IL-23阳性未成熟髓系细胞iMCs亚群诱导肾癌免疫逃逸的作用机制及其意义

Immune checkpoint inhibitor, nivolumab, significantly improves survival in patients with advanced renal cancer, and reactivation of anti-tumor immune responses plays an important role in the treatment. Immune escape is the biggest obstacle to re-activating anti-tumor immune responses, leading to some patients being insensitive to nivolumab. The applicant's previous study found that 1. CXCR1 signaling promotes the development of renal cell carcinoma; 2. the immunosuppressive molecule IL-23 plays an important role in the immune escape of renal cell carcinoma, but its effect on immune escape needs to be clear . Further studies have found that renal cancer CXCR1 signaling plays a key role in the regulation of IL-23 secretion by tumor-infiltrating immature myeloid cells. Based on this, the project aims to focus on the key issue of the cellular and molecular mechanisms of renal cancer immune escape, to study the mechanism and functional significance of CXCR1 signaling-activated renal cancer immune escape mediated by recruitment of immature myeloid cells and expression of IL-23, to find the biological markers for predicting the best benefit of immunological checkpoint inhibitors, and to explore the feasibility of reversing the immune escape of renal cancer with CXCR1 as a target, laying the foundation for expanding the benefit of immune checkpoint inhibitors.

免疫检查点抑制剂纳武单抗显著改善晚期肾癌患者生存，重激活抗肿瘤免疫反应在其中发挥重要作用。免疫逃逸是重激活抗肿瘤免疫反应的最大障碍，导致部分患者对纳武单抗不敏感。促癌信号活化介导的微环境重塑是肾癌免疫逃逸的一种重要机制。申请人前期研究发现，1、CXCR1信号促进肾癌发生发展；2、免疫抑制性分子IL-23在肾癌免疫逃逸过程中发挥关键作用，但其中的联系和机制尚不清楚。进一步研究发现，CXCR1活化型肾癌组织中IL-23阳性未成熟髓系细胞iMCs浸润显著增加，提示CXCR1活化型肾癌细胞可能通过招募未成熟髓系细胞浸润并表达IL-23促进免疫逃逸过程。本项目拟围绕肾癌免疫逃逸的细胞和分子机制这一关键科学问题，阐述IL-23阳性未成熟髓系细胞诱导免疫逃逸的机制及其功能意义，进一步寻找纳武单抗的疗效预测标志，并探索以CXCR1为靶点逆转肾癌免疫逃逸的可行性，为扩大纳武单抗获益人群、提高疗效奠定基础。

在本项目资助下，项目负责人围绕肿瘤免疫逃逸形成的机制方向，深入研究肿瘤细胞促癌信号活化促进肿瘤免疫逃逸形成的细胞和分子机制，并取得一系列研究成果。以通讯作者在国际权威期刊Cancer Immunology, Immunotherapy和Oncoimmunology发表SCI论文2篇。研究发现肿瘤细胞促癌信号CXCR1激活通过招募髓系细胞分泌IL-23等分子调控肿瘤微环境中免疫细胞的表型，形成肿瘤免疫逃逸的微环境状态促进肾癌发生发展。促癌信号CXCR1、新型免疫检查点PDPN、Galecintin-9是具有潜力的肿瘤免疫治疗靶点。这些研究结果对于认识肿瘤免疫逃逸形成机制具有重要意义，对建立基于肿瘤免疫逃逸的预后评估和干预治疗模型、开发新一代肿瘤免疫治疗药物奠定理论基础。