抑制肿瘤相关成纤维细胞FGFR-MAPK信号通路逆转三阴性乳腺癌T淋巴细胞排除的分子机制研究

免疫检查点阻断剂原发性耐药仍是TNBC临床应用面临的重大难题。既往研究表明，肿瘤相关成纤维细胞抑制T淋巴细胞迁移所导致的免疫排除是免疫检查点阻断剂原发性耐药的重要因素，但具体分子机制亟待探究。我们前期研究证实：FGFR信号通路在免疫排除型TNBC中富集，运用FGFR抑制剂（JNJ-42756493）在体内显著增加T淋巴细胞浸润。进一步研究发现：JNJ-42756493可抑制肿瘤相关成纤维细胞的活化、增殖和迁移功能，并且使CXCL1和VCAM-1这类阻碍T淋巴细胞向瘤内募集的细胞因子分泌减少，同时抑制下游MAPK信号通路。本项目拟利用TNBC临床大样本验证、细胞实验和动物实验阐明JNJ-42756493通过阻滞肿瘤相关成纤维细胞FGFR-MAPK信号通路促进T淋巴细胞募集的分子机制。JNJ-42756493联合ICBs这一新型治疗方案的探究有望为TNBC治疗提供新思路。

The primary drug resistance of immune checkpoint blockers remain a major problem in TNBC clinical application. Previous studies have shown that immune exclusion induced by cancer-associated fibroblasts in suppressing T cells trafficking plays an essential role in primary drug resistance of immune checkpoint blockers, but the specific molecular mechanisms is needed to be uncovered urgently. Our experiments illustrated that the FGFR signaling pathway was enriched in the immune-excluded TNBC, and a FGFR inhibitor (JNJ-42756493) significantly increases T lymphocyte infiltration in vivo. Further studies have found that JNJ-42756493 inhibited the activation, proliferation and migration of cancer-associated fibroblasts and reduced the secretion of CXCL1 and VCAM-1 cytokines those hinder T cells recruitment to intratumor meanwhile blocking the downstream MAPK signaling pathway. Our project intends to clarify the molecular mechanism of JNJ-42756493 in blocking cancer-associated fibroblasts through FGFR-MAPK signaling pathway to promote T lymphocyte recruitment by utilizing TNBC clinical sample validation, in vitro and in vivo experiments. The innovation of JNJ-42756493 and immune checkpoint blockers combined therapy is expected to provide new ideas for TNBC treatment.