Conversely, interventions that provoke a surge in circulating inflammatory monocytes and DC levels lessen the frequency of cutaneous and distant metastases spontaneously developing in MT/ret mice. Of note, MT/ret mice that survive the depletion of inflammatory monocytes exhibit an increased occurrence of both cutaneous and distant metastases. In fact, the absence of these cells from birth leads to the rapid death of a high fraction of MT/ret mice. Instead, inflammatory monocytes and DCs appear to be major actors in this setting.
Based on antibody depletion experiments and on the generation of MT/ret mice lacking T cells, we indeed demonstrated that CD8 + T cells and natural killer (NK) cells are not implicated in the control of tumor spread in the skin. Our study provides new and unexpected insights into the mechanisms involved in the control of metastatic spread by highlighting the antitumor properties of inflammatory monocytes and DCs. Ly6C high monocytes are normally recruited to inflamed tissues where they produce high levels of tumor necrosis factor α (TNFα), interleukin (IL)-1 and reactive oxygen species (ROS), earning them the appellation of “inflammatory monocytes.” Of note, inflammatory monocytes can differentiate into inflammatory dendritic cells (DCs), which preserve the capacity to produce TNFα while becoming able to capture and present antigens. As these cells express high levels of chemokine (C-C motif) receptor 2 (CCR2), their egression from the bone marrow as well as their recruitment into tissues is largely based on the CCL2/CCR2 signaling axis. Inflammatory (Ly6C high) monocytes are innate immune cells that are well known for their anti-infectious properties. 5 This model is thus relevant for the study of antitumor immune responses throughout carcinogenesis and tumor progression, in the presence or in the absence of a concomitant autoimmune disease. Interestingly, one third of mice spontaneously develops vitiligo, which is associated to a decreased occurrence of cutaneous metastases. 4 Thereafter, MT/ret mice develop cutaneous metastases and finally distant metastases. 3 In this model (MT/ret mice, harboring RET under the control of the metallothionein 1 promoter/enhancer), tumor cells disseminate early, but remain dormant for several weeks.
We have recently deciphered the role of inflammatory monocytes and inflammatory dendritic cells (DCs) in the early steps of tumor progression in a model of spontaneous uveal melanoma driven by the RET oncogene. Conversely, the potential antineoplastic activity of monocytic cells has been largely disregarded. In recent years, broad classes of cells derived from the mononuclear phagocytic lineage, including myeloid-derived suppressor cells 1 and tumor-associated macrophages, 2 have been intensively investigated and found to promote the growth and metastatic dissemination of malignant cells.
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