Immunological mechanisms elicited at the tumour site by lymphocyte activation gene-3 (LAG-3) versus IL-12: sharing a common Th1 anti-tumour immune pathway
- 7 December 2004
- journal article
- research article
- Published by Wiley in The Journal of Pathology
- Vol. 205 (1), 82-91
- https://doi.org/10.1002/path.1679
Abstract
The experimentally induced TS/A murine mammary carcinoma is poorly immunogenic and mainly infiltrated by antigenâpresenting cells (APCs), namely macrophages and immature dendritic cells (DCs). Human (h) and mouse (m) lymphocyte activation geneâ3 (LAGâ3 or CD233) is a physiological MHC class II ligand and powerful APC activator. A gene transfer approach has revealed its antiâtumour activity in this model: hLAGâ3 was more effective than mLAGâ3. To obtain a clearer picture of the immunoregulatory mechanisms associated with the rejection dynamics of hâ and mâLAGâ3 transfectants, immunohistochemistry and confocal microscopy analyses of TS/AâhLAGâ3, TS/AâmLAGâ3, and control TS/Aâpc tumours were performed. The immune events elicited by mLAGâ3 and mâinterleukin (IL)â12 were also compared, since their rejection kinetics were quite similar, and LAGâ3 enables ILâ12 production by macrophages and DCs. Both the TS/Aâhâ and, to a lesser extent, the mâLAGâ3 rejection areas were characterized by an impressive recruitment of APCs, granulocytes, NK cells, CD4+ T lymphocytes and CD8+ IFNÎłâexpressing cells. In both cases, infiltration by APCs was accompanied by strong CD80 and CD86 expression and macrophage nitric oxide (NO) synthase upâregulation. Distinct expression of ILâ12 and CXCL9 was also found, especially in the draining lymph nodes. T lymphocytes and CD86âexpressing APCs were significantly prevalent in both the TS/Aâhâ and the mâLAGâ3 compared with the TS/AâmILâ12 rejection area. Production of IFNÎł, TNFα and IL1ÎČ, and chemokines, namely CXCL5, CXCL9, CXCL10, CXCL11, CCL5, and CCL2, by infiltrating leukocytes and signs of defective neovascularization were detected in tumours expressing hâLAGâ3â, mâLAGâ3â, and mâILâ12. However, IFNÎł, CCL2, and CCL5 production prevailed in the TS/AâhLAGâ3 rejection area. Taken together, these results indicate that LAGâ3 expression by engineered tumour cells efficiently promotes intraâtumoural recruitment, activation, and Th1 commitment of APCs, and leads to a wide intraâtumoural influx of nonâspecific and specific reactive cells, and the release of immunoregulatory and cytotoxic mediators. Many of LAGâ3's antiâtumour activities are shared with ILâ12. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.This publication has 31 references indexed in Scilit:
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