Myeloid-cell-specific role of Gasdermin D in promoting lung cancer progression in mice

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Abstract The activities of the NLRP3 and AIM2 inflammasomes and Gasdermin D (GsdmD), the final executor of inflammasome activity, are implicated in lung cancer pathophysiology but it’s not clear if their contributions promote or retard lung cancer progression. GsdmD plays a role in release of interleukin-1beta (IL-1 β), and the CANTOS trial and recent studies have highlighted a crucial role of IL-1β in promoting lung cancer. Expression of GsdmD was shown to be upregulated in human non-small cell lung cancer (NSCLC) tissue, but its contribution to in vivo lung cancer metastasis is not known. Using a metastatic Lewis Lung Carcinoma (LLC) cell model, we show that GsdmD knockout (GsdmD -/- ) mice form significantly fewer cancer foci in lung, and exhibit markedly decreased lung cancer metastasis. Furthermore, GsdmD -/- mice show a significant ~ 50% increase in median survival rate vs. isogenic WT C57BL6J mice. The cleaved forms of GsdmD and IL-1 β were detected in lung tumor tissue, indicating inflammasome activity in lung tumor microenvironment (TME). Increased migration and growth of LLC cells was observed upon exposure to the conditioned media derived from inflammasome-induced wild type, but not the GsdmD -/- , macrophages. Exposure of human A549 lung cancer cells to the conditioned media derived from inflammasome-induced THP-1 macrophages also resulted in increased cell migration. Using bone marrow transplantation, we show the myeloid-specific contribution of GsdmD in lung cancer metastasis. Taken together, our data show that inflammasome activation in macrophages promotes lung cancer growth and migration, and GsdmD plays a myeloid-specific role in lung cancer progression in mice.

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