The combined actions of NK and T lymphocytes are necessary to reject an EGFP+ mesenchymal tumor through mechanisms dependent on NKG2D and IFN gamma.
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.
Arina
Ainhoa
A
Gene Therapy Unit, Centro de Investigación Médica Aplicada, University of Navarra, Pamplona, Spain.
Murillo
Oihana
O
Hervás-Stubbs
Sandra
S
Azpilikueta
Arantza
A
Dubrot
Juan
J
Tirapu
Iñigo
I
Huarte
Eduardo
E
Alfaro
Carlos
C
Pérez-Gracia
Jose L
JL
González-Aseguinolaza
Gloria
G
Sarobe
Pablo
P
Lasarte
Juan J
JJ
Jamieson
Amanda
A
Prieto
Jesús
J
Raulet
David H
DH
Melero
Ignacio
I
D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D049452:Green Fluorescent Proteins / Q000235:genetics*; D007371:Interferon-gamma / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology*; D008648:Mesoderm / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009374:Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism; D010534:Peritoneal Neoplasms / Q000276:immunology* / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell; D013601:T-Lymphocytes / Q000276:immunology*
C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D007371:Interferon-gamma