulatory T-cells (Tregs), and myeloid derived suppressor cells (MDSCs) (51,52) which can induce specific changes in cytotoxic lymphocyte phenotype, metabolic program, transcriptional profile, and epigenetic profile (21,53,54). The TME induces inhibitory effects on immune cells through a variety of processes, specifically chronic immune cell activation and an inflammatory microenvironment, secretion of immunomodulatory cytokines and soluble factors, induction of hypoxia, and upregulation of inhibitory checkpoint ligands, which down-regulate immune cell activation when engaged with immune checkpoint receptors, such as Programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (51,55).…”

Microbiome, bile acids, and obesity: How microbially modified metabolites shape anti‐tumor immunity

“…Consequently, TNBC patients who have high levels of circulating MDSCs respond poorly to ICB. 222 The FDA recently approved ICB combination therapy for TNBC using anti-PD-L1 atezolizumab (Tecentriq) plus nab-paclitaxel (Abraxane) for the treatment of unresectable, locally advanced, or metastatic PD-L1+ tumors in March of 2019. However, this combination therapy is effective only in a subset of patients that highly expressed PD-L1.…”

Sculpting tumor microenvironment with immune system: from immunometabolism to immunoediting

“…Of note, these strategies also have impacts on the functions and survival of immunomodulatory cells, including T regs , TAMs, MDSCs and DCs [15][16][17][18]. Among these cancer immunotherapies, immune check-point blockade (ICB), that blocks inhibitory receptors such as cytotoxic T lymphocyte antigen (CTLA)-4 and PD-1, has resulted in tremendous success in the treatments of several types of cancer by rejuvenating dysfunctional tumor-specific T cells.…”

“…Among these cancer immunotherapies, immune check-point blockade (ICB), that blocks inhibitory receptors such as cytotoxic T lymphocyte antigen (CTLA)-4 and PD-1, has resulted in tremendous success in the treatments of several types of cancer by rejuvenating dysfunctional tumor-specific T cells. Of note, these strategies also have impacts on the functions and survival of immunomodulatory cells, including T regs , TAMs, MDSCs and DCs [15][16][17][18]. Several strategies targeting prostaglandin E 2 , cytokines and indoleamine 2,3-dioxygenase (IDO) have been also developed to alleviate immunosuppressive traits in the TME and further improve T cell immunity and tumor control [19][20][21].…”