Targeting ARPC1B Overcomes Immune Checkpoint Inhibitor Resistance in Glioblastoma by Reversing Protumorigenic Macrophage Polarization.

Immunotherapy has elicited significant improvements in outcomes for patients with several tumor types. However, the immunosuppressive microenvironment in glioblastoma (GBM) restricts the therapeutic efficacy of immune checkpoint blockade (ICB). In this study, we investigated the components of the immune microenvironment that contribute to ICB failure in GBM to elucidate the underlying causes of immunotherapeutic resistance. Macrophages were identified as a main contributor to ICB resistance. Expression of actin-related protein 2/3 complex subunit 1B (ARPC1B), a regulatory subunit of the Arp2/3 complex, was elevated in GBM and correlated with macrophage enrichment and prognosis. ARPC1B in tumor cells increased STAT1 expression and subsequent IL10 production, which induced a protumorigenic macrophage state. Mechanistically, ARPC1B inhibited the ubiquitination and degradation of STAT1 by preventing the E3 ubiquitin ligase NEDD4L from binding to STAT1 and by supporting the interaction between STAT1 and the deubiquitinase USP7. Inhibiting ARPC1B reshaped the immunosuppressive microenvironment and increased the efficacy of ICB in GBM models. This study highlights the important role of ARPC1B in macrophage-mediated immunosuppression and proposes a combination treatment regimen for GBM immunotherapy. Significance: ARPC1B induces macrophage-mediated immunosuppression by activating a STAT1/IL10 axis and can be targeted to improve the efficacy of immune checkpoint blockade in glioblastoma.