Journal
BRAIN TUMOR PATHOLOGY
Volume 37, Issue 2, Pages 41-49Publisher
SPRINGER JAPAN KK
DOI: 10.1007/s10014-020-00357-z
Keywords
Immunotherapy; Glioblastoma; PD-L1; IPI-549; M2 macrophage; Immune checkpoint inhibitor
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Funding
- Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT) [18K08962]
- project for promotion of practical applications of advanced medical technologies in Tsukuba University Hospital
- Grants-in-Aid for Scientific Research [18K08962] Funding Source: KAKEN
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Although chemoimmunotherapy often lengthens glioblastoma (GBM) survival, early relapses remain problematic as immunosuppressive M2 macrophages (M phi) 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 M phi infiltration, using a temozolomide (TMZ)-treated glioma model. In addition, we tested combinations of anti-PD-L1 antibody and the M2M phi inhibitor IPI-549 on tumor growth. We simulated late TMZ treatment or relapse stage, persistent GBM cells by generating TMZ-resistant TS (TMZRTS) cells. M2M phi-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 M phi, usually considered as an M2M phi marker into tumor tissues. CD163 expression in samples from human GBM patients were also evaluated. CD163-positive M phi 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 M phi 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.
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