Immune surveillance of brain metastatic cancer cells is mediated by IFITM1

Abstract

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.

Exploring treatment options in cancer: Tumor treatment strategies

“…Numerous clinical studies have employed CRISPR to eliminate PD1 expression on T cells to enhance their anti-cancer properties. 220 – 225 But since this technology is still very new, only one clinical trial (NCT02793856)—a dose-escalation study of ex vivo knocked-out, expanded, and selected PD-1 knockout T cells from autologous origin—has been completed. Others are ongoing.…”

Harnessing immunotherapy for brain metastases: insights into tumor–brain microenvironment interactions and emerging treatment modalities

“…In an intriguing study by She et al [ 109 ], it was discerned that BM of lung cancer correlated with a diminished expression of interferon-induced transmembrane protein 1 (IFITM1). The high expression of IFITM1 in early BM cells potentiated the release of microglia-activating complement 3 and amplified the expression and membrane localization of MHC I.…”

“…Oncolytic viruses function primarily by activating antitumor immunity rather than by destroying infected cancer cells, which makes them an invaluable auxiliary tool in immunotherapy [ 109 , 226 ]. She et al [ 109 ].…”

“…Oncolytic viruses function primarily by activating antitumor immunity rather than by destroying infected cancer cells, which makes them an invaluable auxiliary tool in immunotherapy [ 109 , 226 ]. She et al [ 109 ]. discovered that oncolytic viruses stimulate the overexpression of the immune-enhancing gene IFITM1, thus greatly improving the efficacy of anti-PD-1 Given their mechanism of enhancing T cell immune recognition and microglial activation, it is anticipated that the immuno-inductive capabilities of oncolytic viruses could be combined with CAR-T cells or glial targeting drugs [ 199 , 227 ].…”

The role and mechanism of IFITM1 in developing acquired cisplatin resistance in small cell lung cancer

“…Interferon (IFN)-induced transmembrane protein 1 (IFITM1), a member of the IFN-induced transmembrane protein family, is markedly overexpressed in various tumor tissues and cancer cell lines, establishing itself as an independent prognostic marker for a range of cancers, including those metastasizing to the brain, as well as colorectal, breast, and ovarian cancers [ [9] , [10] , [11] ]. This significant role of IFITM1 across different cancer types suggests that targeting it could pave the way for innovative cancer treatments aimed at improving patient outcomes.…”