Synergistic immunotherapy of glioblastoma by dual targeting of IL-6 and CD40.
Synergistic immunotherapy of glioblastoma by dual targeting of IL-6 and CD40.
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DOI：
10.1038/s41467-021-23832-3
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发表时间：
2021-06-08
影响因子：
16.6
通讯作者：
Fan Y
中科院分区：
文献类型：
--
作者：
Yang F;He Z;Duan H;Zhang D;Li J;Yang H;Dorsey JF;Zou W;Nabavizadeh SA;Bagley SJ;Abdullah K;Brem S;Zhang L;Xu X;Byrne KT;Vonderheide RH;Gong Y;Fan Y
包括胶质母细胞瘤 (GBM) 在内的免疫冷肿瘤对检查点阻断疗法难以治疗，这主要是由于免疫抑制性巨噬细胞 (Mphis) 的广泛浸润。与 IL-6 在替代 Mψs 极化中的促肿瘤作用一致，我们在此表明，通过基因消融或药理抑制来靶向 IL-6 可适度改善 T 细胞浸润 GBM 并提高小鼠存活率；然而，IL-6 抑制不会协同 PD-1 和 CTLA-4 检查点阻断。有趣的是，抗 IL-6 治疗可降低 GBM 相关 Mphi 中 CD40 的表达。我们确定了 Stat3/HIF-1α 介导的轴，IL-6 通过该轴执行抗肿瘤作用，诱导 Mψ 中 CD40 的表达。 IL-6 抑制与 CD40 刺激相结合可逆转 Mphi 介导的肿瘤免疫抑制，使肿瘤对检查点阻断敏感，并延长两个同基因 GBM 模型中的动物存活时间，特别是在检查点阻断后诱导 GL261 肿瘤完全消退。因此，将检查点阻断与 IL-6 和 CD40 双靶向相结合的基于抗体鸡尾酒的免疫疗法可能为 GBM 和其他实体瘤提供令人兴奋的机会。胶质母细胞瘤通常对免疫检查点抑制剂的治疗有抵抗力。作者在此表明，在临床前模型中，IL6 阻断与 CD40 激动剂相结合，可以克服巨噬细胞介导的免疫抑制，并使胶质母细胞瘤对免疫检查点阻断敏感。
Immunologically-cold tumors including glioblastoma (GBM) are refractory to checkpoint blockade therapy, largely due to extensive infiltration of immunosuppressive macrophages (Mϕs). Consistent with a pro-tumor role of IL-6 in alternative Mϕs polarization, we here show that targeting IL-6 by genetic ablation or pharmacological inhibition moderately improves T-cell infiltration into GBM and enhances mouse survival; however, IL-6 inhibition does not synergize PD-1 and CTLA-4 checkpoint blockade. Interestingly, anti-IL-6 therapy reduces CD40 expression in GBM-associated Mϕs. We identify a Stat3/HIF-1α-mediated axis, through which IL-6 executes an anti-tumor role to induce CD40 expression in Mϕs. Combination of IL-6 inhibition with CD40 stimulation reverses Mϕ-mediated tumor immunosuppression, sensitizes tumors to checkpoint blockade, and extends animal survival in two syngeneic GBM models, particularly inducing complete regression of GL261 tumors after checkpoint blockade. Thus, antibody cocktail-based immunotherapy that combines checkpoint blockade with dual-targeting of IL-6 and CD40 may offer exciting opportunities for GBM and other solid tumors. Glioblastomas are generally resistant to treatment with immune checkpoint inhibitors. Here the authors show that IL6 blockade, in combination with a CD40 agonist, overcomes macrophage-mediated immunosuppression and sensitizes glioblastoma to immune checkpoint blockade in preclinical models.
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影响因子：
20.3
作者：
BATAILLE, R;BARLOGIE, B;KLEIN, B
通讯作者：
KLEIN, B
影响因子：
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通讯作者：
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作者：
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