Translational Nanomedicine Boosts Anti-PD1 Therapy to Eradicate Orthotopic PTEN-Negative Glioblastoma

Hiroaki Kinoh, Sabina Quader, Hitoshi Shibasaki, Xueying Liu, Amit Maity, Tatsuya Yamasoba, Horacio Cabral, Kazunori Kataoka

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Glioblastoma (GBM) is resistant to immune checkpoint inhibition due to its low mutation rate, phosphatase and tensin homologue (PTEN)-deficient immunosuppressive microenvironment, and high fraction of cancer stem-like cells (CSCs). Nanomedicines fostering immunoactivating intratumoral signals could reverse GBM resistance to immune checkpoint inhibitors (ICIs) for promoting curative responses. Here, we applied pH-sensitive epirubicin-loaded micellar nanomedicines, which are under clinical evaluation, to synergize the efficacy of anti-PD1antibodies (aPD1) against PTEN-positive and PTEN-negative orthotopic GBM, the latter with a large subpopulation of CSCs. The combination of epirubicin-loaded micelles (Epi/m) with aPD1 overcame GBM resistance to ICIs by transforming cold GBM into hot tumors with high infiltration of antitumor immune cells through the induction of immunogenic cell death (ICD), elimination of immunosuppressive myeloid-derived suppressor cells (MSDCs), and reduction of PD-L1 expression on tumor cells. Thus, Epi/m plus aPD1 eradicated both PTEN-positive and PTEN-negative orthotopic GBM and provided long-term immune memory effects. Our results indicate the high translatable potential of Epi/m plus aPD1 for the treatment of GBM.

Original languageEnglish
Pages (from-to)10127-10140
Number of pages14
JournalACS Nano
Volume14
Issue number8
DOIs
StatePublished - 6 Aug 2020
Externally publishedYes

Keywords

  • anti-PD1 antibodies
  • epirubicin
  • glioblastoma
  • immune checkpoint inhibitor
  • polymeric micelles

ASJC Scopus subject areas

  • General Materials Science
  • General Engineering
  • General Physics and Astronomy

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