Abstract
Myeloid derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that accumulate in circulation of cancer patients and at tumor sites where they suppress anti-tumor immunity. We previously reported that in a colon cancer prevention trial of a MUC1 vaccine tested in individuals at increased risk for colon cancer, those who did not mount immune response to the vaccine had higher pre-vaccination levels of circulating MDSC compared to those who did. We also reported that individuals with pancreatic premalignancy, Intraductal Papillary Mucinous Neoplasm (IPMN), had increased circulating levels of MDSC that inversely correlated with spontaneous antibody responses against the pancreatic tumor associated antigen MUC1, abnormally expressed on IPMN. Accumulation of MDSC in cancer and their immunosuppressive role had been well established but their presence in premalignancy was unexpected. In this study we compared MDSC in premalignancy with those in cancer with the hypothesis that there might be differences in the composition of various MDSC subpopulations and their immunosuppressive functions due to different lengths of exposure to disease and/or different tissue microenvironments. In cohorts of patients with premalignant polyps, colon cancer, premalignant IPMN, and pancreatic cancer, we confirmed higher levels of MDSC in premalignancy compared to healthy controls, higher levels of MDSC in cancer compared to premalignancy, but no difference in their subpopulation composition or immunosuppressive capacity. We show that levels of MDSC in premalignancy correlate negatively in vivo with spontaneous MUC1-specific antibody responses and in vitro with polyclonal T cell proliferation and IFN-γ secretion.
Highlights
Myeloid derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that accumulate in cancer, auto-immunity, and some chronic inflammatory conditions [1, 2]
One of the most important findings that came from several decades of basic and preclinical work in tumor immunity and from many failed attempts at immunotherapy, was the highly immunosuppressive nature of the tumor microenvironment, both at the tumor site as well as at a distance, such as in the circulation
We showed that numbers of CD15+ cells that we characterized initially as granulocytes in the PBMC correlated inversely with patient survival in three different cancers, colon, breast and pancreas
Summary
Myeloid derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that accumulate in cancer, auto-immunity, and some chronic inflammatory conditions [1, 2]. They suppress the function of multiple immune effector cells and in particular T cells through multiple mechanisms. A clear positive association has been reported between peripheral blood MDSC levels and cancer stage in multiple tumor types including malignant myeloma, colon cancer and pancreatic cancer [4,5,6]. PMN-MDSC are the major immunosuppressive population of MDSC found in cancer patients’ blood and at the tumor site [7]. M-MDSC, fewer in number, can have higher T cell suppressive capacity on a per cell basis and are involved in promoting tumor metastasis and serving as biomarkers of tumor prognosis [8, 9]
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