Dendritic cells prolong tumor-specific T-cell survival and effector function after interaction with tumor targets.

Abstract

Tumor specific CTLs are susceptible to tumor-mediated activated induced cell death (AICD) after target engagement. The presence of dendritic cells (DCs) at the site of tumors correlates with an improved prognosis in patients with a variety of histological tumor types. We examined whether DCs can modify the survival of tumor specific CTLs during encounter with tumor targets. HLA-A2+ gp100-specific CD8+ CTLs were used as effectors against gp100+, A2+ melanoma FEM-X, and Mel526 (A2-) targets as well as the melanoma target Mel397. Cytolytic assays and [3H]DNA fragmentation (JAM) assays were used to evaluate CTL specificity and tumor-mediated AICD, respectively. A functional assay, ARK (activity of rescued killer cells), was developed to measure cytolytic activity of surviving CTLs after a 12-h coincubation with tumor. In JAM assays, the CTLs proved more susceptible to apoptosis when exposed to the relevant tumors FEM-X and Mel526 than the irrelevant Mel397 (37 and 23% versus 3%; P < .001). The addition of human A2+ monocyte-derived immature DCs significantly (P < 0.001) limited this tumor-induced death of CTLs. In ARK assays, the presence of DCs decreased tumor-mediated suppression of CTLs, with increases in cytolytic function of CTLs reaching up to 2-fold. These findings suggest that DCs may play an important role during the effector phase of the immune response by enhancing the survival and function of CTLs in the tumor microenvironment.