Systemic administration of a TLR7 agonist attenuates regulatory T cells by dendritic cell modification and overcomes resistance to PD-L1 blockade therapy.
Systemic administration of a TLR7 agonist attenuates regulatory T cells by dendritic cell modification and overcomes resistance to PD-L1 blockade therapy.
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DOI：
10.18632/oncotarget.24327
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发表时间：
2018-03-02
期刊：
影响因子：
--
通讯作者：
Azuma M
中科院分区：
文献类型：
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作者：
Nishii N;Tachinami H;Kondo Y;Xia Y;Kashima Y;Ohno T;Nagai S;Li L;Lau W;Harada H;Azuma M
免疫检查点阻断疗法的研究在癌症免疫治疗方面取得了很大进展，但受益于该疗法的患者数量仍然有限。在这项研究中，我们研究了合成的TLR7激动剂系统小剂量瑞西莫德单独治疗的效果，以及它与PD-L1阻断在两个PD-L1耐药肿瘤模型(SCCVII和Colon 26)中的联合作用。Resiquimod单一疗法在SCCVII肿瘤中表现为CD8+T细胞功能受损和肿瘤内加速调节T细胞(Tregs)，通过更多的CD8+T细胞的募集和Treg的减少，有效地减少了肿瘤的生长。在代表Treg募集受损的26号结肠中，resquimod单一治疗的结果逊于SCCVII。Resiquimod与PD-L1阻断联合治疗具有明显的附加效应，因为它与两种肿瘤的肿瘤体积缩小、Tregs减少和CD8+T细胞/Tregs比值增加有关。小剂量瑞奎莫特全身给药可诱导浆细胞样树突状细胞和常规树突状细胞的瞬时和快速激活，从而增强区域淋巴结内T细胞的启动。更有限剂量的利奎莫特在单一治疗后没有产生有益效果的实验表明，当抗PD-L1治疗的频率降低时，对PD-L1的阻断有额外的效果，并且有类似的抗肿瘤效果。我们的结果表明，小剂量瑞西莫特可作为PD-1/PD-L1阻断治疗的辅助药物。
Research on immune checkpoint blockade therapy has made great progress in cancer immunotherapy, but the number of patients who benefit from this therapy remains limited. In this study, we examined the effects of monotherapy with systemic low-dose resiquimod, a synthesized TLR7 agonist, and examined its combined effects with PD-L1 blockade in two PD-L1 blockade-resistant tumor models (SCCVII and Colon 26). Resiquimod monotherapy in SCCVII tumors, representing impaired CD8+ T cell function and accelerated regulatory T cells (Tregs) within the tumors, efficiently reduced tumor growth with more recruitment of CD8+ T cells and a reduction of Treg. The results of resiquimod monotherapy in Colon 26, representing impaired Treg recruitment, were inferior to that in SCCVII. Combined resiquimod treatment with PD-L1 blockade exerted clear additional effects, as it was associated with reduced tumor size, attenuation of Tregs, and an increased ratio of CD8+ T cells/Tregs in both tumors. Systemic administration of low-dose resiquimod induced a transient and rapid activation of plasmacytoid and conventional dendritic cells, resulting in enhanced priming of T cells in regional lymph nodes. Experiments with more limited doses of resiquimod that did not yield beneficial effects after single treatment, showed additional effects to PD-L1 blockade and comparable antitumor effects when the frequency of anti-PD-L1 therapy was decreased. Our results suggest that systemic administration of low-dose resiquimod is useful as a companion drug to PD-1/PD-L1 blockade therapy.