CCRL2 is a non-signaling seven-transmembrane domain receptor expressed by myeloid cells and by non-hematopoietic cells, such as endothelial cells. In endothelial cells, CCRL2 acts as a chemerin presenting molecule and promotes leukocyte extravasation. We have previously reported that NK cells express CMKLR1, the chemerin functional receptor, and migrate in response to this protein. We have shown that in CCRL2 KO mice NK cells have a defective migration to the lung and this was associated with increased tumor growth in a genetic model of KrasG12D/+/p53LoxP lung adenocarcinoma (TK mice). The same results were obtained by the i.v. injection of LG1233, a tumor cell line isolated from TK mice. On the contrary, no difference in NK cell migration was observed between WT and CCRL2KO mice when LG1233 cells were inoculated subcutaneously. This evidence rises the possibility that CCRL2 might act as a selective lung homing molecule for NK cells.
Immunotherapy represents a promising approach for cancer treatment, including lung cancer, but the efficacy of this therapy is often limited by tumor immune escape strategies, including inhibition of leukocyte infiltration. The possibility to increase NK cell migration to the lung through the upregulation of CCRL2 expression could represent a promising strategy to improve the success of immunotherapy. Preliminary data suggest that this positive regulation can be obtained by the use of demethylating agents, such as 5'-Aza-2-deoxycytidine (AZA). The goals of this research proposal are to demonstrate that CCRL2 is a lung NK cell homing molecule and that the pharmacological regulation of CCRL2 expression can be exploited as a new strategy to improve the localization of immune cells at the tumor site.