Editors' ChoiceCancer Immunology

Brain Cancer Uses TGF-β to Battle Immune Cells

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Science Signaling  26 Aug 2014:
Vol. 7, Issue 340, pp. ec226
DOI: 10.1126/scisignal.2005828

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 (TC) and helper T cells (TH), which help activate TC cells, and promotes differentiation of regulatory T cells (Treg), which suppress activation of TC 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 Treg cells and TH 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 Treg 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 Treg cells and increased the number and activation of TC cells. TC 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 TC cells) and killing tumor cells from Neurod2-SmoA1 mice in coculture assays. In adoptive cell transfer experiments, TC 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 TC 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]

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