Generation of mature dendritic cells fully capable of T helper type 1 polarization OK-432 combined with prostaglandin E2

Abstract

Dendritic cell (DC) administration appears to be a very promising approach for the immunotherapy of cancer. The results of clinical studies have suggested that the nature and the magnitude of antitumor immune responses are critically affected by DC functions, including production of T helper type 1 (Th1)-inducing cytokines, activation of T cell subsets and natural killer (NK) cells, and migration from peripheral tissues to the T cell area of the draining lymph nodes. Administration of immature DCs could fail to fully stimulate antigen-specific immune responses and might induce tolerance under some conditions. In this study, we developed a method to obtain fully mature DCs, and we compared in detail the DCs thus obtained with those obtained using a maturation stimulus termed monocyte-derived medium (MCM)-mimic, which is a mixture of recombinant cytokines and prostaglandin E2 (PGE2) mimicking the components of monocyte-conditioned medium. Using DCs derived from monocytes of advanced cancer patients in this study, we found that DCs stimulated with OK-432 alone showed phenotypes similar to those of mature DCs induced using MCM-mimic, though with better secretion of IL-6 and IL-12. However, these DCs were found to have poor migratory capacity associated with the marginal expression of CCR7. When OK-432 was combined with PGE2, the CCR7 expression and migratory capacity of DCs were significantly improved without impairing other immuno-stimulatory functions. These results suggest that stimulation with the combination of OK-432 and PGE2 could be applicable as an alternative to MCM-mimic in clinical trials which require fully matured DCs to induce Th1-type immune responses against tumor cells even in patients with advanced cancer.