Genetic and antibody-mediated reprogramming of natural killer cell missing-self recognition in vivo.
Natural killer (NK) cells are lymphocytes of the innate immune system able to recognize and kill tumors lacking self-MHC class I molecules. This "missing-self" recognition is mediated by the lack of engagement of MHC class I-specific inhibitory NK cell receptors that include the killer cell Ig-like receptors (KIR) in humans and Ly49 molecules in mice. A promising immunotherapeutic strategy against MHC class I(+) cancer cells is to block NK cell inhibitory receptors using monoclonal antibodies (mAb). However, interactions between MHC class I molecules and their inhibitory receptors are also required for the acquisition of NK cell functional competence, a process referred as to "education." In addition, inhibitory receptors are involved in self-tolerance on educated NK cells. Here, we developed a preclinical mouse model in which all NK cells are educated by a single transgenic inhibitory receptor, human KIR2DL3, through the engagement with its HLA-Cw3 ligand. This approach revealed that NK cells could be reprogrammed to control the development of mouse syngenic tumors in vivo. Moreover, in vivo anti-KIR mAb treatment induced the killing of HLA(+) target cells without breaking self-tolerance. Finally, the long-term infusion of anti-KIR mAb neither abolished NK cell education nor tumor cell recognition. Therefore, these results strongly support the use of inhibitory receptor blockade in cancer patients.
Sola
Caroline
C
Innate-Pharma, 13009 Marseille, France.
André
Pascale
P
Lemmers
Céline
C
Fuseri
Nicolas
N
Bonnafous
Cécile
C
Bléry
Mathieu
M
Wagtmann
Nicolai R
NR
Romagné
François
F
Vivier
Eric
E
Ugolini
Sophie
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002460:Cell Line; D015236:HLA-C Antigens / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D054344:Receptors, KIR2DL3 / Q000276:immunology / Q000502:physiology*; D017634:Self Tolerance
D000911:Antibodies, Monoclonal; D015236:HLA-C Antigens; C038653:HLA-C*03 antigen; D054344:Receptors, KIR2DL3