Dendritic cells prolong tumor-specific T-cell survival and effector function after interaction with tumor targets.
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.
Mailliard
R B
RB
Department of Surgery, University of Pittsburgh Cancer Institute, Pennsylvania 15261, USA. mailliardrb@msx.upmc.edu
Lotze
M T
MT
D017209:Apoptosis; D018122:B7-1 Antigen / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002455:Cell Division; D002470:Cell Survival; D053938:DNA Fragmentation; D003713:Dendritic Cells / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015789:HLA-A2 Antigen / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D014407:Tumor Cells, Cultured
D018122:B7-1 Antigen; D015789:HLA-A2 Antigen; D007371:Interferon-gamma