Hypoxic memory of tumor intrinsic type I interferon suppression promotes breast cancer metastasis

Abstract

SummaryHypoxia is a common feature of many solid tumors due to aberrant proliferation and angiogenesis and has been associated with tumor progression and metastasis. Most of the well- known hypoxia effects are mediated through hypoxia-inducible factors (HIFs), but the long- lasting effect of hypoxia beyond the immediate HIF regulation remains less understood. Here we show that hypoxia exerts a prolonged effect through HIF-independent mechanisms to promote metastasis. Using breast cancer patient-derived circulating tumor cell (CTC) lines and common breast cancer cell lines, we found that hypoxia downregulates tumor intrinsic type I interferon (IFN) signaling and its downstream antigen presentation (AP) machinery in luminal breast cancer cells. This effect does not depend on the canonical HIFs but is mediated, at least partially, via forkhead box protein O1 (FOXO1). Moreover, hypoxia induced IFN/AP suppression can last longer than the hypoxic exposure, presenting a “hypoxic memory” phenotype. Hypoxic memory of IFN/AP downregulation is established by specific hypoxic priming, and cells with hypoxic memory have an enhanced ability for tumorigenesis and metastasis. The histone deacetylase inhibitor (HDACi) Entinostat can erase the hypoxic memory and improve the immune clearance of tumor cells when combined with checkpoint immunotherapies in a syngeneic breast cancer mouse model. These results point to a novel mechanism for hypoxia facilitated tumor progression, through a long-lasting memory that provides advantages for CTCs during the metastatic cascade.