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.

Figure 1

Schematic representation of the balance between tumor growth and immune correlates.

Figure 2

Hierarchical development of mature peripheral blood cells and MDSC through differentiation of hematopoietic stem cells (HSC) in mice. Differentiation of HSC is considered normal until the Granulocyte/Monocyte Precursor (GMP) stage. GMPs fail to differentiate into mature PMN and monocytes in a tumor-bearing host. Instead, GMPs give rise to MDSC that bear markers of both PMN and monocytes, but do not express markers of fully-matured cells. Please note that this diagram is meant primarily to illustrate the origin and main phenotypic markers of MDSC rather than depict in great detail the various differentiation pathways.

Figure 3

Both monocytic and granulocytic MDSC infiltrate human pancreatic adenocarcinoma. A: Immunohistochemistry demonstrates a high prevalence of CD15⁺CD11b⁺ MDSC in tissue samples resected from patients with pancreatic adenocarcinoma. Red (CD11b) and green (CD15) fluorescence is shown with co-localization of CD15⁺CD11b⁺ MDSC indicated by yellow. B: Co-localization of CD11b (blue) and CD14 (red) indicated by pink/purple, and CD11b and CD15 (green) indicated by aqua. Additionally, co-localization of CD14 and CD15 is noted in some cells (pink plus aqua).

Figure 4

Schematic overview of the role of MDSC in promoting tumor development. Developing tumors secrete factors such as VEGF, chemokines and inflammatory cytokines that induce myelopoiesis in the bone marrow. These factors also cause an imbalance in homing mechanisms of myeloid precursors which in turn leads to release of myeloid precursors into the circulation. Chemokine receptor expression on these myeloid cells directs them to various locations in the host where the corresponding ligand is expressed. For example, MDSC recruitment to primary tumor promotes angiogenesis and immune suppression, whereas MDSC recruitment to distant organs, e.g. liver, promotes the formation of metastasis. Mechanisms for MDSC recruitment, e.g. CXCR4 are also exploited by metastatic tumor cells.

Figure 5

Zoledronate treated mice have smaller pancreatic tumors compared with untreated tumor-bearing mice. C57BL/6 mice (n=5) were challenged with 1.0 × 10⁵ viable Pan02 cells on day 0 (injected subcutaneously in the left thigh). Treatment with either placebo or zoledronate was initiated on day 10, when subcutaneous pancreatic tumors were present by palpation. Zoledronate at a dose of 0.1 mg/kg was diluted in saline and administered daily subcutaneously for 5 days per week. Control mice (n=5) received 0.2 mL of saline daily subcutaneously. Shown is the average tumor volume per group; error bars indicate the standard error of the mean (p<0.01).