Targeting Cytokine Therapy to the Pancreatic Tumor Microenvironment Using PD-L1-Specific VHHs.
Targeting Cytokine Therapy to the Pancreatic Tumor Microenvironment Using PD-L1-Specific VHHs.
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DOI：
10.1158/2326-6066.cir-17-0495
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发表时间：
2018-04
影响因子：
10.1
通讯作者：
Dougan SK
中科院分区：
文献类型：
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作者：
Dougan M;Ingram JR;Jeong HJ;Mosaheb MM;Bruck PT;Ali L;Pishesha N;Blomberg O;Tyler PM;Servos MM;Rashidian M;Nguyen QD;von Andrian UH;Ploegh HL;Dougan SK
基于细胞因子的癌症治疗由于固有的毒性而没有取得广泛的临床成功。胰腺癌的治疗受到肿瘤周围致密基质和免疫抑制肿瘤微环境的限制。为了克服这些障碍，我们开发了抗PD-L1的单域抗体（VHH）与IL 2和IFNγ融合的构建体。以这种方式靶向细胞因子递送将胰腺肿瘤负荷降低了50%，而与不相关的VHH融合的细胞因子或单独阻断PD-L1几乎没有效果。IL 2的靶向递送增加了肿瘤内CD 8 + T细胞的数量，而IFNγ减少了CD 11b+细胞的数量，并使肿瘤内巨噬细胞倾向于显示M1样特征。荧光VHH-IFNγ构建体的成像以及转录谱显示IFNγ靶向肿瘤微环境。许多肿瘤和肿瘤浸润性骨髓细胞表达PD-L1，使它们可能对这种形式的靶向免疫治疗敏感。
Cytokine-based therapies for cancer have not achieved widespread clinical success because of inherent toxicities. Treatment for pancreatic cancer is limited by the dense stroma that surrounds tumors and by an immunosuppressive tumor microenvironment. To overcome these barriers, we developed constructs of single-domain antibodies (VHHs) against PD-L1 fused with IL2 and IFNγ. Targeting cytokine delivery in this manner reduced pancreatic tumor burden by 50%, whereas cytokines fused to an irrelevant VHH, or blockade of PD-L1 alone, showed little effect. Targeted delivery of IL2 increased the number of intratumoral CD8+ T cells, whereas IFNγ reduced the number of CD11b+ cells and skewed intratumoral macrophages towards the display of M1-like characteristics. Imaging of fluorescent VHH-IFNγ constructs, as well as transcriptional profiling, demonstrated targeting of IFNγ to the tumor microenvironment. Many tumors and tumor-infiltrating myeloid cells express PD-L1, rendering them potentially susceptible to this form of targeted immunotherapy.