Myeloid-Derived Suppressor Cells: General Characteristics and Relevance to Clinical Management of Pancreatic Cancer

Abstract

Recent studies describe a heterogeneous population of cells of the myeloid lineage, termed myeloid derived suppressor cells (MDSC), which are observed with increased prevalence in the peripheral blood and tumor microenvironment of cancer patients, including pancreatic cancer. Accumulation of MDSC in the peripheral circulation has been related to extent of disease, and correlates with stage. MDSC have primarily been implicated in promoting tumor growth by suppressing antitumor immunity. There is also compelling evidence MDSC are also involved in angiogenesis and metastatic spread. Two main subsets of MDSC have been identified in cancer patients: a monocytic subset, characterized by expression of CD14, and a granulocytic subset characterized by expression of CD15. Both subsets of MDSC actively suppress host immunity through a variety of mechanisms including production of reactive oxygen species and arginase. Just as in humans, accumulation of monocytic and granulocytic MDSC has been noted in the bone marrow, spleen, peripheral circulation, and tumors of tumor bearing mice. Successful targeting of MDSC in mice is associated with improved immune responses, delayed tumor growth, improved survival, and increased efficacy of vaccine therapy. By further elucidating mechanisms of MDSC recruitment and maintenance in the tumor environment, strategies could be developed to reverse immune tolerance to tumor. We discuss here what is currently known about MDSC as well as some potential strategies targeting MDSC in the context of our work on pancreatic cancer and recent literature. Due to the number of new reports on MDSC, the most pertinent ones have been selected.

Patients with pancreatic adenocarcinoma exhibit elevated levels of myeloid-derived suppressor cells upon progression of disease

“…Inhibiting MDSCs in patients with pancreatic adenocarcinoma may reverse immune suppression [30]. It has recently been shown that soluble factors contribute to the up-regulation of murine MDSCs in the murine mode and immune dysfunction of T cells.…”

IL-17 and VEGF are significantly associated with disease progression involving systemic inflammation in patients with gastric and colorectal cancers

“…The presence of IL-17 and Th17 cells has been confirmed in almost all types of invasive cancers, and IL-17 signaling activation related to cell proliferation, tumor growth and progression, and treatment resistance has been shown 7) . Suppressive myeloid cells were previously described in patients with cancer 8,9) , although the functional significance of these cells in the immune system has only recently been evaluated. Accumulating evidence [10][11][12][13] suggests that a population of cells with suppressive activity, referred to as MDSCs, may contribute to the negative regulation of immune responses during cancer and other conditions.…”

Inhibiting MDSC differentiation from bone marrow with phytochemical polyacetylenes drastically impairs tumor metastasis

“…The MDSC population has been shown to increase in cancer patients343536. Relatedly, granulocyte colony-stimulating factor (G-CSF) was shown to be one of the key cytokines secreted by tumor cells to mediate MDSC production27.…”