多价酪氨酸激酶抑制通过肿瘤内源性 IFN-γ 信号限制上皮-间充质转化，促进 T 细胞浸润免疫荒漠型胃癌。
Multivalent tyrosine kinase inhibition promotes T cell recruitment to immune-desert gastric cancers by restricting epithelial-mesenchymal transition via tumour-intrinsic IFN-γ signalling.
机构信息
Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA.
出版信息
Gut. 2023 Nov;72(11):2038-2050. doi: 10.1136/gutjnl-2022-329134. Epub 2023 Jul 4.
OBJECTIVE
Gastric cancer (GC) ranks fifth in incidence and fourth for mortality worldwide. The response to immune checkpoint blockade (ICB) therapy in GC is heterogeneous due to tumour-intrinsic and acquired immunotherapy resistance. We developed an immunophenotype-based subtyping of human GC based on immune cells infiltration to develop a novel treatment option.
DESIGN
A algorithm was developed to reclassify GC into immune inflamed, excluded and desert subtypes. Bioinformatics, human and mouse GC cell lines, syngeneic murine gastric tumour model, and CTLA4 blockade were used to investigate the immunotherapeutic effects by restricting receptor tyrosine kinase (RTK) signalling in immune desert (ICB-resistant) type GC.
RESULTS
Our algorithm restratified subtypes of human GC in public databases and showed that immune desert-type and excluded-type tumours are ICB-resistant compared with immune-inflamed GC. Moreover, epithelial-mesenchymal transition (EMT) signalling was highly enriched in immune desert-type GC, and syngeneic murine tumours exhibiting mesenchymal-like, compared with epithelial-like, properties are T cell-excluded and resistant to CTLA4 blockade. Our analysis further identified a panel of RTKs as potential druggable targets in the immune desert-type GC. Dovitinib, an inhibitor of multiple RTKs, strikingly repressed EMT programming in mesenchymal-like immune desert syngeneic GC models. Dovitinib activated the tumour-intrinsic SNAI1/2-IFN-γ signalling axis and impeded the EMT programme, converting immune desert-type tumours to immune inflamed-type tumours, sensitising these mesenchymal-like 'cold' tumours to CTLA4 blockade.
CONCLUSION
Our findings identified potential druggable targets relevant to patient groups, especially for refractory immune desert-type/ 'cold' GC. Dovitinib, an RTK inhibitor, sensitised desert-type immune-cold GC to CTLA4 blockade by restricting EMT and recruiting T cells.
目的
胃癌（GC）在全球的发病率排名第五，死亡率排名第四。由于肿瘤内在和获得性免疫治疗抵抗，免疫检查点阻断（ICB）治疗在 GC 中的反应存在异质性。我们基于免疫细胞浸润开发了一种基于免疫表型的人类 GC 分型，以开发新的治疗选择。
设计
开发了一种算法将 GC 重新分类为免疫浸润、排除和荒漠亚型。使用生物信息学、人类和小鼠 GC 细胞系、同源小鼠胃肿瘤模型和 CTLA4 阻断来研究通过限制受体酪氨酸激酶（RTK）信号在免疫荒漠（ICB 抵抗）型 GC 中进行免疫治疗的效果。
结果
我们的算法在公共数据库中重新分类了人类 GC 的亚型，并表明与免疫浸润型 GC 相比，免疫荒漠型和排除型肿瘤是 ICB 抵抗的。此外，上皮-间充质转化（EMT）信号在免疫荒漠型 GC 中高度富集，并且表现出间充质样特性而不是上皮样特性的同源小鼠肿瘤是 T 细胞排除的，并且对 CTLA4 阻断有抗性。我们的分析进一步确定了一组 RTK 作为免疫荒漠型 GC 中的潜在可药物靶点。多靶点 RTK 抑制剂多韦替尼显著抑制间充质样免疫荒漠同源 GC 模型中的 EMT 编程。多韦替尼激活肿瘤内在的 SNAI1/2-IFN-γ信号轴，并阻碍 EMT 程序，将免疫荒漠型肿瘤转化为免疫浸润型肿瘤，使这些间充质样“冷”肿瘤对 CTLA4 阻断敏感。
结论
我们的研究结果确定了与患者群体相关的潜在可药物靶点，特别是对于难治性免疫荒漠型/“冷”GC。多韦替尼是一种 RTK 抑制剂，通过限制 EMT 和募集 T 细胞，使荒漠型免疫冷 GC 对 CTLA4 阻断敏感。
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