Li et al. showed that TGFβ receptor 2 (TGFBR2) knockout in CD4+ T cells suppressed tumor growth in the PyMT breast cancer model. A bispecific CD4 TGFβ Trap (4T-Trap) using the human TGFBR2 extracellular domain and antigen-binding (Fab) region of ibalizumab (anti-CD4 antibody) showed efficient CD4 binding and potent TGFβ-signaling inhibition. In transgenic mice expressing human CD4, 4T-Trap reduced PyMT tumor growth, inhibited vascular leakage, increased hypoxia and VGFA expression, and triggered cancer cell death in an IL-4-dependent manner. VEGF-Trap enhanced the tumor suppression and survival benefits of 4T-Trap.
Contributed by Shishir Pant
ABSTRACT: 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-β (TGF-β) suppresses T helper 2 (T(H)2)-cell-mediated cancer immunity(9), we show that blocking TGF-β 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-β receptor II (TGFBR2) in CD4(+) T cells suppressed tumour growth. For pharmacological blockade, we engineered a bispecific receptor decoy by attaching the TGF-β-neutralizing TGFBR2 extracellular domain to ibalizumab, a non-immunosuppressive CD4 antibody(12,13), and named it CD4 TGF-β Trap (4T-Trap). Compared with a non-targeted TGF-β-Trap, 4T-Trap selectively inhibited T(H) cell TGF-β 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-β 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.
Author Info: (1) Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Immunology Program, Sloan Kettering Institute, Memorial Sloan Kett
Author Info: (1) Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (3) Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY, USA. (4) Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (5) Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (6) Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY, USA. (7) Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (8) Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (9) Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (10) Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Louis V. Gerstner Jr Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (11) Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (12) Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (13) Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (14) Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. lim@mskcc.org. Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY, USA. lim@mskcc.org. Louis V. Gerstner Jr Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA. lim@mskcc.org.
