Abstract
Transforming growth factor (TGF)-β is a central immunosuppressive cytokine within tumor microenvironment inhibiting the expansion and function of major cellular components of adaptive and innate immune system. Among them, compelling evidence has demonstrated that TGF-β is a key regulator of natural killer (NK) cells, innate lymphoid cells (ILCs) with a critical role in immunosurveillance against different kinds of cancer cells. A TGF-β rich tumor microenvironment blocks NK cell activity at multiple levels. This immunosuppressive factor exerts direct regulatory effects on NK cells including inhibition of cytokine production, alteration of activating/inhibitory receptor expression, and promotion of the conversion into non cytotoxic group I ILC (ILC1). Concomitantly, TGF-β can render tumor cells less susceptible to NK cell-mediated recognition and lysis. Indeed, accumulating evidence suggest that changes in levels of NKG2D ligands, mainly MICA, as well as an increase of immune checkpoint inhibitors (e.g., PD-L1) and other inhibitory ligands on cancer cells significantly contribute to TGF-β-mediated suppression of NK cell activity. Here, we will take into consideration two major mechanisms underlying the negative regulation of ILC function by TGF-β in cancer. First, we will address how TGF-β impacts the balance of signals governing NK cell activity. Second, we will review recent advances on the role of this cytokine in driving ILC plasticity in cancer. Finally, we will discuss how the development of therapeutic approaches blocking TGF-β may reverse the suppression of host immune surveillance and improve anti-tumor NK cell response in the clinic.
Highlights
Transforming growth factor (TGF)-β is a potent immunosuppressive cytokine playing a key role in the regulation of cancer immunosurveillance
We focus on two major mechanisms whereby TGF-β strongly contributes to functional impairment of these immune effectors in tumor context: (1) regulation of natural killer (NK) cell activating/inhibitory signals; (2) guide of innate lymphoid cells (ILCs) plasticity
Despite the large amount of experimental in vitro and in vivo data concerning the wide spectrum of effects mediated by TGF-β in the tumor microenvironment, and in the regulation of the anticancer response mediated by various populations of effector lymphocytes, the development of therapeutic strategies able to inhibit TGF-β-mediated pathways did not proceed at the same speed as observed for other immuno-therapeutic approaches
Summary
Transforming growth factor (TGF)-β is a potent immunosuppressive cytokine playing a key role in the regulation of cancer immunosurveillance. Mhoer cbeellsstincrhesaproancsteetroidzieffdereNntKtypceeslol-facceltliuvlaartsitnregssrteypciecpaltor playing a prominent role inIt thuasmboeerniwmidmeluy nreopsourtredvethilaltatnumceori-sdeNrivKedGT2GDF,-βwchouolsdebelitghaensodlusb(lMe faIcCtoAr ,reMspIoCnsBib,leULBP1-6) are frequently infdour tcheeddeocnreatsheed sNuKrGfa2DceexopfretsusmionoorncNelKlsceilnlsraensdp/oornCsDe8+toTdceilfflseorbesnertvteydpinesseovefrcaletlylupelsarofstress typical tumor patients [30,37,38,39,40,41,42] In some of these studies, increased plasma levels of TGF-β inversely of a neoplasticcortrrelaantesdfowritmh tahteioexnpr[e3ss5io,3n6o]f.NKG2D, as well as of other activating receptors, such as DNAM-1, It has beNeKnp3w0,iadnedlyNKrepp46o, rotnepdertiphhaetratlubmlooodr-NdKecreilvlse[d30T,37G].FM-βorecooveurl,dexbveivtoheexpseorilmuebnltsesfhaocwteodr responsible for the decretahastedincNubKatiGon2Dof peaxtpiernet-sdseiroivnedoNnKNorKCcDe8l+lsT acneldls/owrithCpDla8sm+aTancde/ollrsceorbebsreorspvienadl filnuidseveral types of tumor patients [30,37,38,39,40,41,42]. Tumor-derived TGF-β severely affects the NKG2D-dependent anti-tumor immune response, by acting on both tumor and effector cells It inhibits the expression of the ligands on one side, while on the other, it potentiates receptor down-regulation on various effector cells, NK cells
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