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.

中文翻译：

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在使用抗替莫唑胺的鼠神经胶质瘤起始细胞的体内模型中，抗PD-L1抗体处理后，CD163阳性巨噬细胞在神经胶质瘤组织中的浸润和PI3Kγ抑制剂与抗PD-L1抗体联合治疗的作用。

尽管化学免疫疗法通常会延长胶质母细胞瘤（GBM）的生存期，但早期复发仍然存在问题，因为通过抑制性细胞因子和PD-L1产生的免疫抑制性M2巨噬细胞（Mϕ）引起了免疫疗法的耐药性。在这里，我们使用替莫唑胺（TMZ）处理的神经胶质瘤模型详细描述了抗PD-L1抗体对肿瘤微环境的影响，包括M +浸润。另外，我们测试了抗PD-L1抗体和M2Mϕ抑制剂IPI-549对肿瘤生长的组合。我们通过产生耐TMZ的TS（TMZRTS）细胞来模拟TMZ晚期治疗或复发阶段的持久性GBM细胞。研究了这些细胞中M2Mϕ相关的细胞因子产生和PD-L1表达。然后将TMZRTS细胞皮下植入C57BL / 6小鼠，以确定抗PD-L1抗体和/或IPI-549治疗对CD163阳性Mϕ（通常被认为是M2Mϕ标志物）浸润到肿瘤组织中的有效性。还评估了来自人GBM患者的样本中的CD163表达。在体内抗PD-L1抗体治疗后，CD163阳性的M +大量浸润TMZRS肿瘤组织。抗PD-L1抗体和IPI-549联合疗法强烈抑制了肿瘤的生长。抗PD-L1抗体治疗可显着减少CD163阳性Mϕ向肿瘤的浸润，而PD-L1抗体和IPI-549联合治疗可显着抑制肿瘤的生长。这些疗法对于TMZ治疗后的复发性或慢性GBM可能有用，但是需要临床安全性和有效性研究。