Microenvironment-derived ADAM28 impacts the onset of lung cancer

Background
ADAM28 expression is upregulated in non-small cell lung carcinoma and correlated with cell proliferation and metastatic dissemination. Moreover, in vivo studies have shown that knockdown of ADAM28 in tumor cells decreased the primary tumor growth and formation of lung metastasis. Besides, ADAM28 is thought to be an important regulator of inflammatory signaling pathways as it sheds the pro-inflammatory cytokine, pro-TNF-alpha. ADAM28 protease also interacts with integrins and the P-selectin glycoprotein ligand-1 leading to inflammatory cell migration. Altogether, these findings suggest that ADAM28 contributes to cellular mechanisms leading to cancer development and progression.

Methods
This study aims to characterize the effects of microenvironment-derived ADAM28 on lung metastasis formation. To achieve this purpose, we generated ADAM28-/- mice into two different mouse strains (C57BL/6 and BALB/c). Lung metastatic dissemination was assessed in both ADAM28-/- and wild-type (WT) mice after intravenous injection of Lewis Lung Carcinoma cells, B16K1 melanoma cells or 4T1 breast carcinoma cells. As ADAM28 promotes leukocyte transendothelial migration, lymphocyte subtypes implicated in tumor cytotoxicity or in regulation of immune response were studied by flow cytometry.

Results
An unexpected increased tumor burden was found in lungs of ADAM28-/- mice as compared to WT mice. Flow cytometry analysis revealed that less CD8+ T were infiltrated within lungs of ADAM28-/- tumor-bearing mice. Moreover, a reduced CD8+ T cell population was observed in the spleen of naïve ADAM28-/- mice that is not caused by an impaired T cell maturation in the thymus. Ex vivo assays demonstrated that intrinsic properties of CD8+ T cells from ADAM28-/- mice were not affected by ADAM28 deficiency as their proliferation, migration and activation was similar. Besides, we found no expression of ADAM28 in isolated CD8+ T cells from the spleen of ADAM28-/- and WT mice. Therefore, we hypothesized that ADAM28 indirectly modulates the anti-tumor cytotoxic immune response. We also found that ADAM28 depletion is associated with a reduced infiltration of NK cell within lungs of ADAM28-/- tumor-bearing mice.

Conclusion
Our results demonstrate a protective effect of microenvironment-derived ADAM28 by regulating the tumor-associated immune response.