Harry Perkins Institute of Medical Research, Centre for Medical Research, The University of Western Australia, Nedlands, Western Australia, Australia.
Centre for Microscopy, Characterization and Analysis, The University of Western Australia, Crawley, Western Australia, Australia.
Nat Immunol. 2017 Nov;18(11):1207-1217. doi: 10.1038/ni.3836. Epub 2017 Sep 11.
The tumor microenvironment confers profound resistance to anti-cancer immunotherapy. By targeting LIGHT, a member of the TNF superfamily of cytokines, to tumor vessels via a vascular targeting peptide (VTP), we developed a reagent with the dual ability to modulate the angiogenic vasculature and to induce tertiary lymphoid structures (TLSs). LIGHT-VTP triggered the influx of endogenous T cells into autochthonous or syngeneic tumors, which are resistant to immunotherapy. LIGHT-VTP in combination with checkpoint inhibition generated a large number of intratumoral effector and memory T cells with ensuing survival benefits, while the addition of anti-tumor vaccination achieved maximal therapeutic efficacy. Thus, the combination treatments stimulated the trafficking of pre-existing endogenous effector T cells as well as their intratumoral activation and were more successful than current immunotherapies, which fail due to tumor-intrinsic resistance mechanisms.
肿瘤微环境赋予了抗肿瘤免疫疗法强大的抵抗力。通过将肿瘤血管靶向肽（VTP）靶向细胞因子 TNF 超家族的 LIGHT，我们开发了一种具有双重能力的试剂，既能调节血管生成血管，又能诱导三级淋巴结构（TLSs）。LIGHT-VTP 触发内源性 T 细胞涌入对免疫疗法有抵抗力的同源或同基因肿瘤。LIGHT-VTP 与检查点抑制联合使用产生了大量的肿瘤内效应器和记忆 T 细胞，从而带来生存获益，而抗肿瘤疫苗的添加则实现了最大的治疗效果。因此，联合治疗刺激了先前存在的内源性效应 T 细胞的迁移及其在肿瘤内的激活，并且比目前的免疫疗法更成功，这些疗法由于肿瘤内在的抵抗机制而失败。
