Study interactions between lung microbiota and immune cells in NSCLC

利用我们开发的新的空间元转录方法，我们发现NSCLC的瘤内细菌与免疫细胞相比富含肿瘤细胞，并与肿瘤细胞中的多条致癌途径相关。从肿瘤旁的正常肺和三级淋巴组织到肿瘤细胞再到呼吸道，细菌载量增加。我们的研究结果强调了肿瘤细胞和细菌之间直接相互作用的重要性，支持了减少肿瘤微环境中细菌负担的治疗潜力。我们题为《空间元转录组学揭示肿瘤内细菌负荷与肺癌细胞表现出明显致癌特征的关联》的手稿已被《癌症免疫治疗杂志》接受，目前正在出版中。为了跟进我们的观察结果，我们与宾夕法尼亚大学的金博士合作，通过给予雾化抗生素，成功地降低了非小细胞肺癌基因工程小鼠(GEM)模型的肿瘤内细菌负担。当我们将其与抗PD-1抗体结合时，它进一步减轻了肿瘤负担。这是第一次在非小细胞肺癌的GEM模型中显示出疗效的非化疗疗法。基于我们的临床前数据，我们设计了一项I期临床研究，测试雾化抗生素和培溴利单抗联合治疗晚期非小细胞肺癌患者的安全性和可行性。我们已经成功地为这项试验获得了资金和支持。该临床方案已由TGMB和CCR科学审查委员会审查。我们正在向IRB提交申请，预计将于今年晚些时候开始招生。这将是调节非小细胞肺癌患者肿瘤内微生物组的第一项临床研究。与以前的回顾性研究相比，我们的临床试验结果将为深入了解患者肿瘤内微生物组的功能和开发新的治疗方法奠定基础。为了能够进一步对患者的肿瘤内微生物组进行机械研究，我们已经开始创建一个GEM模型，通过气管内接种来容纳患者的肿瘤内微生物组。我们的动物实验方案获得了CCR诺生生物设施审查委员会的批准，目前我们正在建立无菌条件下的GEM模型。这个模型将帮助我们弥合小鼠和人类之间肿瘤内微生物组之间的差距。除了研究患者肿瘤内微生物群、免疫细胞和肿瘤细胞之间的相互作用外，我们计划通过这个模型来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.