Editors' ChoiceCancer Immunology

New connections: Reprogramming NK and T cells to attack cancer

Sci. Signal.  08 Mar 2016:
Vol. 9, Issue 418, pp. ec55
DOI: 10.1126/scisignal.aaf6256

Getting the immune system to attack cancer cells is now recognized as an important aspect of cancer therapy strategies. This week’s issue includes an article that describes a molecular target that could be leveraged to reduce the immunosuppressive effect of the cytokine transforming growth factor–β (TGF-β) on T cells. Newman et al. found that T cells with abundant PECAM-1, an adhesion protein, were more sensitive to TGF-β–mediated suppression than were those lacking this adhesion protein. Tumors formed by injecting tumor cells under the skin were smaller in mice lacking PECAM-1 than in wild-type mice. Mechanistically, PECAM-1 formed a complex with the TGF-β receptor and recruited a phosphatase that inhibited signaling by the T cell receptor. In a similar study, but of cells in the innate immune system, Viel et al. found a different mechanism for inhibition of natural killer (NK) cells by TGF-β. In these cells, TGF-β reduced cellular metabolism by inhibiting the kinase mTOR, which reduced NK cell proliferation and cytotoxic activity. T cells are also affected by environmental signals or conditions that affect cellular metabolism. Klysz et al. found that, even in the presence of cytokines that normally promote differentiation into cytotoxic T cells, naïve CD4+ T cells differentiated into Treg cells, which are immunosuppressive, when glutamine was unavailable. In the tumor microenvironment, especially in poorly vascularized regions or in a rapidly growing tumor, glutamine could easily become limited, thus promoting the formation of immunosuppressive Treg cells. However, adding a membrane-permeable form of the glutamine-derived metabolite α-ketoglutarate blocked this immunosuppressive transition. Together, these studies suggest that targeting PECAM-1 may specifically enhance the antitumor activity of T cells without compromising the other necessary functions of TGF-β and that understanding how signals affect immune cell metabolism and the identification of key regulatory metabolites could point to new directions for reprogramming the immune system to eliminate cancer cells.

D. K. Newman, G. Fu, T. Adams, W. Cui, V. Arumugam, T. Bluemn, M. J. Riese, The adhesion molecule PECAM-1 enhances the TGF-β–mediated inhibition of T cell function. Sci. Signal. 9, ra27 (2016). [Abstract]

S. Viel, A. Marçais, F. S.-F. Guimaraes, R. Loftus, J. Rabilloud, M. Grau, S. Degouve, S. Djebali, A. Sanlaville, E. Charrier, J. Bienvenu, J. C. Marie, C. Caux, J. Marvel, L. Town, N. D. Huntington, L. Bartholin, D. Finlay, M. J. Smyth, T. Walzer, TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway. Sci. Signal. 9, ra19 (2016). [Abstract]

D. Klysz, X. Tai, P. A. Robert, M. Craveiro, G. Cretenet, L. Oburoglu, C. Mongellaz, S. Floess, V. Fritz, M. I. Matias, C. Yong, N. Surh, J. C. Marie, J. Huehn, V. Zimmermann, S. Kinet, V. Dardalhon, N. Taylor, Glutamine-dependent α-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation. Sci. Signal. 8, ra97 (2015). [Abstract]