Transforming Growth beta (TGF-b) signaling in T cells protects from intestinal cancer

Transforming growth factor β (TGF-β) is secreted by cancer cells in many solid tumors and can mediate potent immune-regulatory effects. TGF-β signaling within T lymphocytes impairs their ability to kill cancer cells, but interfering with this activity can provoke fatal T cell-mediated autoimmunity. Large amounts of cancer cell-derived TGFβ tend to be stored in the extracellular matrix in an inactive latent form. Recent work from the Marie lab revealed that this latent pool can be activated by tumor-infiltrating regulatory T cells through their expression of integrin αvβ8. This unique cooperation between cancer cells and Tregs favors tumor immune escape by creating an immunosuppressive micro-environment for effector T cells. On the other hand, unpublished work presented in this seminar reveals an unexpected mechanism by which TGF-β signaling in differentiated Th17 cells instead protects intestinal epithelial cells against transformation. Analysis of loss and gain of TGF-β receptor signaling specifically in already differentiated Th17 cells, combined with in vivo fate mapping and with single cell (sc) RNA-seq, scATAC-seq and scMethylome approaches shows that epigenetic stabilization of the Th17 cell program by TGF-β prevents them from inducing cancer. Taken together, these studies shed important new light on how TGF-β can promote or inhibit tumor formation depending on the context.

Related publications from the Marie lab:  Marie et al Immunity 2006, Havenar-Daughton Blood 2012,  Soudja et al Immunity 2012, Mc Carron et al., Journal of Clinical Investigation 2014, Ruiz et al., Nature communications 2014, Worthington et al., Immunity 2015,  Mc Carron et al., Nature communications 2019, Ferreira et al., Nature Immunology 2020, Lainé et al., Nature communications 2021, Igalouzene et al., J.
ournal of Clinical Investigation 2022