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.
Cancer is one of the major causes of morbidity and mortality among an ageing population. Among others, lung malignancies, are an urgent medical need for which the relevance of immune mediators and circuits have been described. The challenge is now to translate scientific findings into more effective therapeutic strategies, which will impact on the improvement of health of the population at large. The analysis that we propose in this project aims at tackling these important health-related challenges and opens the possibility to identify novel tools, based on insights obtained by studying complex preclinical models.
Innate lymphocytes represent and emerging compartment of the immune system and their role in tumor progression is only partially known. On the other hand, a subset of this complex family, namely NK cells, are well known for their cytotoxic activity and their potential in controlling tumor growth, in vitro and in vivo. New therapies based on the anti tumor functions of these cells are being under clinical investigation and emerging therapies based on the use of the so-called checkpoint inhibitors are being exploited aimed at increasing NK cell cytotoxic functions. However, boosting the anti-tumor potential of immune effector cells may not be fully rewarding because of the ability of tumor cells to evade immune strategies. For instance, activated immune cells are often excluded from tumor tissue and confined to peritumoral areas. Therefore, addressing immune effector cells to the compartments were their action in needed, still remains a major open issue in immunotherapy.
In this proposal we aim at characterize the role of a new addressing molecule for the localization of NK cells to the lung compartment. This proposal stems from an extensive experience of the proponent developed along the past several years that also brought to the generation of original tools, such as different types of genetically engineered mice, monoclonal antibodies and Crispr-cas edited cells. By the use of these original experimental models we will provide experimental evidence on the ability of CCRL2 to function as a lung selective addressin for NK cells. A specific task (Task 4) is also developed to explore the possibility to use this function to improve the targeting on NK cells to lung tumors. We believe that this proposal is original, innovative and with the potential to uncover a new pathway to improve immunotherapy in one of the still most aggressive type of tumors.