Abstract
Dendritic cells (DC) play a pivotal role in the tumor microenvironment (TME). As the primary antigen-presenting cells in the tumor, DCs modulate anti-tumor responses by regulating the magnitude and duration of infiltrating cytotoxic T lymphocyte responses. Unfortunately, due to the immunosuppressive nature of the TME, as well as the inherent plasticity of DCs, tumor DCs are often dysfunctional, a phenomenon that contributes to immune evasion. Recent progresses in our understanding of tumor DC biology have revealed potential molecular targets that allow us to improve tumor DC immunogenicity and cancer immunotherapy. Here, we review the molecular mechanisms that drive tumor DC dysfunction. We discuss recent advances in our understanding of tumor DC ontogeny, tumor DC subset heterogeneity, and factors in the tumor microenvironment that affect DC recruitment, differentiation, and function. Finally, we describe potential strategies to optimize tumor DC function in the context of cancer therapy.
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Abbreviations
- CDPs:
-
Common DC precursors
- cMoP:
-
Common monocyte progenitors
- CTLs:
-
Cytotoxic T lymphocytes
- DAMP:
-
Danger-associated molecular patterns
- DCs:
-
Dendritic cells
- ER:
-
Endoplasmic reticulum
- FABP4:
-
Fatty acid-binding protein 4
- Flt3L:
-
FMS-like tyrosine kinase 3 ligand
- GM-CSF:
-
Granulocyte/macrophage colony-stimulating factor
- HMGB1:
-
High mobility group box 1
- ICD:
-
Immunogenic cell death
- IDO:
-
Indoleamine 2,3-dioxygenase
- IL-10R:
-
Interleukin-10 receptor
- LC:
-
Langerhans cells
- LPL:
-
Lipoprotein lipase
- MDP:
-
Monocyte/macrophage and DC progenitor
- MDSC:
-
Myeloid-derived suppressor cells
- MHC:
-
Major histocompatibility complex
- NO:
-
Nitric oxide
- pDC:
-
Plasmacytoid dendritic cells
- STAT3:
-
Signal transducer and activator of transcription 3
- TAG:
-
Triacylglycerols
- TAMs:
-
Tumor-associated macrophages
- TF:
-
Transcription factor
- TIM-3:
-
T-cell immunoglobulin and mucin-domain containing-3
- TLR:
-
Toll-like receptor
- TME:
-
Tumor microenvironment
- Tregs:
-
Regulatory T cells
- UPR:
-
Unfolded protein response
- VEGF:
-
Vascular endothelial growth factor
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Acknowledgments
We thank R. Gorczynski for helpful comments and advice. The authors declare no competing financial interests. This work was supported by the Canadian Institutes for Health Research (130438 to M.S.C.), Astellas Canada Inc., and the Toronto General Hospital Transplant Program. M.S.C. is a recipient of CIHR/Astellas Research Chair. M.T. is a recipient of a CIHR training award (121831).
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Tang, M., Diao, J. & Cattral, M.S. Molecular mechanisms involved in dendritic cell dysfunction in cancer. Cell. Mol. Life Sci. 74, 761–776 (2017). https://doi.org/10.1007/s00018-016-2317-8
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DOI: https://doi.org/10.1007/s00018-016-2317-8