Cancer immunotherapy via targeted TGF-β signalling blockade in T(H) cells Journal Article
| Authors: | Li, S.; Liu, M.; Do, M. H.; Chou, C.; Stamatiades, E. G.; Nixon, B. G.; Shi, W.; Zhang, X.; Li, P.; Gao, S.; Capistrano, K. J.; Xu, H.; Cheung, N. K. V.; Li, M. O. |
| Article Title: | Cancer immunotherapy via targeted TGF-β signalling blockade in T(H) cells |
| 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. © 2020, The Author(s), under exclusive licence to Springer Nature Limited. |
| Keywords: | signal transduction; controlled study; protein expression; unclassified drug; gene deletion; cancer growth; nonhuman; antineoplastic agent; animal cell; mouse; animal tissue; cancer immunotherapy; transforming growth factor beta; interleukin 4; animal experiment; animal model; antineoplastic activity; th2 cell; cellular immunity; lymph node; cd4+ t lymphocyte; vasculotropin a; tumor immunity; tumor growth; tumor vascularization; colon adenocarcinoma; tumor hypoxia; extracellular space; tumor microenvironment; molecularly targeted therapy; gamma interferon antibody; cytokine response; female; priority journal; article; cd4 transforming growth factor beta trap; ibalizumab; interleukin 4 antibody |
| Journal Title: | Nature |
| Volume: | 587 |
| Issue: | 7832 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2020-11-05 |
| Start Page: | 121 |
| End Page: | 125 |
| Language: | English |
| DOI: | 10.1038/s41586-020-2850-3 |
| PUBMED: | 33087933 |
| PROVIDER: | scopus |
| PMCID: | PMC8353603 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 December 2020 -- Source: Scopus |
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