Project 2: Chemotherapy-induced Immunomodulation in Colon Cancer

项目概要：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）和亚拉巴马大学， 伯明翰奥尼尔综合癌症中心（UAB OCCC）U 54合作伙伴关系促进合作 在各机构及其服务的社区中开展研究、教育和外联活动。这一联合 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。这些不应状态的机制不是 完全理解，我们对所涉及的免疫因素的知识仍然存在巨大的差距 在CRCs中，尤其是那些正在接受治疗的患者。我们建议开发联合治疗策略， 调节CRC中的免疫微环境。我们的目标是通过阐明化疗- CRCs中的诱导性免疫调节和识别适应于个性化药物的替代靶点。在 初步的体外研究中，我们发现了一个主要的炎症和T细胞调节细胞因子谱后， 用喜树碱治疗，包括SPP 1、CXCL 8、SOCS 1、IL 12、CXCL 1和CD 274/PDL 1的上调。 此外，SPP 1的同源受体CD 44是3期复发性CRC中上调的基因之一。 SPP 1是一种预后生物标志物，低表达与更好的生存相关，并且已经出现， 这是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 治疗诱导免疫调节机制和可指导组合的指导性生物标志物 为个别患者量身定制的治疗。我们将使用体外、离体、临床前、类器官和PDX模型， 我们的目标是：1）鉴定原发性结肠癌患者中的免疫调节细胞因子 用伊立替康（一种临床化疗剂）处理的细胞; 2）建立节拍式伊立替康作为 免疫调节和治疗诊断生物标志物;和3）鉴定SPP 1-CD 44和CXCL 1-CXCR 2的作用 拓扑异构酶抑制疗法中的信号通路。尽管标准治疗药物在 CRC的治疗仍然无法实现持久且无复发的结果。目前，免疫疗法使用 检查点抑制剂也不适用于大多数CRC患者。通过识别治疗诱导的免疫 景观和功能的诱导细胞因子在高加索人和非洲裔美国人的起源，结果来自 本研究将阐明化疗后免疫应答的调节机制， 联合收割机联合免疫治疗结直肠癌的策略。

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.