Immune surveillance of brain metastatic cancer cells is mediated by IFITM1.

Brain metastasis, most commonly originating from lung cancer, increases cancer morbidity and mortality. Although metastatic colonization is the rate-limiting and most complex step of the metastatic cascade, the underlying mechanisms are poorly understood. Here, in vivo genome-wide CRISPR-Cas9 screening revealed that loss of interferon-induced transmembrane protein 1 (IFITM1) promotes brain colonization of human lung cancer cells. Incipient brain metastatic cancer cells with high expression of IFITM1 secrete microglia-activating complement component 3 and enhance the cytolytic activity of CD8+ T cells by increasing the expression and membrane localization of major histocompatibility complex class I. After activation, microglia (of the innate immune system) and cytotoxic CD8+ T lymphocytes (of the adaptive immune system) were found to jointly eliminate cancer cells by releasing interferon-gamma and inducing phagocytosis and T-cell-mediated killing. In human cancer clinical trials, immune checkpoint blockade therapy response was significantly correlated with IFITM1 expression, and IFITM1 enhanced the brain metastasis suppression efficacy of PD-1 blockade in mice. Our results exemplify a novel mechanism through which metastatic cancer cells overcome the innate and adaptive immune responses to colonize the brain, and suggest that a combination therapy increasing IFITM1 expression in metastatic cells with PD-1 blockade may be a promising strategy to reduce metastasis.

A high-throughput screen identifies inhibitors of lung cancer stem cells.

Metastasis is the main cause of cancer morbidity and mortality. Cancer stem cells (CSCs) are a rare subpopulation of cancer cells that can drive metastasis. The identification of CSC inhibitors and CSC-related genes is an alluring strategy for suppressing metastasis. Here, we established a simple and repeatable high-throughput CSC inhibitor screening platform that combined tumor sphere formation assays and cell viability assays. Human lung cancer cells were cocultured with 1280 pharmacologically active compounds (FDA-approved). Fifty-four candidate compounds obtained from our screening system completely or partially inhibited tumor sphere formation. A total of 5 of these 54 compounds (prochlorperazine dimaleate, thioridazine hydrochloride, ciproxifan hydrochloride, Ro 25-6981 hydrochloride, and AMN 082) completely inhibited the self-renewal of CSCs without cytotoxicity in vitro via their targets and suppressed lung cancer metastasis in vivo, suggesting that our screening platform is selective and reliable. DRD2, HRH3, and GRIN2B exhibited potent genes promoting CSCs in vitro experiments and clinical datasets. Further validation of the top hit (DRD2) and previously published studies demonstrate that our screening platform is a useful tool for CSC inhibitor and CSC-related gene screening.

MLN4924 protects against bleomycin-induced pulmonary fibrosis by inhibiting the early inflammatory process.

Pulmonary fibrosis is a complex pathological process characterized by massive destruction of the structure of lung tissues and aggravated pulmonary function impairment. The underlying mechanisms of pulmonary fibrosis are incompletely understood and therefore limited treatment options are available currently. Here, we report that MLN4924, an NEDD8 activation enzyme (NAE) activity-inhibiting molecule, blocks the maintenance and progression of established pulmonary fibrosis. We found that MLN4924 acts against bleomycin-induced pulmonary fibrosis mainly at the early inflammatory stage. Pharmacologically targeting the neddylation of Cullin-Ring E3 ligase (CRL) by MLN4924, significantly abrogated NF-κB responses, suppressed MAPK activity, and reduced secretion of TNF-α-elicited pro-inflammatory cytokines and MCP1-induced chemokines. MLN4924 inhibited pro-inflammatory responses while maintaining or increasing the production of the anti-inflammatory mediators such as anti-inflammatory interleukins (ILs) following bleomycin administration, which is closely correlated to its blocking NF-κB-mediated signaling. Consistently, our studies identified MLN4924 as a promising therapeutic drug for pulmonary fibrosis and suggested a potential role of MLN4924 that fine tunes the MAPK signaling pathway controlling the inflammatory reactions at the early stages of pulmonary fibrosis. In addition, our findings may broaden the potential practical application of MLN4924 as an effective therapeutic strategy against other inflammation-associated diseases.