Effect of adenovirus mediated heat shock protein expression and oncolysis in combination with low-dose cyclophosphamide treatment on anti-tumor immune responses

摘要

Heat shock proteins such as gp96 have the ability to chaperone peptides and activate antigen presenting cells. In this study we tested whether adenovirus (Ad)-mediated overexpression of secreted or membrane-associated forms of gp96 in tumor cells would stimulate an anti-tumor immune response. Studies were carried out in C57Bl/6 mice bearing aggressively growing subcutaneous tumors derived from syngeneic TC-1 cells, a cell line that expresses HPV16 E6 and E7 proteins. We found that secreted gp96 can induce protective and therapeutic anti-tumor immune responses. Our data also indicate that the anti tumor effect sgp96 expression appears to be limited by induction of suppressive regulatory T cells (Tregs). TC-1 tumor transplantation increased the number of splenic and tumor infiltrating Tregs. Importantly, treatment of mice with low-dose cyclophosphamide decreased the number Tregs and enhanced the immunostimulatory effect of sgp96 expression. We also tested whether an oncolytic vector (Ad.IR-E1A/TRAIL), that is able to induce tumor cell apoptosis and, potentially, release cryptic tumor epitopes in immunogenic form, can stimulate anti-tumor immune responses. While tumor cells infected ex vivo with Ad.IR-E1A/TRAIL had no anti-tumor effect when used as a vaccine alone, the additional treatment with low-dose cyclophosphamide resulted in elimination of pre-established tumors. This study gives a rationale for testing approaches that suppress Tregs in combination with oncolytic or immunostimulatory vectors.