ß2-microglobulin maintains glioblastoma stem cells and induces M2-like polarization of tumor-associated macrophages

Glioblastoma (GBM) is a complex ecosystem that includes a heterogeneous tumor population and the tumor immune microenvironment (TIME), prominently containing tumor- associated macrophages (TAM) and microglia. Here, we dem- onstrated that ß2-microglobulin (B2M), a subunit of the class I major histocompatibility complex (MHC-I), promotes the maintenance of stem-like neoplastic populations and repro- grams the TIME to an anti-inflammatory, tumor-promoting state. B2M activated PI3K/AKT/mTOR signaling by interacting with PIP5K1A in GBM stem cells (GSC) and promoting MYC- induced secretion of transforming growth factor-ß1 (TGFß1). Inhibition of B2M attenuated GSC survival, self-renewal, and tumor growth. B2M-induced TGFß1 secretion activated para- crine SMAD and PI3K/AKT signaling in TAMs and promoted an M2-like macrophage phenotype. These findings reveal tumor-promoting functions of B2M and suggest that targeting B2M or its downstream axis may provide an effective approach for treating GBM. Overall design: Comparative gene expression profiling analysis of RNA-seq data for 4121/3264 cells and its KD derivatives (shB2M).