NKT ligand loaded E6/E7 Antigen expressing B cell & Monocyte based Vaccine effectively controls growth of heterogeneous tumors containing MHC Class I deficient cells by reversal of NK cell anergy

Abstract

Abstract MHC Class I downregulation or deficiency has been reported in advanced tumor microenvironments of clinical cases. Malignant transformation and in vivo selection of highly metastatic cells show MHC Class I loss neoplasm, which contributes to the evasion of tumor from the host immune system. These tumor microenvironments are major impediments for cancer immunotherapy, thereby imposing restriction of cytotoxic T lymphocytes. Besides, it has been reported MHC Class I low states induce NK cell anergy, which interrupt NK cell mediated antitumor immune responses. To overcome these limitations, we designed NKT ligand loaded, E6/E7 Ag expressing b cell & monocyte based vaccine. We found our vaccine elicited NKT, NK cell and Ag specific CTL response, and effectively eradicated solid tumors. We also found a negative correlation between tumor growth and MHC Class I expression level. When the MHC Class I expression level was lowered, the major antitumor effector cell is changed from CTL to NK cells. Thus, we generated a MHC Class I knock out tumor cell line for testing our vaccine effects on MHC Class I deficient situation to mimic actual clinical cases. We established heterogeneous tumor models, which contains various percent of MHC Class I KO tumor cells. The data show our vaccine eliminated heterogeneous tumors, which contains up to 10% MHC Class I KO cells, and effectively eradicated of MHC Class I KO cells via NKT, NK cell. Moreover, our data show this NK anergy in MHC class I KO tumor-bearing mice was reversed by our vaccination via NKT cell producing cytokines. Taken together, our vaccine induced diverse immune responses overcoming immunoresistant tumor microenvironment and is expected to effectively cure advanced tumor patients in clinical trials.