Abstract
Several host factors may affect the spread of cancer to distant organs; however, the intrinsic role of dendritic cells (DC) in controlling metastasis is poorly described. Here, we show in several tumor models that although the growth of primary tumors in Batf3-deficient mice, which lack cross-presenting DCs, was not different from primary tumors in wild-type (WT) control mice, Batf3-deficient mice had increased experimental and spontaneous metastasis and poorer survival. The increased metastasis was independent of CD4+ and CD8+ T lymphocytes, but required NK cells and IFNγ. Chimeric mice in which Batf3-dependent DCs uniformly lacked the capacity to produce IL12 had metastatic burdens similar to the Batf3-deficient mice, suggesting that Batf3+ DCs were the only cell type whose IL12 production was critical for controlling metastasis. We found that IL12-YFP reporter mice, whose lungs were injected with B16F10 melanoma, had increased numbers of IL12-expressing CD103+ DCs with enhanced CD86 expression. Bone-marrow-derived DCs from WT, but not Batf3-deficient, mice activated NK cells to produce IFNγ in an IL12-dependent manner and therapeutic injection of recombinant mouse IL12 decreased metastasis in both WT and Batf3-deficient mice. Analysis of TCGA datasets revealed an association between high expression of BATF3 and IRF8 and improved survival of breast cancer patients; BATF3 expression also significantly correlated with NK-cell receptor genes, IL12, and IFNG Collectively, our findings show that IL12 from CD103+ DCs is critical for NK cell-mediated control of tumor metastasis. Cancer Immunol Res; 5(12); 1098-108. ©2017 AACR.
Highlights
Cancer immunotherapy with immune checkpoint blockade and adoptive T-cell therapies has established the ability of a remobilized immune system to control tumor growth and metastasis and to improve the survival of cancer patients
Consistent with the data obtained from Batf3–/– mice, the lack of Irf8 expression in CD11cþ dendritic cells (DC) (Irf8fl/flCD11ccreþ) made no difference to the growth of primary tumors in mice but significantly increased the number of lung metastases compared with their littermate controls (Fig. 2D and Supplementary Fig. S1C), providing further evidence for an important role of CD8aþCD103þ DC in metastasis control
NK cells stimulated with WT Bone-marrow–derived DC (BMDC) supernatant had higher IFNg expression compared with stimulation with supernatant from Batf3–/– BMDCs, whereas NK cells stimulated with supernatant from IL12p35–/– BMDCs had the lowest IFNg expression (Supplementary Fig. S7). These results suggested that IL12 from CD103þ BMDCs activated NK cells to produce IFNg
Summary
Cancer immunotherapy with immune checkpoint blockade and adoptive T-cell therapies has established the ability of a remobilized immune system to control tumor growth and metastasis and to improve the survival of cancer patients. CDC1 consist of CD8aþ tissue-resident or CD103þ migratory DCs that are specialized for antigen cross-presentation. CDC2, or CD11bþ DCs, directly present antigens via MHC class II. Crosspresenting DCs are of special interest because of their ability to phagocytose cellular proteins, directing them to the MHC class I antigen presentation pathway that will activate CD8þ cytotoxic T cells [5, 6]. Batf3-deficient mice show impaired ability to crossprime cytotoxic T lymphocytes (CTL) against tumor antigens in immunogenic fibrosarcomas and lack virus-specific CTL responses to West Nile infection [7]. Batf deficiency increased resistance to helminth infections by augmenting Th2 type immunity, which was dependent on constitutive expression of IL12 by CD103þ Batf3-dependent DCs, but was independent of Toll-like receptors or microbial signals [11]. The Batf deficiency was dispensable for antifungal immune responses [12]
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