Abstract
Immunotherapy of cancer utilizes dendritic cells (DCs) for antigen presentation and the induction of tumor-specific immune responses. However, the therapeutic induction of anti-tumor immunity is limited by tumor escape mechanisms. In this study, immortalized dendritic D2SC/1 cells were transduced with a mutated version of the p53 tumor suppressor gene, p53M234I, or p53C132F/E168G, which are overexpressed in MethA fibrosarcoma tumor cells. In addition, D2SC/1 cells were fused with MethA tumor cells to generate a vaccine that potentially expresses a large repertoire of tumor-antigens. Cellular vaccines were transplanted onto Balb/c mice and MethA tumor growth and anti-tumor immune responses were examined in vaccinated animals. D2SC/1–p53M234I and D2SC/1–p53C132F/E168G cells induced strong therapeutic and protective MethA tumor immunity upon transplantation in Balb/c mice. However, in a fraction of immunized mice MethA tumor growth resumed after an extended latency period. Analysis of these tumors indicated loss of p53 expression. Mice, pre-treated with fusion hybrids generated from D2SC/1 and MethA tumor cells, suppressed MethA tumor growth and averted adaptive immune escape. Polyclonal B-cell responses directed against various MethA tumor proteins could be detected in the sera of D2SC/1–MethA inoculated mice. Athymic nude mice and Balb/c mice depleted of CD4+ or CD8+ T-cells were not protected against MethA tumor cell growth after immunization with D2SC/1–MethA hybrids. Our results highlight a potential drawback of cancer immunotherapy by demonstrating that the induction of a specific anti-tumor response favors the acquisition of tumor phenotypes promoting immune evasion. In contrast, the application of DC/tumor cell fusion hybrids prevents adaptive immune escape by a T-cell dependent mechanism and provides a simple strategy for personalized anti-cancer treatment without the need of selectively priming the host immune system.
Highlights
Progress in understanding the molecular basis of cancer etiology and insights into immunological defense mechanisms have led to promising new treatment options in the past decade [1,2,3,4,5]
D2SC/1 cells were nearly as efficient in stimulating T-cell proliferation as primary dendritic cell (DC) isolated from mouse spleen or differentiated from bone-marrow cells (Figure 1B)
Gene transfer of tumor antigen (TA) into DCs predetermines the presentation of the transgene via the major histocompatibility complexes (MHC)-class I pathway and induction of cytolytic antigen-specific target cells [41]
Summary
Progress in understanding the molecular basis of cancer etiology and insights into immunological defense mechanisms have led to promising new treatment options in the past decade [1,2,3,4,5]. The enhancement of the immune system has been validated as a promising therapeutic strategy to elicit tumor-specific responses, to induce durable tumor regression, and to improve survival intervals of patients [6]. Benefits have only been observed in a fraction of patients and tumor-specific immune responses often did not correlate with tumor rejection, stabilization of disease, or overall survival [7]. Considerable efforts are necessary to further improve immunotherapy of cancer and to gain insight into the complex interplay of tumor cells with the immune system [8, 9]
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