Naked RNA vaccine controls tumors with down-regulated MHC class I expression through NK cells and perforin-dependent pathways.

One of the major issues facing cancer immunotherapy is that many human cancers down-regulate expression of MHC class I molecules. The understanding of the mechanisms of antitumor effects against tumors with down-regulated MHC class I will facilitate rational design of vaccines and immunotherapeutic strategies to control such tumors. A naked Sindbis RNA replicon vector (SINrep5) encoding the herpes simplex virus type 1 protein VP22 linked to E7 (SINrep5-VP22/E7) generated significant antitumor effects against TC-1 and TC-1 P3(A15), tumors with down-regulated MHC class I expression. Naked SINrep5 RNA without the insert or an E7 vaccine also produced antitumor effects against TC-1 P3(A15) but not TC-1. Mice vaccinated with any of these naked RNA vaccines generated higher percentages of NK cells. In vivo Ab depletion experiments revealed that NK cells were important for the antitumor effects of naked RNA vaccines against TC-1 P3(A15) and that the antitumor effects were perforin-dependent. Poly I:C also increased the percentage of NK cells and generated antitumor effects against the tumors with down-regulated MHC class I. Thus, the SINrep5-VP22/E7 naked RNA vaccine controls MHC class I-positive and MHC class I-down-regulated tumor cells via different mechanisms, and NK cells play an important role in the antitumor effects generated by naked RNA replicon vaccines.