암 환경에서 IL-21에 의한 자연 살해 세포의 기능 저하 회복에 관한 연구

Abstract

During cancer immunoediting, tumor cells with spontaneous loss of Major Histocompatibility Complex (MHC) class I expression tend to gradually increase in the tumor microenvironment by preferentially escaping from immune surveillance of cytotoxic T cells even though MHC class I-deficient tumors have been historically considered to be susceptible to NK cell-dependent cytotoxicity. Recent studies demonstrated that most NK cells found in the tumor microenvironment of advanced cancers are defective, releasing the malignant MHC class I-deficient tumors from NK cell-dependent immune control. Here, I showed that an NKT cell-ligand loaded tumor-antigen expressing APC (Antigen Presenting Cell)-based vaccine effectively eradicated these advanced tumors that are not curable with a single immunotherapy. In this process, I found that the co-expression of Tim-3 and PD-1 marks functionally exhausted NK cells in advanced tumors and that MHC class I downregulation in tumors was closely associated with the induction of NK cell exhaustion in tumor-bearing mice as well as in cancer patients. Furthermore, the recovery of NK cell function by IL-21 was critical for the anti-tumor effect of the vaccine against these advanced tumors. These results reveal the process involved in the induction of NK-cell dysfunction in advanced cancers and provide a guidance for the development of strategies for cancer immunotherapy.