Role of antigen-presenting cells in long-term antitumor response based on tumor-derived apoptotic body vaccination

Cellular therapy prospects for cancer are based on the development of T cel l response, resulting in efficient tumor rejection and long-term protection . We have previously shown that treatment combining injection of interleuki n-2 and tumor-derived apoptotic bodies, but not tumor cell extracts, permit s to reject parental tumor in 40% of rats. We observed the implication of a ntigen-presenting cells (APCs) and tumor-derived apoptotic bodies in the re jection of established peritoneal carcinamatosis. We demonstrated that apop totic bodies could be efficiently phagocytosed by monocytes, triggering the m to an APC phenotype. When using these phagocytosing APCs, derived from pe ritoneal or blood monocytes, the remission Fate reached 80% of rats. Howeve r, due to the lack of specific markers of rat monocyte-derived cells, the p recise role of APCs, dendritic cells and/or macrophages responsible for thi s therapeutic improvement remained to be clarified. In order to elucidate t his question, we developed an in vivo preventive cellular therapy based on tumor-derived apoptotic bodies, where macrophages were either depleted or a ctivated. We report here that in a preventive antitumoral apoptotic body va ccination that allows survival for 40% of treated rats, the antitumor respo nse was characterized by a specific long-term memory (cured rats rejected a second parental tumor cell challenge). Depletion of resident macrophages w ith silica or clodronate liposomes appeared to promote apoptotic body vacci nation efficiency, increasing the treatment to 66% of success, in this case , FAGS analysis showed that peritoneal cells present are essentially immatu re APCs and freshly recruited NK cells. In contrast, the onset of peritonea l inflammation by thioglycollate, inducing massive recruitment and activati on of macrophages, reduced the overall survival, whatever the treatment was . Also, even though the surviving rate was better in silica-treated rats th an control, no longterm protection was elicited. Our data suggest that mass ive inflammation, recruiting numerous activated macrophages, could inhibit tumor antigen presentation by 'professional' APCs having phagocytosed apopt otic bodies, and defavor a specific antitumoral T cell response. Although e ffective responses were developed against parental tumor cells with silica/ apoptotic body treatment, they seemed only partial, limited to primary cyto toxic efficiency. In conclusion, even if macrophages did not appear necessa ry for a primary response to tumor cells, these cells seemed to be implicat ed in the establishment of memory and long-term antitumor response. Copyrig ht (C) 2000 S. Karger AG, Basel.