Cell-surface CD200 expression by mouse EMT6 breast tumor cells increased primary tumor growth and metastasis to the draining lymph nodes (DLN) in normal (WT) BALB/c female recipients, while lack of CD200R1 expression in a CD200R1-/- host negated this effect. Silencing CD200 expression in EMT6siCD200 tumor cells also reduced their ability to grow and metastasize in WT animals. The cellular mechanisms responsible for these effects have not been studied in detail. We report characterization of tumor infiltrating (TILs) and draining lymph node (DLN) cells in WT and CD200-/- BALB/c mice, receiving WT tumor cells, or EMT6 lacking CD200 expression (EMT6siCD200 cells). Our data show an important correlation with augmented CD8+ cytotoxic T cells and resistance to tumor growth in mice lacking exposure (on either host cells or tumor) to the immunoregulatory molecule CD200. Confirmation of the importance of such CD8+ cells came from monitoring tumor growth and characterization of the TILs and DLN cells in WT mice challenged with EMT6 and EMT6siCD200 tumors and treated with CD8 and CD4 depleting antibodies. Finally, we have assessed the mechanisms(s) whereby addition of metformin as an augmenting chemotherapeutic agent in CD200-/- animals given EMT6 tumors and treated with a previously established immunotherapy regime can increase host resistance. Our data support the hypothesis that increased autophagy in the presence of metformin increases CD8+ responses and tumor resistance, an effect attenuated by the autophagy inhibitor verteporfin.
CD200 is a widely expressed cell surface glycoprotein that inhibits excessive inflammation in autoimmunity, transplantation, and viral infections. We previously observed that visceral metastasis of highly aggressive and inflammatory 4THM breast carcinoma cells was markedly decreased in CD200 transgenic mice. The goal of this study was to determine whether exogenous exposure to CD200fc mimics the effects of endogenously over expressed CD200. Female BALB/c mice were injected with CD200fc two times a week for five times. Injection was started two days after orthotopic injection of 4THM cells. Tumor infiltrating Gr1+Cd11b+ cells were decreased while CD8+ cells were increased in CD200fc-treated animals. CD200fc injection significantly decreased lung and liver metastasis and the growth of primary tumors. CD200fc injection enhanced the tumor-induced IFN-g response while suppressing the IL-10 response. We observed excessive basal IL-6 secretion in MLC which was significantly decreased in CD200fc treated mice 12 days after injection of 4TM cells. These results are in accord with previous data from CD200 transgenic mice, and demonstrate for the first time that CD200 analogues might have therapeutic potential in the treatment of aggressive breast carcinoma which induces excessive systemic inflammation.
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