Niu Boning, Tian Tianyi, Wang Lu, Tian Yinmei, Tian Tian, Guo Yuanyuan, Zhou Hu, Zhang Zhiping
Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China.
Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Acta Pharm Sin B. 2024 Aug;14(8):3711-3729. doi: 10.1016/j.apsb.2024.05.009. Epub 2024 May 11.
SMAD4 deficiency in colorectal cancer (CRC) is highly correlated with liver metastasis and high mortality, yet there are few effective precision therapies available. Here, we show that CCR1-granulocytic myeloid-derived suppressor cells (G-MDSCs) are highly infiltrated in SMAD4-deficient CRC CCL15/CCR1 and CCL9/CCR1 axis in clinical specimens and mouse models, respectively. The excessive TGF-, secreted by tumor-infiltrated CCR1-G-MDSCs, suppresses the immune response of cytotoxic T lymphocytes (CTLs), thus facilitating metastasis. Hereby, we develop engineered nanovesicles displaying CCR1 and TGFBR2 molecules (C/T-NVs) to chemotactically target the tumor driven by CCL9/CCR1 axis and trap TGF- through TGF--TGFBR2 specific binding. Chemotactic C/T-NVs counteract CCR1-G-MDSC infiltration through competitive responding CCL9/CCR1 axis. C/T-NVs-induced intratumoral TGF- exhaustion alleviates the TGF--suppressed immune response of CTLs. Collectively, C/T-NVs attenuate liver metastasis of SMAD4-deficient CRC. In further exploration, high expression of programmed cell death ligand-1 (PD-L1) is observed in clinical specimens of SMAD4-deficient CRC. Combining C/T-NVs with anti-PD-L1 antibody (aPD-L1) induces tertiary lymphoid structure formation with sustained activation of CTLs, CXCL13-CD4 T, CXCR5-CD20 B cells, and enhanced secretion of cytotoxic cytokine interleukin-21 and IFN- around tumors, thus eradicating metastatic foci. Our strategy elicits pleiotropic antimetastatic immunity, paving the way for nanovesicle-mediated precision immunotherapy in SMAD4-deficient CRC.
结直肠癌（CRC）中SMAD4缺陷与肝转移及高死亡率高度相关，但目前几乎没有有效的精准治疗方法。在此，我们发现趋化因子受体1（CCR1）⁺粒细胞来源的髓系抑制细胞（G-MDSCs）在SMAD4缺陷型CRC中高度浸润，分别通过临床标本和小鼠模型中的CCL15/CCR1和CCL9/CCR1轴发挥作用。肿瘤浸润的CCR1⁺G-MDSCs分泌的过量转化生长因子-β（TGF-β）抑制细胞毒性T淋巴细胞（CTLs）的免疫反应，从而促进转移。因此，我们开发了展示CCR1和TGFBR2分子的工程化纳米囊泡（C/T-NVs），以趋化方式靶向由CCL9/CCR1轴驱动的肿瘤，并通过TGF-β-TGFBR2特异性结合捕获TGF-β。趋化性C/T-NVs通过竞争性响应CCL9/CCR1轴来对抗CCR1⁺G-MDSC浸润。C/T-NVs诱导的肿瘤内TGF-β耗竭减轻了TGF-β对CTLs免疫反应的抑制。总体而言，C/T-NVs减轻了SMAD4缺陷型CRC的肝转移。在进一步探索中，在SMAD4缺陷型CRC的临床标本中观察到程序性细胞死亡配体1（PD-L1）的高表达。将C/T-NVs与抗PD-L1抗体（aPD-L1）联合使用可诱导三级淋巴结构形成，持续激活CTLs、CXCL13⁺CD4⁺ T细胞、CXCR5⁺CD20⁺ B细胞，并增强肿瘤周围细胞毒性细胞因子白细胞介素-21和干扰素-γ的分泌，从而根除转移灶。我们的策略引发了多效性抗转移免疫，为SMAD4缺陷型CRC的纳米囊泡介导的精准免疫治疗铺平了道路。
