Cancer immunotherapy via targeted TGF-β signalling blockade in TH cells

Shun Li, Ming Liu, Mytrang H. Do, Chun Chou, Efstathios G. Stamatiades, Briana G. Nixon, Wei Shi, Xian Zhang, Peng Li, Shengyu Gao, Kristelle J. Capistrano, Hong Xu, Nai-Kong V. Cheung and Ming O. Li ()
Additional contact information
Shun Li: Memorial Sloan Kettering Cancer Center
Ming Liu: Memorial Sloan Kettering Cancer Center
Mytrang H. Do: Memorial Sloan Kettering Cancer Center
Chun Chou: Memorial Sloan Kettering Cancer Center
Efstathios G. Stamatiades: Memorial Sloan Kettering Cancer Center
Briana G. Nixon: Memorial Sloan Kettering Cancer Center
Wei Shi: Memorial Sloan Kettering Cancer Center
Xian Zhang: Memorial Sloan Kettering Cancer Center
Peng Li: Memorial Sloan Kettering Cancer Center
Shengyu Gao: Memorial Sloan Kettering Cancer Center
Kristelle J. Capistrano: Memorial Sloan Kettering Cancer Center
Hong Xu: Memorial Sloan Kettering Cancer Center
Nai-Kong V. Cheung: Memorial Sloan Kettering Cancer Center
Ming O. Li: Memorial Sloan Kettering Cancer Center

Nature, 2020, vol. 587, issue 7832, 121-125

Abstract: 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 patients1,2, but acquired resistance frequently develops3,4. An alternative therapeutic strategy aims to rectify the host tissue pathology, including abnormalities in the vasculature that foster cancer progression5,6; however, neutralization of proangiogenic factors such as vascular endothelial growth factor A (VEGFA) has had limited clinical benefits7,8. Here, following the finding that transforming growth factor-β (TGF-β) suppresses T helper 2 (TH2)-cell-mediated cancer immunity9, 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 therapies10,11, 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 antibody12,13, and named it CD4 TGF-β Trap (4T-Trap). Compared with a non-targeted TGF-β-Trap, 4T-Trap selectively inhibited TH cell TGF-β signalling in tumour-draining lymph nodes, causing reorganization of tumour vasculature and cancer cell death, a process dependent on the TH2 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.

Date: 2020
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-020-2850-3 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:587:y:2020:i:7832:d:10.1038_s41586-020-2850-3

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-020-2850-3

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().