Study interactions between lung microbiota and immune cells in NSCLC

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

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.