Editors' ChoiceTumor Immunology

Finding a Needle in a Myeloid Haystack

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Science Translational Medicine  19 Nov 2014:
Vol. 6, Issue 263, pp. 263ec199
DOI: 10.1126/scitranslmed.aaa2062

Immune evasion is a hallmark of cancer, and tumors progress despite the accumulation of immune cells within a tumor and at the margin. By performing a systematic analysis of immune cell components in mouse tumor models and human specimens, Broz and colleagues identified a rare population of dendritic cells capable of enhancing the function of cytotoxic T cells.

Although much is known as to how the immune system functions to prevent disease, the mechanisms by which cytotoxic immune cells are suppressed in tumors are poorly understood. The authors used mouse models of breast cancer and melanoma, as well as human melanoma specimens, to dissect the myeloid lineage, which consists of tumor-associated macrophages (TAMs), monocytes, and dendritic cells that have the capacity to present antigens to T cells and induce cytotoxic T cell function. The authors identified a rare subset of dendritic cells (CD11b+/CD103+) that had a distinct transcription factor signature (IRF8, BATF3, and ZBTB46) as demonstrated by the reduction of this cell population in knockout mice lacking one of these transcription factors. The homing of this dendritic population was independent of colony-stimulating factor 1, which is essential for TAM infiltration, and dependent on granulocyte macrophage colony-stimulating factor (GM-CSF) and the Fms-related tyrosine kinase 3 (Flt3) ligand. These cells had elevated phagocytic capacity compared with TAMs and could stimulate cytotoxic T cells, whereas ablation of this dendritic cell population decreased the efficacy of adoptive cytotoxic T cell therapy in vivo. Bioinformatics analysis revealed that patients with a reduction in these dendritic cells had a much poorer prognosis in multiple cancers, including breast, lung, and head and neck tumors.

Cancer immunotherapy is under intense investigation and offers the potential for therapeutic intervention in a variety of cancer types. The identification of stimulatory dendritic cells may provide an additional approach for immune checkpoint inhibition strategies to generate a favorable environment for the function of cytotoxic T cells.

M. L. Broz et al., Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 10.1016/j.ccell.2014.09.007 (2014). [Abstract]

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