Myeloid-Derived Suppressor Cells and Pancreatic Cancer: Implications in Novel Therapeutic Approaches

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains a devastating human malignancy with poor prognosis and low survival rates. Several cellular mechanisms have been linked with pancreatic carcinogenesis and also implicated in inducing tumor resistance to known therapeutic regimens. Of various factors, immune evasion mechanisms play critical roles in tumor progression and impeding the efficacy of cancer therapies including PDAC. Among immunosuppressive cell types, myeloid-derived suppressor cells (MDSCs) have been extensively studied and demonstrated to not only support PDAC development but also hamper the anti-tumor immune responses elicited by therapeutic agents. Notably, recent efforts have been directed in devising novel approaches to target MDSCs to limit their effects. Multiple strategies including immune-based approaches have been explored either alone or in combination with therapeutic agents to target MDSCs in preclinical and clinical settings of PDAC. The current review highlights the roles and mechanisms of MDSCs as well as the implications of this immunomodulatory cell type as a potential target to improve the efficacy of therapeutic regimens for PDAC.

Keywords: myeloid-derived suppressor cells; pancreatic cancer; pancreatic cancer therapies.

Figure 1

Differentiation of MDSCs. The generation of immature myeloid cells (myelopoiesis) begins in the bone marrow. The hematopoietic stem cells (HSC) differentiate into common myeloid progenitor (CMP) cells and then to immature myeloid cells (IMC). IMCs migrate to blood and various peripheral organs and under normal physiological conditions, differentiate into granulocyte- macrophage progenitors (GMP) cells to further differentiate into other progenitor cells and lineage-specific cell populations. Under pathological conditions including cancer, MDSCs are generated and acquire immunosuppressive functions. These MDSCs inhibit the antitumor immunity of effector T cells (Teff) directly or via mechanisms including the crosstalk with other immunosuppressive cell types such as regulatory T cells (Tregs), tumor-associated macrophages (TAMs) and dendritic cells (DCs).

Figure 2

Mechanisms involve in mediating the immunosuppressive function of MDSC, which include various cytokines and chemokines, immune cells and major factors, implicated in inhibiting T-cell responses as it related to tumorigenesis.

Figure 3

Schematic representations of A) other signaling pathways and B) factors involved in the regulation of MDSCs differentiation, accumulation, migration and function. The mediators (i.e., cytokines, chemokines, angiogenesis and immune cells) involved in the context of these pathways or factors, have been summarized in the text and also included in Figure 2, thus, are not repeated here. The sign → denotes induction or regulation, inhibition and increase or upregulation.