Transforming growth factor-beta (
TGF-beta), found at the site of most
tumors, has been recognized as one of the mechanisms involved in
tumor immunological escape. To evaluate its impact on adoptive immunotherapy against
cancer, we examined the susceptibility of
tumor-specific T cells to
TGF-beta in the setting of these T cells being prepared for adoptive transfer. Hepatitis B virus (HBV)-specific CD4(+) T cells were ex vivo generated by activating with HBV-transfected dendritic cells and selecting with
antibodies to CD25 activation molecules, and then expanded with
antibodies to CD3/CD28. These T cells expressed higher levels of the
type II TGF-beta receptor than nai;ve T cells and exhibited enhanced apoptosis when exposed to
TGF-beta. The underlying apoptotic pathway was linked to the dissipation of the mitochondrial inner membrane potential and activation of
caspase-9. The absence of
caspase-8 activity in
TGF-beta-treated T cells suggests that the
death receptor system may not be involved in this type of apoptosis.
Interleukin-2 (IL-2), which is concomitantly administered with
tumor-specific T cells in adoptive immunotherapy, was unable to protect HBV-specific CD4(+) T cells from the pro-apoptotic effect of
TGF-beta when added simultaneously with
TGF-beta. Interesting, IL-2-pretreated T cells displayed the
type II TGF-beta receptor at lower levels and were more resistant to
TGF-beta. Together, our findings indicate that the effectiveness of adoptive
cancer immunotherapy may be impaired by
tumor-derived
TGF-beta and appropriate manipulation of exogenous
IL-2 might overcome this hurdle.