Study interactions between lung microbiota and immune cells in NSCLC

使用我们开发的新的空间元转录组学方法，我们发现 与免疫细胞相比，NSCLC的肿瘤内细菌富含肿瘤细胞， 与肿瘤细胞中的多种致癌途径相关。细菌负荷增加， 肿瘤邻近的正常肺和三级淋巴结构到肿瘤细胞到气道。的 我们的研究结果强调了肿瘤细胞之间直接相互作用的重要性， 细菌，支持降低肿瘤中细菌负荷的治疗潜力 微环境我们的手稿题为“空间元转录组学揭示协会的 肿瘤内细菌负荷与肺癌细胞显示出明显的致癌特征”， 已被癌症免疫治疗杂志接受，目前正在印刷中。遵循 在我们的观察基础上，我们与宾夕法尼亚大学的金博士合作， 成功降低了基因工程小鼠（GEM）的肿瘤内细菌负荷 通过给予雾化抗生素治疗NSCLC模型。它进一步降低了肿瘤负荷， 与抗PD-1抗体结合这是第一个非化疗为基础的治疗 在NSCLC的GEM模型中显示出功效。根据我们的临床前数据，我们设计了一个阶段 一项临床研究，测试雾化抗生素和 帕博利珠单抗治疗晚期NSCLC患者的疗效。我们成功地获得了资金， 支持这次审判。临床方案已由TGMB和CCR Scientific审查 审查委员会。我们正在将其提交给IRB，预计将开始入组 今年晚些时候这将是第一个调节肿瘤内微生物组的临床研究 在NSCLC患者中。与之前的回顾性研究相比，我们的临床试验结果 将为深入了解肿瘤内微生物组的功能奠定基础， 患者和新的治疗方法的发展。为了使进一步的机械化 研究患者的肿瘤内微生物组，我们已经开始创建一个GEM模型， 患者的肿瘤内微生物组。我们的动物实验方案 已获得CCR Gnotobiotic设施审查委员会的批准，我们目前正在进行中 在无菌条件下建立GEM模型。这个模型将帮助我们架起 小鼠和人类之间肿瘤内微生物组的差距。除了调查 患者的肿瘤内微生物组，免疫细胞和肿瘤细胞之间的相互作用，我们计划 通过这个模型优化我们的雾化抗生素治疗。

Using the novel spatial meta-transcriptomic method we developed, we discovered intratumor bacteria of NSCLC were enriched with tumor cells compared to immune cells and associated with multiple oncogenic pathways in tumor cells. Bacteria burden increased from tumor-adjacent normal lung and tertiary lymphoid structures to tumor cells to the airways. The findings of our study emphasized the importance of direct interaction between tumor cells and bacteria, supporting the therapeutic potential of reducing bacteria burden in the tumor microenvironment. Our manuscript titled "spatial meta-transcriptomics reveal associations of intratumor bacteria burden with lung cancer cells showing a distinct oncogenic signature" has been accepted by the Journal for ImmunoTherapy of Cancer and is currently in press. To follow up on our observations, we collaborated with Dr. Jin at the University of Pennsylvania and successfully reduced the intratumor bacterial burden in genetically engineered mouse (GEM) models of NSCLC by giving aerosolized antibiotics. It further reduced tumor burden when we combined it with an anti-PD-1 antibody. This is the first non-chemotherapy-based treatment showing efficacy in the GEM model of NSCLC. Based on our preclinical data, we designed a Phase I clinical study testing the safety and feasibility of combining aerosolized antibiotics and pembrolizumab in patients with advanced NSCLC. We have successfully obtained funding and support for this trial. The clinical protocol has been reviewed by TGMB and CCR Scientific Review Committee. We are in the process of submitting it to IRB and expect to start enrollment later this year. This will be the first clinical study to modulate the intratumor microbiome in patients with NSCLC. Compared to prior retrospective studies, our clinical trial results will lay the ground for a deep understanding of the function of the intratumor microbiome in patients and the development of novel therapeutic approaches. To enable further mechanistic studies of patients' intratumor microbiome, we have started creating a GEM model harboring patients' intratumor microbiome via intra-tracheal inoculation. Our animal experiment proposal was approved by CCR Gnotobiotic Facility Review Committee, and we are currently in the process of establishing the GEM model under germ-free conditions. This model will help us bridge the gap in the intratumor microbiome between mice and humans. Besides investigating the interactions among patients' intratumor microbiome, immune cells, and tumor cells, we plan to optimize our aerosolized antibiotics treatments via this model.