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Tumor-derived lactic acid modulates dendritic cell activation and antigen expression
Eva Gottfried1, Leoni A Kunz-Schughart, Stephanie Ebner
1Department of Hematology and Oncology, Institute of Pathology, University of Regensburg, Franz-Josef Strauss Allee 11, 93042 Regensburg, Germany.
Blood
|November 10, 2005
Summary
Tumor cells alter dendritic cell (DC) differentiation, creating tumor-associated dendritic cells (TADCs). Tumor-derived lactic acid, particularly from melanoma and prostate cancers, significantly drives this TADC phenotype, contributing to tumor immune evasion.
Area of Science:
- Immunology
- Cancer Biology
- Cellular Microenvironment
Background:
- The tumor microenvironment significantly impacts immune cell function, including dendritic cell (DC) differentiation.
- Dendritic cells are crucial for initiating anti-tumor immune responses.
- Understanding how tumors modulate DCs is key to developing effective cancer therapies.
Purpose of the Study:
- To investigate DC differentiation within a 3D tumor model.
- To elucidate novel mechanisms by which the tumor environment modulates DC phenotype.
- To identify specific tumor-derived factors responsible for DC modulation.
Main Methods:
- Monocytes were cultured within multicellular tumor spheroids (MCTSs) derived from various cancer cell lines.
- Analysis of antigen expression and cytokine secretion (e.g., IL-12) on differentiated DCs.
- Investigation of conditioned media and specific cytokines (M-CSF, IL-6) and metabolites (lactic acid) effects on DC differentiation.
- In vitro experiments involving the addition or blocking of lactic acid during DC differentiation.
Main Results:
- Monocytes differentiated into tumor-associated dendritic cells (TADCs) within MCTSs, exhibiting altered antigen expression and reduced IL-12 secretion.
- Tumor cell line-dependent factors influenced TADC phenotype; urothelial carcinoma MCTSs produced M-CSF and IL-6, while melanoma and prostate carcinoma MCTSs produced high lactic acid.
- Lactic acid addition in vitro mimicked the TADC phenotype observed in melanoma and prostate cancer models.
- Blocking lactic acid production reversed the TADC phenotype in melanoma MCTS cocultures.
Conclusions:
- Tumor-derived lactic acid is a critical factor modulating DC phenotype within the tumor microenvironment.
- This lactic acid-induced modulation of DCs contributes to tumor immune evasion.
- Targeting lactic acid metabolism could be a potential strategy to enhance anti-tumor immunity.