Macrophages reprogrammed by lung cancer microparticles promote tumor development via release of IL-1β

Abstract

Despite their mutual antagonism, inflammation and immunosuppression coexist in tumor microenvironments due to tumor and immune cell interactions, but the underlying mechanism remains unclear. Previously, we showed that tumor cell-derived microparticles induce an M2 phenotype characterized by immunosuppression in tumor-infiltrating macrophages. Here, we further showed that lung cancer microparticles (L-MPs) induce macrophages to release a key proinflammatory cytokine, IL-1β, thus promoting lung cancer development. The underlying mechanism involves the activation of TLR3 and the NLRP3 inflammasome by L-MPs. More importantly, tyrosine kinase inhibitor treatment-induced L-MPs also induce human macrophages to release IL-1β, leading to a tumor-promoting effect in a humanized mouse model. These findings demonstrated that in addition to their antiinflammatory effect, L-MPs induce a proinflammatory phenotype in tumor-infiltrating macrophages, promoting the development of inflammatory and immunosuppressive tumor microenvironments.

Immunoregulatory Roles of Extracellular Vesicles and Associated Therapeutic Applications in Lung Cancer

“…Understanding this difference and the underlying mechanisms can help us select EVs that work best as the most effective cell-free vaccines against tumors. However, other studies show that UV-processed TMPs are not invariably immunostimulatory ( 47 , 78 ) as discussed in previous sections.…”

“…EVs produced by lung tumor cells or immune cells contain plenty of bioactive substances, such as proteins, lipids, and genetic DNA/mRNA/non-coding RNA, which are transported between cells and can deliver information about immune processes ( 11 ). In most cases, EVs from lung tumor cells contain certain cargo that induces immune escape ( 19 , 21 , 46 , 47 ). Nonetheless, after modification, immunogenic components (e.g., tumor-associated antigens) on EVs derived from tumor cells gradually function and can activate antitumor immunity ( 24 – 26 , 48 , 49 ).…”

“…These infiltrating neutrophils would be polarized into tumor-promoting subtypes (tumor-associated neutrophils, TANs) ( 76 , 77 ) and eventually enhance the formation of a pre-metastatic niche in the lung ( 22 ). The mechanism is akin to that by which the non-coding RNA in lung tumor–derived microparticles (TMPs) stimulates TAM to secrete IL-1β as described below ( 47 ).…”

“…MPs from UV-treated lung cancer cells could induce polarization of M2 macrophages to suppress antitumor immunity and promote tumor progression in vitro and in vivo ( 47 , 78 ). Specifically, macrophages treated with MPs from UV-treated lung cancer cells upregulate the expression of M2-type surface markers CD163, CD206, VEGF, IL-10, and arginase 1 and downregulate the level of M1-type surface markers IL-12, iNOS, and TNF-α ( 47 , 78 ). The mechanism of MPs stimulating M2 type macrophages and promoting tumor progression involves the activation of cGAS/STING/TBK1/STAT6 pathways in macrophages ( 78 ).…”

“…Furthermore, whether DNAs in these TMPs activate the cGAS/STING pathway in M2 macrophages needs further investigation ( 78 ). Meanwhile, the tumor-promoting effects of M2 macrophages induced by lung cancer microparticles are associated with increased IL-1β secretion after macrophages sense the non-coding RNA in TMPs through the TLR3 signaling pathway ( 47 ). IL-1β has been proven to promote the angiogenesis ( 79 ) and stemness of tumor cells ( 80 ).…”