基于Vps34介导的T细胞浸润探索温阳健脾法调节肠癌免疫微环境“冷”“热”表型转化的机制研究

转移性结直肠癌(mCRC)严重影响患者生存，真实世界研究中其中位生存仅14月，提高其治疗水平是研究的热点。以PD-1单抗为代表的免疫治疗为多种肿瘤带来长期生存获益，然而其在mCRC中仍无突破。95%的mCRC为“冷肿瘤”，因内核缺乏T细胞对治疗无响应。因此，调节肿瘤“冷/热”表型转化是提升其反应的核心。最新研究发现：Vps34/Stat1/IRF调控肿瘤来源CCL5分泌，诱导T细胞迁移，决定“冷/热”转化的开启。我们前期发现：温阳健脾法可提高肠癌内CD45+及CD8+T细胞数，下调Vps34水平。为此我们推测：温阳健脾法通过Vps34途径调节微环境表型转化，提高肿瘤对PD-1单抗的反应。本课题拟复制Vps34野生及基因敲除肠癌小鼠模型，并进行类器官/PBMC共培养，采用流式细胞术等方法，探索其对Vps34途径的影响，阐明温阳健脾法调节肿瘤“冷/热”转化的机制，为中西医协同治疗肿瘤提供依据。

Metastatic colorectal cancer(mCRC) is a severe disease that shortens the overall survival of patients. A real-world study revealed that the median overall survival of mCRC is only 14 months. Immune checkpoint inhibitors(ICIs) have prolonged the overall survival of various advanced cancers. However, mCRC showed no response to ICIs treatment. 95% of the mCRC are “cold tumor”, they showed no response to ICIs due to barely infiltration of T cells. Thus, firing up the tumor and turning “cold” to “hot” is the key strategy to promote the objective response of mCRC to ICIs. It’s newly reported that Vps34/Stat1/IRF could modulate the expression of CCL5 in tumor cells and then induce the infiltration of T cells. Our preliminary data showed that warming yang and tonifying the spleen can promote the infiltration of CD45 lymphocytes and CD8+T cells as well as inhibit the expression of Vps34. We propose that warming yang and tonifying the spleen could promote the objective response of mCRC via the Vps34 mediated tumor immune microenvironment transition. This project schemed to replicate the Vps34 wild-type and Vps34 gene knock out CT-26 xenograft colon tumor model and establish the colon tumor organoids and PBMC co-culture system to explore the underlying mechanisms of warming yang and tonifying the spleen in modulating tumor immune microenvironment and provide preclinical evidence for the coordination of traditional Chinese medicine and western medicine in cancer treatment.