Type I IFNs promote cancer cell stemness by triggering the epigenetic regulator KDM1B

Abstract

Cancer stem cells (CSCs) are a subpopulation of cancer cells endowed with high tumorigenic, chemoresistant and metastatic potential. Nongenetic mechanisms of acquired resistance are increasingly being discovered, but molecular insights into the evolutionary process of CSCs are limited. Here, we show that type I interferons (IFNs-I) function as molecular hubs of resistance during immunogenic chemotherapy, triggering the epigenetic regulator demethylase 1B (KDM1B) to promote an adaptive, yet reversible, transcriptional rewiring of cancer cells towards stemness and immune escape. Accordingly, KDM1B inhibition prevents the appearance of IFN-I-induced CSCs, both in vitro and in vivo. Notably, IFN-I-induced CSCs are heterogeneous in terms of multidrug resistance, plasticity, invasiveness and immunogenicity. Moreover, in breast cancer (BC) patients receiving anthracycline-based chemotherapy, KDM1B positively correlated with CSC signatures. Our study identifies an IFN-I → KDM1B axis as a potent engine of cancer cell reprogramming, supporting KDM1B targeting as an attractive adjunctive to immunogenic drugs to prevent CSC expansion and increase the long-term benefit of therapy.

Type I interferon induces cancer stem cells-mediated chemotherapy resistance

“…Importantly, doxorubicin-mediated ICD induction combined with repeated injections of 2 × 10 4 U IFN-I prevented the induction of CSC-like cells thus resulting in an improved tumor control and mice survival. 8 Therefore, these data demonstrate that accumulation of CSC from suboptimal IFN-I response can be reverted with repeated administration of IFN-I.…”

“…Importantly, the oxaliplatin-induced accumulation of CSC amongst MCA205 cells was reduced by the actin inhibitor cytochalasin D, indicating the contribution of extracellular vesicles (EV) that contain stemness-related transcriptional factors, namely Sox2, Nanog, Myc and Oct3/4 . 8 Globally, these data indicate that CSC expansion occurs via free and EV-mediated transfer of nucleic acids and stem-related genes. These data confirm and expand on previous findings demonstrating the transfer of IFN-I stimulatory nucleic acid species via EV.…”

“…Recently, Musella et al demonstrate that the expansion of cancer stem cells (CSC; a rare population of cancer cells with great treatment resistance, immunoevasive and metastatic properties) is associated with IFN-I response. 8 …”

“…Moreover, MCA205 cells exposed to IFN-I led to an increase of CSC markers in both CD133+ (CSC) and CD133- (non-CSC) cells, indicating that IFN-I drives stemness in both subsets; findings that were further substantiated by morphological, phenotypical and functional evidence. 8 …”

“…Interestingly, local treatment with a single dose of 10 5 U IFN-I promoted the expansion of CSC within the MCA205 tumors growing in syngeneic animals as compared to repeated administration of IFN-I (7 injections of 2 × 10 4 U each administered over the entire course of the experiment); 8 therefore highlighting distinct responses of the tumor microenvironment in respect to the magnitude of induction and timing of IFN-I signaling.…”