Lung cancer is the leading cause of cancer-related mortality worldwide. Although immune checkpoint inhibitors have shown encouraging results in the treatment of lung adenocarcinoma, the response rate and overall survival are still low, especially in patients with low PD-L1 expression in the tumor site. Existing evidence suggests that interactions involving lung cancer cells, microbes, and immune cells in the tumor microenvironment affect tumor progression and patients’ responses to treatments. Therefore, the discovery of new therapeutic targets and more effective immunotherapies requires a deeper understanding of these complex interactions, especially in the tissue context rather than as isolated elements. However, traditional investigation methods, such as flow cytometry and low-plex histology, lack the ability to measure cells, mediators, and the microbiota simultaneously while also collecting critical spatial information.

To address this gap in our knowledge, we have been using advanced multiplex, multimode, two-dimensional (2D), and three-dimensional (3D) imaging techniques, together with spatial-transcriptomic analysis, to investigate these complex interactions in the tumor microenvironment. We collaborate with Dr. Chengcheng Jin at the University of Pennsylvania and have shown that commensal microbiota promote lung cancer development via gamma-delta T cells.

Taking advantage of these techniques and the translational research opportunities at CCR, we are studying the composition and spatial changes of the lung microbiota during lung cancer development as well as the interactions between lung microbiota and immune cells in patients with lung cancer. We developed a novel spatial meta-transcriptomic analysis method and revealed the spatial distribution of the intratumor microbiome in lung cancer. The findings of our laboratory findings are brought back to patients as the first clinical trial targeting the intratumor microbiome, "Study of Aerosolized Antibiotics and Pembrolizumab in Advanced Non-small Cell Lung Cancer"(NCT05777603).