Li Shun, Liu Ming, Do Mytrang H, Chou Chun, Stamatiades Efstathios G, Nixon Briana G, Shi Wei, Zhang Xian, Li Peng, Gao Shengyu, Capistrano Kristelle J, Xu Hong, Cheung Nai-Kong V, Li Ming O
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.
Nature. 2020 Nov;587(7832):121-125. doi: 10.1038/s41586-020-2850-3. Epub 2020 Oct 21.
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, but acquired resistance frequently develops. An alternative therapeutic strategy aims to rectify the host tissue pathology, including abnormalities in the vasculature that foster cancer progression; however, neutralization of proangiogenic factors such as vascular endothelial growth factor A (VEGFA) has had limited clinical benefits. Here, following the finding that transforming growth factor-β (TGF-β) suppresses T helper 2 (T2)-cell-mediated cancer immunity, 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, 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, and named it CD4 TGF-β Trap (4T-Trap). Compared with a non-targeted TGF-β-Trap, 4T-Trap selectively inhibited T cell TGF-β signalling in tumour-draining lymph nodes, causing reorganization of tumour vasculature and cancer cell death, a process dependent on the T2 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.
癌症源于与宿主组织存在动态多级相互作用的恶性细胞。旨在直接杀死癌细胞的癌症治疗方法，包括靶向癌基因治疗和恢复肿瘤反应性细胞毒性T淋巴细胞的免疫检查点治疗，在一些患者中有效，但常常会产生获得性耐药。另一种治疗策略旨在纠正宿主组织病理学异常，包括促进癌症进展的血管系统异常；然而，中和血管内皮生长因子A（VEGFA）等促血管生成因子的临床益处有限。在此，在发现转化生长因子-β（TGF-β）抑制辅助性T细胞2（T2）介导的癌症免疫后，我们表明阻断CD4 T细胞中的TGF-β信号可重塑肿瘤微环境并抑制癌症进展。在对免疫检查点或抗VEGF治疗耐药的乳腺癌小鼠模型中，CD4 T细胞中TGF-β受体II（TGFBR2）的诱导性基因缺失抑制了肿瘤生长。对于药物阻断，我们通过将中和TGF-β的TGFBR2细胞外结构域与非免疫抑制性CD4抗体ibalizumab连接，构建了一种双特异性受体诱饵，并将其命名为CD4 TGF-β Trap（4T-Trap）。与非靶向TGF-β Trap相比，4T-Trap选择性抑制肿瘤引流淋巴结中的T细胞TGF-β信号，导致肿瘤血管系统重组和癌细胞死亡，这一过程依赖于T2细胞因子白细胞介素-4（IL-4）。值得注意的是，4T-Trap诱导的肿瘤组织缺氧导致VEGFA表达增加。抑制VEGF增强了饥饿引发的癌细胞死亡，并放大了4T-Trap的抗肿瘤作用。因此，辅助性T细胞中靶向TGF-β信号阻断引发了有效的组织水平癌症防御反应，可为针对癌症微环境的治疗提供基础。
