Lipopolysaccharide suppresses lung metastasis by activating CD8+ T cells despite promoting effect via cancer-associated fibroblasts

Inflammation plays a dual role in tumor progression, and its overall effect depends on the complex interactions between the nature of the stimuli and the dynamic changes within the tumor microenvironment. Lipopolysaccharide (LPS) is a bacterial endotoxin whose immune effects on tumors may be either promoting or inhibiting, depending on the dose and timing. This study investigates the effects of LPS on tumor cells, fibroblasts, and immune cells in a mouse model of lung metastasis. To investigate the effects of LPS on tumor progression, we employed C57BL/6 immune-competent mice, immune-compromised nude mice and immune-deficient NOD-SCID mice. We assessed metastasis through in vivo experiments, while in vitro studies were conducted to evaluate the proliferation of tumor cells in the presence of LPS and LPS-treated fibroblasts. Additionally, we analyzed immune cell infiltration and the role of specific immune cell populations, such as CD8+ T cells, macrophages, and dendritic cells, in mediating the effects of LPS. LPS treatment significantly suppressed metastasis in immune-competent C57BL/6 mice but had no effect in immune-compromised nude mice, and even promoted metastasis in severely immune-deficient NOD-SCID mice. In vitro, LPS inhibited tumor cell proliferation. However, when tumor cells were co-cultured with LPS-treated fibroblasts, their growth was promoted compared to those co-cultured with untreated fibroblasts. In vivo, LPS enhanced the infiltration of mature macrophages, neutrophils, and CD8+ T cells while reducing M2 macrophages in the tumor microenvironment. Depletion of CD8+ T cells, macrophages, or dendritic cells individually abolished the protective effect of LPS, demonstrating their essential roles. Furthermore, LPS boosted the cytotoxicity of CD8+ T cells against tumor targets. LPS exerts a dual influence on tumors: overall LPS suppresses metastasis by activating cell-mediated immunity, specifically cytotoxic CD8+ T cells, despite promoting effect via inflamed fibroblasts.