Infiltration of CD163-positive macrophages in glioma tissues after treatment with anti-PD-L1 antibody and role of PI3Kγ inhibitor as a combination therapy with anti-PD-L1 antibody in in vivo model using temozolomide-resistant murine glioma-initiating cells

Brain Tumor Pathol. 2020 Apr;37(2):41-49. doi: 10.1007/s10014-020-00357-z. Epub 2020 Jan 24.

Abstract

Although chemoimmunotherapy often lengthens glioblastoma (GBM) survival, early relapses remain problematic as immunosuppressive M2 macrophages (Mϕ) that function via inhibitory cytokine and PD-L1 production cause immunotherapy resistance. Here, we detail anti-PD-L1 antibody effects on the tumor microenvironment, including Mϕ infiltration, using a temozolomide (TMZ)-treated glioma model. In addition, we tested combinations of anti-PD-L1 antibody and the M2Mϕ inhibitor IPI-549 on tumor growth. We simulated late TMZ treatment or relapse stage, persistent GBM cells by generating TMZ-resistant TS (TMZRTS) cells. M2Mϕ-associated cytokine production and PD-L1 expression in these cells were investigated. TMZRTS cells were then subcutaneously implanted into C57BL/6 mice to determine the effectiveness of an anti-PD-L1 antibody and/or IPI-549 treatment on infiltration of CD163-positive Mϕ, usually considered as an M2Mϕ marker into tumor tissues. CD163 expression in samples from human GBM patients were also evaluated. CD163-positive Mϕ heavily infiltrated TMZRS tumor tissues after in vivo anti-PD-L1 antibody treatment. Tumor growth was strongly inhibited by anti-PD-L1 antibody and IPI-549 combination therapy. Anti-PD-L1 antibody treatment significantly reduced infiltration of CD163-positive Mϕ into tumors, while combined PD-L1 antibody and IPI-549 therapy remarkably inhibited tumor growth. These therapies may be useful for recurrent or chronic GBM after TMZ treatment, but clinical safety and effectiveness studies are needed.

Keywords: Glioblastoma; IPI-549; Immune checkpoint inhibitor; Immunotherapy; M2 macrophage; PD-L1.

MeSH terms

  • Animals
  • Antibodies / therapeutic use*
  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • B7-H1 Antigen / immunology*
  • Brain Neoplasms / therapy*
  • Cell Line, Tumor
  • Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
  • Drug Resistance, Neoplasm
  • Enzyme Inhibitors / therapeutic use*
  • Glioma / immunology*
  • Glioma / therapy*
  • Immunotherapy*
  • Macrophage Activation
  • Macrophages
  • Male
  • Mice, Inbred C57BL
  • Receptors, Cell Surface
  • Temozolomide*

Substances

  • Antibodies
  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • B7-H1 Antigen
  • CD163 antigen
  • CD274 protein, human
  • Enzyme Inhibitors
  • Receptors, Cell Surface
  • Class I Phosphatidylinositol 3-Kinases
  • Temozolomide