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.

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.
Authors	Tsubasa Miyazaki, Eiichi Ishikawa, Masahide Matsuda, Narushi Sugii, Hedihiro Kohzuki, Hiroyoshi Akutsu, Noriaki Sakamoto, Shingo Takano, Akira Matsumura
Journal	Brain tumor pathology (Brain Tumor Pathol) Vol. 37 Issue 2 Pg. 41-49 (Apr 2020) ISSN: 1861-387X [Electronic] Japan
PMID	31980975 (Publication Type: Journal Article)
Chemical References	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
Topics	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, therapy) Immunotherapy Macrophage Activation Macrophages Male Mice, Inbred C57BL Receptors, Cell Surface Temozolomide

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