Brain Cancer Uses TGF-β to Battle Immune Cells

Medulloblastoma occurs in the hindbrain in or near the cerebellum and is the most common pediatric brain cancer. In about 30% of patients, this cancer results from hyperactivation of hedgehog (HH) signaling. Mice overexpressing a constitutively active form of the HH receptor Smoothened (Smo) in cerebellar granule neuron precursor cells ( Neurod2-SmoA1 mice) develop medulloblastoma. Similar to peripheral cancers, brain cancers contain infiltrating T cells, but the immune response is impaired. Transforming growth factor–β (TGF-β) is an immunosuppressive cytokine secreted by diverse cancers. TGF-β inhibits the differentiation of cytotoxic T cells (T C ) and helper T cells (T H ), which help activate T C cells, and promotes differentiation of regulatory T cells (T reg ), which suppress activation of T C cells. Gate et al . found that human medulloblastoma samples had increased abundance of TGF-β compared to normal brain and to other gliomas and contained T reg cells and T H cells that were positive for TGF-βRII, a subunit of the TGF-β receptor. Analysis of Neurod2-SmoA1 mice revealed that tumors had increased abundance of TGF-β and increased numbers of T reg cells compared to the hindbrain of tumor-free mice with the same genotype. Expressing a dominant-negative (DN) form of TGF-βRII in T cells of Neurod2-SmoA1 mice increased life span, ameliorated behavioral abnormalities, decreased tumor size, and, in the tumors, reduced the number of T reg cells and increased the number and activation of T C cells. T C cells from DN-TGF-βRII , Neurod2-SmoA1 mice isolated from tumors were more effective than those isolated from tumor-free hindbrains at delivering fluorescently tagged exogenous granzyme B (a cytotoxic protease normally found in T C cells) and killing tumor cells from Neurod2-SmoA1 mice in coculture assays. In adoptive cell transfer experiments, T C cells isolated from the spleen of tumor-bearing, but not tumor-free, DN-TGF-βRII , Neurod2-SmoA1 mice infiltrated the tumors of genetically immunocompromised Neurod2-SmoA1 mice. Thus, TGF-β from HH-driven medulloblastomas suppressed T C cell infiltration and differentiation and, thereby, enabled evasion from the immune system. D. Gate, M. Danielpour, J. Rodriguez Jr., G.-B. Kim, R. Levy, S. Bannykh, J. J. Breunig, S. M. Kaech, R. A. Flavell, T. Town, T-cell TGF-β signaling abrogation restricts medulloblastoma progression. Proc. Natl. Acad. Sci. U.S.A. 111 , E3458–E3466 (2014). [Abstract][Full Text]