One way in which tumour cells avoid the host tumour-specific T-cell response is by producing, or inducing host cells to produce, transforming growth factor-β (TGFβ). TGFβ has a broad range of immunosuppressive effects, but the specific mechanism by which it inhibits T-cell-mediated clearance of tumours is not known. Now, in a report published in Cancer Cell, it is shown that TGFβ inhibits the expression of effectors of cytotoxic T-lymphocyte (CTL)-mediated cytotoxicity.

Although TGFβ can inhibit the growth of tumour cells, as tumours progress they often become resistant to these growth-inhibitory effects, enabling the tumour to take advantage of the immunosuppressive properties of this cytokine. The importance of this was shown by the authors, as they found that (consistent with previous studies), in a mouse tumour model, systemic neutralization of TGFβ in vivo results in tumour clearance. Tumour clearance was associated with an increase in CD8+ T-cell-mediated tumour-cell-specific cytotoxicity. Consistent with this, the gene-expression profiles of T cells activated in vitro, in the presence or absence of TGFβ, showed that the genes encoding perforin, granzyme A, granzyme B, interferon-γ (IFNγ) and CD95 ligand (CD95L, also known as FASL) — which are the effectors of CTL-mediated cytotoxicity — were downregulated in the presence of TGFβ. Further analysis showed that the intracellular concentration of each of these proteins was also decreased after in vitro activation of CD8+ T cells in the presence of TGFβ, as was the ability of the CTLs to mediate target-cell lysis. Most importantly, in the mouse tumour model, in which systemic neutralization of TGFβ in vivo results in tumour clearance, tumour-specific CD8+ T cells were shown to recover expression of perforin, granzyme A, granzyme B and IFNγ, but not CD95L, if TGFβ was neutralized in vivo.

This study indicates that TGFβ not only inhibits the clonal expansion of tumour-specific CD8+ T cells, but also suppresses the ability of these cells to mediate cytotoxicity. These data led the authors to suggest that further understanding of the mechanisms by which TGFβ mediates these effects might provide new impetus to the development of therapies that inhibit TGFβ, because such therapies would not only target the immunosuppressive effects of TGFβ, but also target the pro-metastatic effects of this cytokine on tumour cells.