Conventional dendritic cells type I with an enhanced type-I-IFN signaling underpin anti-tumor immune responses in brain metastases
James, F.; Revalova, A.; Fife, C.; Williams, J.; Guglietta, D. V.; Hadi, Z.; Vasconcelos, E. J. R.; Sunderland, A.; Mallett, G.; Ingram, N.; Kaisho, T.; Brackenbury, W. J.; Lawrence, M.; Westhead, D. R.; MacDonald, A. S.; Lorger, M.
Show abstract
Brain metastases (BrM) are associated with poor prognosis. A better understanding of anti-tumor immune responses in the context of immune specialized microenvironment of the brain is required to develop improved therapeutic strategies for this disease. We demonstrate that the conventional dendritic cells type 1 (cDC1) gene signature positively correlates with a prolonged BrM-dependent survival in melanoma and breast cancer patients. Furthermore, intracranial anti-tumor immune responses in preclinical BrM models consistently rely on cDC1s for tumor growth control, BrM-dependent survival and maintenance of the intra-tumoral CD8+ T cell pool, in contrast to variable, cancer type-dependent cDC1 roles in extracranial tumors. This is underpinned by tumor site-specific cDC1 molecular profiles with distinct Toll like receptor repertoires, upregulation of co-stimulatory molecules and IL-12, and enhanced type-I-IFN signaling in intracranial cDC1s, with the latter driving increased cDC1 activation. cDC1s also promote the conversion of progenitor exhausted CD8+ T cells to transient effectors, which is further enhanced by immune checkpoint blockade therapy. These findings pinpoint cDC1s as a major cell population of interest in the development of future immunotherapies for BrM.
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