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Tumor's other immune targets: dendritic cells
C Esche1, A Lokshin, G V Shurin
1Biologic Therapeutics Program, University of Pittsburgh Cancer Institute, Pennsylvania 15213, USA.
Abstract:
The induction of apoptosis in T cells is one of several mechanisms by which tumors escape immune recognition. We have investigated whether tumors induce apoptosis in dendritic cells (DC) by co-culture of murine or human DC with different tumor cell lines for 4-48 h. Analysis of DC morphological features, JAM assay, TUNEL, caspase-3-like and transglutaminase activity, Annexin V binding, and DNA fragmentation assays revealed a time- and dose-dependent induction of apoptosis in DC by tumor-derived factors. This finding is both effector and target specific. The mechanism of tumor-induced DC apoptosis involved regulation of Bcl-2 and Bax expression. Double staining of both murine and human tumor tissues confirmed that tumor-associated DC undergo apoptotic death in vivo. DC isolated from tumor tissue showed significantly higher levels of apoptosis as determined by TUNEL assay when compared with DC isolated from spleen. These findings demonstrate that tumors induce apoptosis in DC and suggest a new mechanism of tumor escape from immune recognition. DC protection from apoptosis will lead to improvement of DC-based immunotherapies for cancer and other immune diseases.
Insights
Tumors induce apoptosis in dendritic cells (DC) via tumor-derived factors, representing a novel immune evasion strategy. Protecting these crucial immune cells from tumor-induced death could enhance cancer immunotherapies.
Area of Science:
- Immunology
- Cancer Biology
- Cell Death
Background:
- Tumors evade immune recognition partly through T cell apoptosis.
- Dendritic cells (DCs) are critical for initiating anti-tumor immune responses.
- Understanding DC apoptosis mechanisms is key to overcoming tumor immune evasion.
Purpose of the Study:
- To investigate if tumors induce apoptosis in dendritic cells (DCs).
- To elucidate the mechanisms and in vivo relevance of tumor-induced DC apoptosis.
- To explore the therapeutic implications of protecting DCs from apoptosis.
Main Methods:
- Co-culture of murine/human DCs with tumor cell lines.
- Assessment of DC apoptosis using morphological analysis, JAM assay, TUNEL, Annexin V binding, and DNA fragmentation.
- Analysis of Bcl-2 and Bax expression.
- In vivo confirmation via double staining of tumor tissues and TUNEL assay on isolated DCs.
Main Results:
- Tumor-derived factors induce apoptosis in DCs in a time- and dose-dependent manner.
- Tumor-induced DC apoptosis involves regulation of Bcl-2 and Bax expression.
- DCs within tumor tissues exhibit significantly higher apoptosis rates in vivo compared to splenic DCs.
Conclusions:
- Tumors actively induce apoptosis in dendritic cells as a mechanism of immune evasion.
- This tumor-induced DC apoptosis occurs in vivo and is mediated by specific molecular pathways.
- Strategies to protect DCs from apoptosis may improve DC-based cancer immunotherapies.