Abstract
Dendritic cells function as potent regulators of both innate and adaptive immunity to tumors and the regulatory activities of these cells are tightly linked to their maturation and activation status. Despite the critical role played by dendritic cells in the induction of anti-tumor immune responses, the number of dendritic cells that can be isolated from experimental animals is limiting and often precludes in-depth analyses of these cells. To overcome this limitation, dendritic cell lines have been established and have facilitated the experimental study of dendritic cell biology. In this study we compare the dendritic cell lines DC2.4 and JAWSII as in vitro model systems for studying the influence of melanoma-derived factors on dendritic cell maturation and activation. Using flow cytometry and ELISA analyses, we evaluate the expression of costimulatory/MHC class II molecules and proinflammatory cytokines/chemokines by these dendritic cell lines in their resting state and following LPS stimulation in the presence or absence of B16-F1 melanoma-derived factors. Results: We demonstrate that soluble B16-F1-derived factors suppress the LPS-induced upregulation of CD40, CD80, CD86 and MHC class II on both the DC2.4 and JAWSII dendritic cell lines. Interestingly, LPS-induced secretion by DC2.4 cells of the proinflammatory cytokines/chemokines TNF-α, IP-10, MIP-1α, MIP-1β and MCP-1 is also altered by B16-F1-derived factors, whereas JAWSII cell cytokine/chemokine production is affected to a lesser extent by such factors, with only IL-1β and IP-10 production being suppressed. Conclusions/Recommendations: We conclude that melanoma-derived factors can suppress dendritic cell maturation/activation and that the DC2.4 and JAWSII dendritic cell lines are effective in vitro models for future studies that aim to (1) identify factors that influence both the susceptibility and the resistance of dendritic cells to tumor-mediated immunosuppression and (2) investigate the influence of tumor-altered dendritic cells on the quality of anti-tumor T cell responses.
Highlights
Dendritic Cells (DC) are a population of lymphoidand peripheral tissue-resident innate immune cells derived from lymphoid and myeloid bone marrow progenitors
Using the C57Bl/6-derived DC2.4 cell line, we have previously reported that B16-F1 melanoma-derived factors are capable of suppressing the LPS-induced expression of costimulatory molecules and proinflammatory cytokines/chemokines by these cells and that the extent of this suppression correlates with the tumorigenicity of the melanoma variant under study (Hargadon et al, 2012)
B16-F1 is a highly aggressive murine melanoma that grows progressively and metastasizes upon tumor challenge of mice (Fidler, 1975). This tumor has been shown to induce dysfunctional anti-tumor CD8+ T cell responses (Hargadon et al, 2006) that are similar to those often observed in melanoma patients (Mortarini et al, 2003; Anichini et al, 2003; Zippelius et al, 2004) and it has been suggested that this dysfunction may arise from an influence of the tumor on the functional quality of DC
Summary
Dendritic Cells (DC) are a population of lymphoidand peripheral tissue-resident innate immune cells derived from lymphoid and myeloid bone marrow progenitors. Immature DC induce either immunologic ignorance or tolerance to self antigens and antigens derived from sources that do not represent “danger” to the host. Acquisition of antigens in the presence of “danger signals” that stimulate DC maturation and activation induces DC to express costimulatory molecules and proinflammatory cytokines and chemokines that are necessary to activate and recruit T cells and other immune effectors to the source of antigen within the body for elimination from the host (Albert et al, 2001; Filatenkov et al, 2006; Sousa, 2006; Joffre et al, 2009).
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