Cancer immunotherapy via targeted TGF-β signalling blockade in T(H) cells.
Cancer immunotherapy via targeted TGF-β signalling blockade in T(H) cells.
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DOI：
10.1038/s41586-020-2850-3
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发表时间：
2020-11
期刊：
影响因子：
64.8
通讯作者：
Li MO
中科院分区：
文献类型：
--
作者：
Li S;Liu M;Do MH;Chou C;Stamatiades EG;Nixon BG;Shi W;Zhang X;Li P;Gao S;Capistrano KJ;Xu H;Cheung NV;Li MO
恶性肿瘤细胞与宿主组织发生动态的多层次相互作用。旨在直接破坏癌细胞的癌症治疗，包括癌基因靶向治疗和免疫检查点治疗，在一些患者中是有效的；然而，获得性耐药性经常随之而来。另一种治疗策略旨在纠正宿主组织病理，包括促进癌症进展的脉管系统异常；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。在发现转化生长因子-β (TGF-β)抑制T辅助2 （Th2）介导的癌症免疫之后（引用Liu M et al.的论文），这里我们发现阻断CD4+ T细胞中的TGF-β信号重塑肿瘤微环境并抑制癌症进展。在免疫检查点或抗vegf治疗的乳腺癌小鼠模型中，诱导CD4+ T细胞中TGF-β受体II （TGF-β rii）的基因缺失可抑制肿瘤生长。对于药物阻断，我们设计了一个双特异性受体诱饵，通过将TGF-β-中和TGF-β rii细胞外结构域连接到ibalizumab（一种非免疫抑制性CD4抗体）上，将其命名为CD4 TGF-β陷阱（4t -陷阱）。与非靶向TGF-β- trap相比，4T-Trap选择性地抑制肿瘤引流淋巴结中Th细胞TGF-β信号传导，导致肿瘤血管重组和癌细胞死亡，这一过程依赖于Th2细胞因子白介素-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。VEGF抑制增强了饥饿引发的癌细胞死亡，放大了4T-Trap的抗肿瘤作用。因此，靶向TGF-β信号阻断辅助性T细胞引发有效的组织水平癌症防御反应，可以锚定癌症环境导向治疗。
Cancer arises from malignant cancer cells in dynamic multilevel interactions with the host tissue. Cancer therapies aiming to directly destruct cancer cells including oncogene-targeted therapy and immune checkpoint therapy that revives tumor-reactive cytotoxic T lymphocytes are effective in some patients; yet, acquired resistance frequently ensues. An alternative therapeutic strategy aspires to rectify the host tissue pathology including vasculature abnormalities that foster cancer progression; however, neutralization of proangiogenic factors such as vascular endothelial growth factor A (VEGFA) has limited clinical benefits. Following the finding that transforming growth factor-β (TGF-β) suppresses T helper 2 (Th2)-mediated cancer immunity (cite accompanying paper from Liu M et al.), here we show that blocking TGF-β signaling in CD4+ T cells remodels the tumor microenvironment and restrains cancer progression. In a murine model of breast cancer resistant to immune checkpoint or anti-VEGF therapies, inducible genetic deletion of the TGF-β receptor II (TGF-βRII) in CD4+ T cells suppressed tumor growth. For pharmacological blockade, we engineered a bispecific receptor decoy by attaching the TGF-β-neutralizing TGF-βRII extracellular domain to ibalizumab, a non-immunosuppressive CD4 antibody, naming it CD4 TGF-β Trap (4T-Trap). Compared to a non-targeted TGF-β-Trap, 4T-Trap selectively inhibited Th cell TGF-β signaling in tumor-draining lymph nodes, causing tumor vasculature reorganization and cancer cell death, a process dependent on the Th2 cytokine interleukin-4 (IL-4). Notably, the 4T-Trap-induced tumor tissue hypoxia led to increased VEGFA expression. VEGF inhibition enhanced the starvation-triggered cancer cell death and amplified the anti-tumor effect of 4T-Trap. Thus, targeted TGF-β signaling blockade in helper T cells elicits an effective tissue-level cancer defense response that can anchor the cancer environment-directed therapies.
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分子机制和血管生成的临床应用。
影响因子：
64.8
作者：
Carmeliet, Peter;Jain, Rakesh K.
通讯作者：
Jain, Rakesh K.
DOI：
10.1038/nrc2442
发表时间：
2008-08
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
肿瘤相关巨噬细胞的细胞和分子起源。
DOI：
10.1126/science.1252510
发表时间：
2014-05-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Franklin RA;Liao W;Sarkar A;Kim MV;Bivona MR;Liu K;Pamer EG;Li MO
通讯作者：
Li MO
影响因子：
11.4
作者：
KILLEEN, N;SAWADA, S;LITTMAN, DR
通讯作者：
LITTMAN, DR
影响因子：
8.8
作者：
Rigamonti, Nicolo;Kadioglu, Ece;De Palma, Michele
通讯作者：
De Palma, Michele