Abstract
Pulmonary immunological tolerance to inhaled particulates might create a permissive milieu for lung metastasis. Lung microbiota contribute to pulmonary tolerance; here, we explored whether its manipulation via antibiotic or probiotic aerosolization favors immune response against melanoma metastasis. In lungs of vancomycin/neomycin-aerosolized mice, a decrease in bacterial load was associated with reduced regulatory Tcells and enhanced Tcell and NK cell activation that paralleled a significant reduction of melanoma B16 lung metastases. Reduction of metastases also occurred in lungs transplanted with bacterial isolates from antibiotic-treated lungs. Aerosolized Lactobacillus rhamnosus strongly promoted immunity against B16 lung metastases as well. Furthermore, probiotics or antibiotics improved chemotherapy activity against advanced B16 metastases. Thus, we identify a role for lung microbiota in metastasis and show that its targeting via aerosolization is a therapy that can prevent metastases and enhance responses to chemotherapy.
Highlights
The lung microenvironment is characterized by a high immune tolerance, which is essential for preventing excessive inflammation in response to inhaled particulates
This status is maintained by lung antigen-presenting cells (APCs), primarily alveolar macrophages (AMs) and dendritic cell (DC) subpopulations (Hussell and Bell, 2014), which promote immunosuppression, inducing regulatory T cells (Tregs) (Soroosh et al, 2013) and the release of prostaglandin E2 (PGE2), transforming growth factor b (TGF-b), and interleukin (IL)-10 (Hussell and Bell, 2014)
Vancomycin and Neomycin Aerosolization Modifies Lung Tissue Immunity and Prevents Tumor Implantation To evaluate whether a reduction of the lung microbiota mitigates the immunosuppressive status in the lung microenvironment, mice were treated with broad-spectrum antibiotics by airway delivery
Summary
The lung microenvironment is characterized by a high immune tolerance, which is essential for preventing excessive inflammation in response to inhaled particulates This status is maintained by lung antigen-presenting cells (APCs), primarily alveolar macrophages (AMs) and dendritic cell (DC) subpopulations (Hussell and Bell, 2014), which promote immunosuppression, inducing regulatory T cells (Tregs) (Soroosh et al, 2013) and the release of prostaglandin E2 (PGE2), transforming growth factor b (TGF-b), and interleukin (IL)-10 (Hussell and Bell, 2014). A study in HIV patients with pneumonia demonstrated that distinct lower-airway microbiota are associated with specific local host immune responses (Shenoy et al, 2017)
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