PO-371 ADAM28 deletion in mice induces CD8 +T cell decrease and impacts the onset of lung metastasis

Abstract

IntroductionADAM28 is highly overexpressed in NSCL cancer. In addition, intrinsic characteristics of this proteinase argue for considering it as a potential regulator of cellular signalling pathways leading to an inflammatory pulmonary microenvironment and to carcinogenesis. Indeed, ADAM28 bears an active catalytic domain and interacts in a non-proteolytic manner with integrins α4β1 and P-selectin ligands involved in inflammatory cell migration. The aim of this project is to characterise effects of host-ADAM28 on physiological and pathological processes.Material and methodsADAM28 conditional KO mice have been developed in our laboratory. This unique mouse strain provides a precious tool to investigate ADAM28 implication in lung tumour growth and dissemination. Indeed, mice were intravenously injected with Lewis Lung, 4 T1 carcinoma cells and B16K1 melanoma cells. Since ADAM28 is expressed by thymic epithelial cells and implicated in lymphocyte transendothelial migration, FACS analysis has been performed to study lymphocyte subsets implicated in tumour cytotoxicity or in regulation of immune response.Results and discussionsFirst analysis showed that there is no spontaneous phenotype for ADAM28 full knockout animals as they are fertile and do not display any abnormality or defect. Surprisingly, an increased metastasic dissemination in lungs has been observed in KO mice compare to WT littermates. Among infiltrating immune cells implicated in anti-tumour response, only CD8 T cells are decreased in metastatic lungs of ADAM28 KO mice. Interestingly, this decrease is already observed in spleen of tumour free-ADAM28 KO mice. These data suggest a potential role of ADAM28 during lymphocyte maturation process, which could further impact antitumoral functions. Moreover, ex vivo analyses of CD8 T cells demonstrate an increase of PD-L1 at cell surface of CD8 T cells isolated from ADAM28 KO mice. PD-L1 interacts with its PD-1 receptor and their interaction induces CD8 apoptosis and exhaustion. Further investigations are required to demonstrate the link between ADAM28 and PD-L1 and their implication in the decrease of CD8 T cell infiltration.ConclusionThe role of tumour cell-derived ADAM28 as a pro-tumour factor is widely described in the literature. However, our results demonstrate an anti-metastatic function of host derived-ADAM28 suggesting a dual role of ADAM28, depending on the origin of the protease. Based on our results, ADAM28 seems to play a major role in the control of anti-tumour immune response mediated by CD8 T cells.