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

P.      Goedegebuure; J.      B. Mitchem; M.      R. Porembka; M.      C.B. Tan; B.      A. Belt; A.      Wang-Gillam; W.      E. Gillanders; W.      G. Hawkins; D.      C. Linehan

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.

Keywords: Myeloid-derived suppressor cells, pancreatic cancer, immune suppression, bone marrow, metastasis, Mesothelin, premetastatic niche, myelopoiesis, Zoledronic acid, indoleamine 2,3-dioxygenase, inducible nitric oxide synthase