Urokinase-mediated recruitment of myeloid-derived suppressor cells and their suppressive mechanisms are blocked by MUC1/sec

Abstract

IntroductionMucin 1 (MUC1) is a tumor antigen that is overexpressed on the surface of various epithelial tumor cells. The transmembrane isoform of MUC1 can promote tumor progression by creating a barrier around tumor cells against immune cells, sequestering compounds that suppress immune responses, interacting with growth-promoting signaling molecules, and aiding in the metastatic process. 1 Furthermore, MUC1 has been shown to accelerate premalignant inflammatory lesion transformation to malignancy. 2 We have previously reported on antitumor properties of a splice variant of MUC1, which is secreted and known as MUC1/sec. [3][4][5] MUC1/sec is found in normal 6,7 and tumor tissue, 8 but, interestingly, malignancy in ovarian lesions has been correlated with loss of its expression. 9 DA-3 murine mammary tumor cells expressing MUC1/sec (DA-3/sec) are rejected from BALB/c mice, whereas expression of the transmembrane isoform of MUC1 (MUC1/TM; DA-3/TM) has little effect. [3][4][5] DA-3/sec cells, however, lead to tumor development in immunocompromised BALB/c nude mice, or BALB/c mice depleted of T lymphocytes. Furthermore, depletion of innate immune cells allows initial tumor growth, followed by tumor regression once the adaptive immune response develops. 3 We have determined that MUC1/sec modulates various factors involved in tumorigenesis, such as up-regulating signal transducer and activator of transcription 1 (Stat1), leading to the downregulation of tumor-derived urokinase plasminogen activator (uPA), a serine protease correlated with tumor progression in human cancers. 5 Other investigators have reported that tumor cell expression of MUC1/TM recruits immature dendritic cells (DCs). 10 In our previous studies, we analyzed whether there was a difference in recruitment of immune cells to DA-3/TM or DA-3/sec cells, and we reported that DA-3/TM cells recruit more GR-1 ϩ cells than DA-3/sec tumor cells. 3 We and others have also previously described that a myeloid population that accumulates in many tumor models, and are known as CD11b ϩ GR-1 ϩ myeloid-derived suppressor cells (MDSCs), [11][12][13][14][15][16] orchestrate immunosuppression by suppressing T cells. 13 In this study, we show that GR-1 ϩ cells that are recruited to high levels by DA-3/TM cells, but not DA-3/sec, are in fact MDSCs. Furthermore, we report for the first time that uPA, which is down-regulated by MUC1/sec, is capable of recruiting MDSCs. This is a new mechanism by which uPA may be augmenting and contributing to tumor development.MUC1 has also been shown to impair differentiation and function of DCs, 17 along with inducing a regulatory phenotype with immune-suppressive cytokine secretion. 10,17,18 We therefore investigated whether in addition to modulating recruitment of MDSCs, MUC1/sec can alter MDSC-suppressive mechanisms. We found that whereas DA-3/TM cells induce high levels of arginase in MDSCs, associated with suppression, 19 DA-3/sec cells block that induction. Furthermore, a unique peptide found in MUC1/sec and called immunoenhancing pe...

Myeloid derived suppressor cells and their role in tolerance induction in cancer

“…Finally, urokinase plasminogen activator (uPA), which is known to induce tumor progression, also correlates with the recruitment of MDSCs in murine mammary carcinoma models [31,32]. These results are supported by findings of Hanson et al, demonstrating that intraperitoneal injection of uPA significantly elevated the numbers of MDSCs in spleens.…”

Identification of a Subpopulation of Macrophages in Mammary Tumor–Bearing Mice That Are Neither M1 nor M2 and Are Less Differentiated

“…Our T-PEMs do not express characteristic markers of MDSC, such as arginase and/or nitric oxide (15). In contrast to our T-PEMs, splenic MDSCs isolated from DA-3-tumor-bearing mice do not express F4/80 (47). Our data suggest that T-PEMs are a less differentiated cell population and thus represent recently recruited monocytes from the blood that may become apoptotic during differentiation into macrophages.…”

Functional Changes in Myeloid-Derived Suppressor Cells (MDSCs) during Tumor Growth: FKBP51 Contributes to the Regulation of the Immunosuppressive Function of MDSCs

“…2A, 2B), suggesting that the APC function of MDSCs might decrease with tumor growth. In contrast, some genes related to MDSC immunosuppressive function, such as S100a8 and S100a9 (26) in Mo-MDSCs and urokinase (Plau) (27) in PMN-MDSCs, were increased with tumor growth (Fig. 2C, 2D).…”

“…These genetic changes may license the functional changes of MDSC observed during the tumor growth. Although we and others have identified the function of several genes important in the immunosuppressive function of MDSCs (26)(27)(28)(29)(30), many genes still remain unknown. For instance, it is interesting that all neutrophil serine proteases (NSPs), including neutrophil elastase, cathepsin G, and proteinase-3, are increased in Mo-MDSCs, and serpinb1, which is an NSP inhibitor, was increased in both Mo-MDSCs and PMN-MDSCs (Fig.…”