No abstract

CC chemokine ligand 21 (CCL21) is a known attractant for CCR7-positive (CCR7+) cells, but its additional role in the immunogenicity of CCR7+ cells remains poorly understood. This study explored the effects of CCL21-CCR7 ligation on cancer immunogenicity and related antitumor immune response, in the presence and absence of mitomycin C (MMC) treatment. CCL21-CCR7 binding upregulated human leukocyte antigen class I-restricted tumor antigen presentation with increased expression of human leukocyte antigen class I and transporter associated with antigen processing-1. In addition, CCL21 restrained the tumor-derived immunosuppressive factors FasL and transforming growth factor-β. Consequently, CCL21 facilitated cancer-educated lymphocytes reaction in vitro. In the tumor-bearing mouse, CCL21 inhibited tumor growth and prolonged mouse survival via lymphocytes, especially in CCR7+ cancer cells. Furthermore, Toll-like receptor 2 activation of lymphocytes assisted the tumor-suppression functions of CCL21, in vitro and in vivo. This study implies that CCL21 improved the immunogenicity of the CCR7+ breast cancer cell line even with MMC treatment and triggered antitumor response by lymphocytes. These findings provide a new insight into the research and application of CCL21-associated antitumor response.

SummaryAn insulinoma cell line, NIT-1, transfected with glucose-regulated protein 78 (GRP78) was established, namely NIT-GRP78, and used to study the immunosuppressive and protective ability of GRP78. In extended cytotoxic T lymphocyte (CTL) killing assay, NIT-1-primed lymphocytes were more cytotoxic in killing b cells than NIT-GRP78-primed lymphocytes. Severe necrosis was observed only when the NIT-1-primed lymphocytes were cultured with NIT-1 b cells, but not with NIT-GRP78 cells. In addition, an increase of interleukin (IL)-4 secretion from b cell-primed splenocytes when GRP78 presence was observed in cytokine enzyme-linked immunosorbent assay (ELISA). Diabetic mice reached normoglycaemia promptly and gained weight after transplantation of either NIT-1 or NIT-GRP78 cells. However, the recipient mice transplanted with NIT-GRP78 cells lived much longer than those recipients transplanted with NIT-1 cells, which was due apparently to prolonged insulin production by the transplanted NIT-GRP78 cells. In fact, we observed a significant increase of insulin concentration after glucose stimulation of diabetic mice received NIT-GRP78 cells at day 7 post-transplantation. From the results we propose that GRP78 could have a dual function in both protecting NIT-1 cells from CTL-mediated lysis and stimulating a population of T helper 2 cells to down-regulate the immune response to the transplanted b cells.