胃肠道间质瘤（GIST）含有多种免疫细胞群，但迄今为止，患者的免疫治疗效果令人失望。在这里，我们建立了局部和播散性胃肠道间质瘤的脐带血人源化小鼠模型，以探索肿瘤环境的重塑以改善免疫治疗。具体来说，我们评估了癌症血管靶向肽 (VTP) 与小鼠和患者 GIST 血管生成血管结合并将 TNF 超家族成员 LIGHT (TNFS14) 递送到肿瘤中的能力。 LIGHT-VTP 治疗人源化小鼠 GIST 改善血管功能和肿瘤氧合，这与肿瘤内人类效应 T 细胞的总体增加相关。伴随着光介导的血管重塑，我们观察到瘤内高内皮微静脉（HEV）和三级淋巴结构（TLS），这类似于 GIST 患者中发现的自发 TLS。因此，通过克服免疫缺陷异种移植模型的局限性，我们证明了血管靶向和免疫启动在人类胃肠道间质瘤中的治疗可行性。由于 TLS 与患者预后和改善对免疫检查点抑制的反应呈正相关，因此 GIST 中的血管 LIGHT 靶向是一种改善免疫治疗结果的高度可转化的方法。© 2024 作者。经泰勒许可出版

Gastrointestinal stromal tumors (GISTs) harbor diverse immune cell populations but so far immunotherapy in patients has been disappointing. Here, we established cord blood humanized mouse models of localized and disseminated GIST to explore the remodeling of the tumor environment for improved immunotherapy. Specifically, we assessed the ability of a cancer vascular targeting peptide (VTP) to bind to mouse and patient GIST angiogenic blood vessels and deliver the TNF superfamily member LIGHT (TNFS14) into tumors. LIGHT-VTP treatment of GIST in humanized mice improved vascular function and tumor oxygenation, which correlated with an overall increase in intratumoral human effector T cells. Concomitant with LIGHT-mediated vascular remodeling, we observed intratumoral high endothelial venules (HEVs) and tertiary lymphoid structures (TLS), which resemble spontaneous TLS found in GIST patients. Thus, by overcoming the limitations of immunodeficient xenograft models, we demonstrate the therapeutic feasibility of vascular targeting and immune priming in human GIST. Since TLS positively correlate with patient prognosis and improved response to immune checkpoint inhibition, vascular LIGHT targeting in GIST is a highly translatable approach to improve immunotherapeutic outcomes.© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.