Boosting lung cancer immunotherapy targeting NK cell homing

Anno
2021
Proponente Silvano Sozzani - Professore Ordinario
Sottosettore ERC del proponente del progetto
LS6_3
Componenti gruppo di ricerca
Componente Categoria
Marco Cippitelli Componenti strutturati del gruppo di ricerca / Structured participants in the research project
Cinzia Fionda Componenti strutturati del gruppo di ricerca / Structured participants in the research project
Alessandra Soriani Componenti strutturati del gruppo di ricerca / Structured participants in the research project
Alessandra Zingoni Componenti strutturati del gruppo di ricerca / Structured participants in the research project
Luana Tomaipitinca Dottorando/Assegnista/Specializzando componente non strutturato del gruppo di ricerca / PhD/Assegnista/Specializzando member non structured of the research group
Componente Qualifica Struttura Categoria
Mattia Laffranchi Borsista Medicina Molecolare/Sapienza Altro personale aggregato Sapienza o esterni, titolari di borse di studio di ricerca / Other aggregate personnel Sapienza or other institution, holders of research scholarships
Abstract

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.

ERC
LS6_1, LS6_3, LS6_4
Keywords:
IMMUNITA¿ INNATA, CANCRO, BIOLOGIA CELLULARE

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