Activation of TGF-β requires release from this latency complex ( 21). During the intracellular processing of this precursor protein, LAP is cleaved but remains associated with the TGF-β dimer forming an inactive latency complex that is sequestered into the extracellular matrix. The three members of the human TGF-β family, TGF-β1,−2, and−3 are synthesized as precursor proteins containing an N-terminal latency-associated peptide (LAP) (~280–300 amino acids) followed by a shorter C-terminal polypeptide (112–114 amino acids) which represents the biologically active mature cytokine ( 19, 20). TGF-β: Expression, Receptors, and Signaling The function and biology of TGF-β as well as of NKG2D will be summarized only briefly as both have extensively been reviewed elsewhere ( 4, 10, 16– 18). In this review, we specifically focus on the TGF-β-mediated impairment of immunorecognition through the NKG2D axis and its implications for tumor immunity and cancer therapies. Hence, evasion from NKG2D-mediated recognition is thought to represent a major mechanism allowing tumors to escape from tumor immunity.
NKG2D ligation by stress-induced MHC class I-like glycoproteins on tumor cells transmits a potent stimulatory signal into cytotoxic lymphocytes and therefore promotes immunosurveillance of malignant cells ( 14, 15). Importantly, there is emerging evidence that TGF-β also impairs immunorecognition of tumor cells by NK cells and cytotoxic T cells through down-regulation of activating immunoreceptors such as NKG2D. In physiological settings, the TGF-β-mediated immune suppression is crucial for the establishment of immune tolerance and prevention of chronic inflammation, e.g., in the gastrointestinal tract ( 4, 8, 9), but in malignant disease TGF-β promotes immune escape, tumor progression and metastasis ( 4, 10– 13). TGF-β also promotes the differentiation of suppressive immune cells subsets ( 5– 7). For example, TGF-β impairs MHC class II expression ( 2, 3), thus potentially impairing priming of CD4 T cells, and suppresses the activity of cytotoxic lymphocytes by inhibiting the differentiation, proliferation, and effector functions of CD8 T cells and NK cells ( 1, 4). Transforming growth factor-β (TGF-β) is a potent suppressor of immune responses affecting many subsets of immune cells in various ways ( 1). Consequently, novel therapies targeting the TGF-β pathway are expected to reinvigorate NKG2D-mediated tumor elimination and thereby to improve the survival of cancer patients. By reducing tumor-associated expression of NKG2DL and blinding cytotoxic lymphocytes through down-regulation of NKG2D, TGF-β is acting upon both sides of the NKG2D axis severely compromising NKG2D-mediated tumor rejection. Here, we review the current knowledge on the impairment of NKG2D-mediated cancer immunity through TGF-β and discuss therapeutic approaches aiming at counteracting this major immune escape pathway. There is mounting evidence that TGF-β, produced by tumor cells and immune cells in the tumor microenvironment, plays a key role in blunting the NKG2D-mediated tumor surveillance. Hence, the NKG2D axis is thought to play a decisive role in cancer immunosurveillance and, obviously, often is compromised in clinically apparent tumors. While NKG2DL are mostly absent from healthy cells, their expression is induced by cellular stress and malignant transformation, and, accordingly, frequently detected on various tumor cells. NKG2D is a homodimeric C-type lectin-like receptor expressed on virtually all human NK cells and cytotoxic T cells, and stimulates their effector functions upon engagement by NKG2D ligands (NKG2DL). Amongst others, TGF-β impairs tumor recognition by cytotoxic lymphocytes via NKG2D. TGF-β also importantly contributes to the formation of an immunosuppressive tumor microenvironment thereby promoting tumor growth. Transforming growth factor-β (TGF-β) suppresses innate and adaptive immune responses via multiple mechanisms.