Diana M. Lopez, Ph.D.
Professor of Microbiology & Immunology
Description of Research
The transmembrane isoform of mucin 1 (MUC1/TM) is a well-recognized tumor antigen, contributing to tumorigenesis and immune evasion. Although MUC1/TM has been correlated with malignancy, Dr. Lopez has previously reported on antitumor properties and prevention of tumor development by a secreted splice variant of MUC1 (MUC1/sec). Because myeloid-derived suppressor cells (MDSCs) play a critical role in tumor-induced immunosuppression, her laboratory investigated their recruitment by tumor cells expressing either MUC1/TM or MUC1/sec. DA-3 tumor cells expressing MUC1/sec recruit dramatically lower levels of MDSCs, relative to MUC1/TM-expressing DA-3 cells. Because MUC1/sec was previously shown to down-regulate tumor expression of urokinase plasminogen activator (uPA), a protease linked to tumor aggressiveness and metastasis, the potential role of uPA in MDSC recruitment was investigated. In addition to diminishing recruitment of MDSCs, the effect of MUC1/sec on MDSC-suppressive mechanisms was investigated. MUC1/sec, or its unique immunoenhancing peptide, is capable of blocking expression of arginase 1 and production of reactive oxygen species in MDSCs, implicated in the suppression of T cells. These findings demonstrate a new mechanism of MDSC recruitment, and provide evidence that MUC1/sec has antitumor properties affecting MDSCs.
Tumor-induced immunosuppression plays a key role in tumor evasion of the immune system. As described above, MDSCs contribute to and help orchestrate this immunosuppression. MDSCs can interact with T cells, macrophages, and natural killer cells to create an environment favorable for tumor progression. In various tumor models, their presence at high levels has been reported in the bone marrow, blood, spleen, and tumor. Interestingly, Dr. Lopez found that MDSCs accumulate and home to the liver in addition to the other organs. Liver MDSCs suppress T cells and accumulate to levels comparable with splenic MDSCs. Furthermore, MDSCs in the liver interact with macrophages, also known as Kupffer cells, and cause their up-regulation of PD-L1, a negative T-cell costimulatory molecule. The liver is thus an organ in which MDSCs accumulate and can contribute to immunosuppression directly and indirectly.During mammary tumorigenesis, there is a profound thymic involution associated with severe depletion of the most abundant subset of thymocytes, CD4(+)CD8(+) immature cells, and an early arrest in at least two steps of T cell differentiation. Thymic atrophy that is normally related with aging has been observed in other model systems, including Graft-Versus-Host disease (GVHD) and tumor development. However, the mechanisms involved in this phenomenon remain to be elucidated. Vascular endothelial growth factor (VEGF) has been associated with thymic involution, when expressed at high levels systemically. In thymuses of D1-DMBA-3 tumor-bearing mice, this growth factor is diminished relative to the level of normal thymuses. Interestingly, the expression of hepatocyte growth factor (HGF), which has been associated with proliferation, cell survival, angiogenesis and B-cell differentiation, is profoundly down-regulated in thymuses of tumor bearers. In parallel, IL-7 and IL-15 mRNA, crucial cytokines involved in thymocytes development and cellular homeostasis, respectively, are also down-regulated in the thymuses of tumor hosts as compared to those of normal mice. Injection of HGF into mice implanted with mammary tumors resulted in normalization of thymic volume and levels of VEGF, IL-7 and IL-15. While, injections of IL-7 partially restored the thymic involution observed in the thymuses of tumor-bearing mice, injection of IL-15 did not have any significant effects. Our data suggest that the downregulation of HGF and IL-7 may play an important role in the thymic involution observed in tumor-bearing hosts.
- The thymus is crucial for the development of T lymphocytes involved in cell-mediated immunity to tumors. The thymuses of mammary tumor bearers are profoundly involuted and their studies have shown that this is not due to a decrease of the thymocytes proliferation. A minor increase of apoptosis was noted, however, the major cause of this phenomenon appears to be an arrest at an early stage of differentiation possibly brought about by the direct or indirect effects of tumor derived factors.
- A unique peptide with immunoenhancing properties has been identified in a secreted form of human MUC1 and used in vaccination experiments. This peptide inhibits tumor development not only in the mammary cells transfected with the secreted MUC1, but also provides protection against a variety of other tumor types.
- The very important molecule MMP-9 has been shown to be overproduced by T lymphocytes from tumor bearing mice due in part to the overexpression of vascular endothelial growth factor. The intriguing possibility that this molecule may be helping tumor spread is being evaluated.
Selected Cancer-Related Publications
- Ilkovitch D, Lopez DM. Urokinase-mediated recruitment of myeloid-derived suppressor cells and their suppressive mechanisms are blocked by MUC1/sec. Blood 113:4729-39, 2009. Read more »
- Carrio R, Lopez DM. Impaired thymopoiesis occurring during the thymic involution of tumor-bearing mice is associated with a down-regulation of the antiapoptotic proteins Bcl-XL and A1. Int J Mol Med 23:89-98, 2009. Read more »
- Handel-Fernandez ME, Ilkovitch D, Iragavarapu-Charyulu V, Herbert LM, Lopez DM. Decreased levels of both stat1 and stat3 in T lymphocytes from mice bearing mammary tumors. Anticancer Res 29:2051-8, 2009. Read more »
- Ilkovitch D, Lopez DM. The liver is a site for tumor-induced myeloid-derived suppressor cell accumulation and immunosuppression. Cancer Res 69:5514-21, 2009. Read more »