The combined actions of NK and T lymphocytes are necessary to reject an EGFP+ mesenchymal tumor through mechanisms dependent on NKG2D and IFN gamma.
Ainhoa Arina (1), Oihana Murillo (1), Sandra Hervás-Stubbs (1), Arantza Azpilikueta (1), Juan Dubrot (1), Íñigo Tirapu (1), Eduardo Huarte (1), Carlos Alfaro (1), José L. Pérez-Gracia (1), Gloria González-Aseguinolaza (1), Pablo Sarobe (1), Juan J. Lasarte (1), Amanda Jamieson (2), Jesús Prieto (1), David H. Raulet (2), Ignacio Melero (1)
(1) Gene Therapy Unit, Centro de Investigación Médica Aplicada, University of Navarra, Pamplona, Spain.
(2) Department of Molecular and Cell Biology and Cancer Research Laboratory, University of California, Berkeley, CA 94720-3200.
Better understanding of the mechanisms that mediate spontaneous immune rejections ought to be important in the quest for improvements in immunotherapy of cancer.
A set of intraperitoneal tumors of mesenchymal origin that had been chemically induced in ubiquitously expressing EGFP transgenic mice provided a model in which both T and NK cells were absolutely required for tumor rejection. Tumor cells were traceable because of being fluorescent and readily grafted in RAG1(-/-) immunodeficient mice, whereas they were rejected in a majority of syngeneic C57BL/6 and EGFP-transgenic mice.
Tumor-cell clones with the highest EGFP expression tended to be rejected, but a direct involvement of EGFP as the antigen recognized for the immune rejections was ruled out. Rejections were absolutely dependent on NK cells as well as on CD4(+) and CD8(+) T lymphocytes according to selective depletion studies. Furthermore, CD8(+) and CD4(+) T lymphocytes as well as NK cells were detected in the inflammatory infiltrate that mediates tumor rejection along with some DC. The effects of IFN gamma, produced at the tumor site by T and NK lymphocytes, were only required at the malignant cell level and were necessary for tumor eradication.
NK recognition of tumor cells was mediated by the NKG2D-activating receptor and blocking its function in vivo partially interfered with rejection.
Therefore, complete rejection of these mesenchymal tumors requires a concerted set of activities including direct tumor-cell destruction and IFN gamma production that are mediated by both NK and T cells.
CITATION Int J Cancer. 2007 Sep 15;121(6):1282-95