Cancer immunotherapy via targeted TGF-β signalling blockade in THcells

4T-Trap, a bispecific molecule designed to recognize CD4 and bind TGF-beta, blocks TGF-beta signalling in T helper cells, causing interleukin-4-dependent vascular reorganization and cancer cell death in a mouse model of breast cancer. Cancer arises from malignant cells that exist in dynamic multilevel interactions with the host tissue. Cancer therapies aiming to directly kill cancer cells, including oncogene-targeted therapy and immune-checkpoint therapy that revives tumour-reactive cytotoxic T lymphocytes, are effective in some patients(1,2), but acquired resistance frequently develops(3,4). An alternative therapeutic strategy aims to rectify the host tissue pathology, including abnormalities in the vasculature that foster cancer progression(5,6); however, neutralization of proangiogenic factors such as vascular endothelial growth factor A (VEGFA) has had limited clinical benefits(7,8). Here, following the finding that transforming growth factor-beta (TGF-beta) suppresses T helper 2 (T(H)2)-cell-mediated cancer immunity(9), we show that blocking TGF-beta signalling in CD4(+)T cells remodels the tumour microenvironment and restrains cancer progression. In a mouse model of breast cancer resistant to immune-checkpoint or anti-VEGF therapies(10,11), inducible genetic deletion of the TGF-beta receptor II (TGFBR2) in CD4(+)T cells suppressed tumour growth. For pharmacological blockade, we engineered a bispecific receptor decoy by attaching the TGF-beta-neutralizing TGFBR2 extracellular domain to ibalizumab, a non-immunosuppressive CD4 antibody(12,13), and named it CD4 TGF-beta Trap (4T-Trap). Compared with a non-targeted TGF-beta-Trap, 4T-Trap selectively inhibited T(H)cell TGF-beta signalling in tumour-draining lymph nodes, causing reorganization of tumour vasculature and cancer cell death, a process dependent on the T(H)2 cytokine interleukin-4 (IL-4). Notably, the 4T-Trap-induced tumour tissue hypoxia led to increased VEGFA expression. VEGF inhibition enhanced the starvation-triggered cancer cell death and amplified the antitumour effect of 4T-Trap. Thus, targeted TGF-beta signalling blockade in helper T cells elicits an effective tissue-level cancer defence response that can provide a basis for therapies directed towards the cancer environment.