Project 2: Chemotherapy-induced Immunomodulation in Colon Cancer

项目摘要：项目-2(该项目对所有三个合作机构都是相同的) 莫尔豪斯医学院(MSM)、塔斯基吉大学(TU)和阿拉巴马大学 伯明翰奥尼尔综合癌症中心(UAB OCCC)U54合作伙伴关系促进合作 在它们所服务的机构和社区之间开展研究、教育和外联活动。这个关节 TU和UAB OCCC之间的研究项目符合这些目标。不到15%的结直肠癌 (CRC)患者可能受益于目前的免疫疗法。这些难熔状态的机制并不是 完全了解，我们对其中涉及的免疫因素的了解仍然存在巨大的差距 在癌症患者中，尤其是那些接受治疗的患者。我们建议开发联合治疗策略， 调节CRCs的免疫微环境。我们的目标是通过阐明化疗- CRCs的可诱导免疫调节和确定适用于个性化药物的替代靶点。在……里面 初步的体外研究，我们发现了一个主要的炎性和T细胞调节细胞因子的图谱 喜树碱治疗，包括上调SPP1、CXCL8、SOCS1、IL12、CXCL1和CD274/PDL1。 此外，CD44，SPP1的同源受体，是3期复发CRC中上调的基因之一。 SPP1是一个预测预后的生物标志物，低表达与更好的生存相关，并已出现为 预后不良的标志性微环境标志。因此，我们假设拓扑异构酶抑制 治疗既可以诱导免疫调节机制，也可以诱导指导联合治疗的指导性生物标志物 针对个别患者量身定做的治疗方法。我们将使用体外、体外、临床前、有机和PDX模型来 追求这些特定的目标：1)确定患者来源的原发性结肠癌中的免疫调节细胞因子 用临床化疗药物伊立替康处理细胞；2)建立节律伊立替康作为诱导剂 免疫调节和治疗生物标志物；以及3)确定SPP1-CD44和CXCL1-CXCR2的作用 拓扑异构酶抑制治疗中的信号通路。尽管标准护理药物在美国取得了成功 治疗结直肠癌、持久和无复发的结果仍然是不可能实现的。目前，免疫疗法使用 检查点抑制剂也不适用于大多数结直肠癌患者。通过鉴定治疗诱导的免疫 白种人和非裔美国人血统中的景观和诱导细胞因子的功能，结果是 这项研究将阐明化疗后免疫反应的调节机制，并有助于我们开发 结直肠癌患者常规治疗与免疫治疗相结合的策略。

PROJECT SUMMARY: PROJECT-2 (This Project is identical for all three Partnering Institutions) The Morehouse School of Medicine (MSM), Tuskegee University (TU), and the University of Alabama at Birmingham O’Neal Comprehensive Cancer Center (UAB OCCC) U54 partnership fosters collaborative research, educational and outreach activities among the institutions and the communities they serve. This joint research project between TU and UAB OCCC aligns with those objectives. Fewer than 15% of colorectal cancer (CRC) patients may benefit from current immunotherapies. The mechanisms for these refractory states are not completely understood, and an immense gap remains in our knowledge of the immune factors that are involved in CRCs, especially those undergoing therapy. We propose to develop combination therapy strategies that modulate the immune microenvironment in CRCs. We aim to accomplish this by elucidating chemotherapy- inducible immunomodulation in CRCs and identifying alternative targets adaptable to personalized medicine. In preliminary in vitro studies, we found a predominantly inflammatory and T-cell modulating cytokine profile after treatment with camptothecin, including upregulation of SPP1, CXCL8, SOCS1, IL12, CXCL1 and CD274/PDL1. Further, CD44, the cognate receptor for SPP1, was one of the up-regulated genes in stage 3 recurrent CRC. SPP1 is a prognostic biomarker, with low expression being associated with better survival, and has emerged as a signature microenvironment marker of poor prognosis. Therefore, we hypothesize that topoisomerase inhibition therapy induces both immunomodulatory mechanisms and instructive biomarkers that can guide combination therapy tailored to individual patients. We will use in vitro, ex vivo, preclinical, organoid, and PDX models to pursue these Specific Aims: 1) Identify immune modulatory cytokines in patient-derived primary colon cancer cells treated with irinotecan, a clinical chemotherapy agent; 2) Establish metronomic irinotecan as an inducer of immunoregulatory and theranostic biomarkers; and 3) Identify the role of SPP1-CD44 and CXCL1-CXCR2 signaling pathways in topoisomerase inhibition therapy. Despite the success of standard care drugs in the treatment of CRC, durable and relapse-free outcomes are still not achievable. Currently, immunotherapy using checkpoint inhibitors is also unavailable for most CRC patients. By identifying the therapy-induced immune landscape and the functions of induced cytokines in both Caucasian and African American origins, results from this study will elucidate the mechanisms regulating immune response after chemotherapy, and help us to develop a strategy to combine conventional therapy with immunotherapy for CRC patients.