435회 Elicitation of Potent Antitumor Therapeutic Activity by both Acti…

435회 

연사:  신 정 임, 강원대학교 의과대학 미생물학교실

제목:  Elicitation of Potent Antitumor Therapeutic Activity by both Active and Adoptive Immunotherapy plus Chemoradiotherapy, or DNA-based therapy in Animal Tumor Models

Abstract 

CD8+ CTL plays a critical role against malignancy in both active and adoptive immunotherapy. Nonetheless, the success of antitumor CD8+ CTL responses might be improved by additional therapeutic modalities. Chemotherapy and radiotherapy, which have a long-standing use in treating malignancy, might alter the phenotypes of tumors, thus improving the overall tumor lytic activity of CTL. Here, in an animal tumor model, we investigated whether chemotherapy or radiation might influence cell surface markers or intracellular gene expression, thus improving antitumor activity in vivo by active and adoptive immunotherapy. In the study, we observed that immunotherapy in combination with either chemotherapy or radiation induced synergistic antitumor lytic activity and thereby dramatically improving tumor cure rates, response rates and recurrence rates. This therapeutic synergy was mediated mainly through increased sensitivity of cytotoxic drug- or radiation-treated tumors to CTL-mediated killing. Furthermore, chemotherapy or radiotherapy increased the expression of cell surface markers (Fas, ICAM-1, MHC class I) without affecting apoptosis-related intracellular gene expression. Despite this finding, the increased tumor cell sensitivity to CTL was found to be mediated mainly via the granzyme/perforin tumor killing pathway but not the Fas/FasL tumor killing pathway, based upon our in vitro and animal studies using Ab blocking, EGTA treatment, adoptive T cell transfer, tumor regression and cytotoxicity assay. These data suggest the potential benefit of chemoradioimmunotherapy in treating cancer patients in clinics. In DNA-based antitumor therapeutic modalities, moreover, genes coding for either a tumor antigen or IL-12 were dramatically effective at controlling established tumors when they were delivered by electroporation (EP). This study also shows that EP is a powerful method to deliver DNA in vivo for antitumor gene therapy.