Genetic and antibody-mediated reprogramming of natural killer cell missing-self recognition in vivo

作者：Sola Caroline; Andre Pascale; Lemmers Celine; Fuseri Nicolas; Bonnafous Cevile; Blery Mathieu; Wagtmann Nicolai R; Romagne Francois; Vivier Eric^*; Ugolini Sophie

来源：Proceedings of the National Academy of Sciences of the United States of America, 2009, 106(31): 12879-12884.

DOI：10.1073/pnas.0901653106

• anti-tumor therapy
• innate immunity
• pre-clinical model
• tolerance

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.

• 出版日期2009-8-4