Depletion of tumor associated macrophages enhances local and systemic platelet-mediated anti-PD-1 delivery for post-surgery tumor recurrence treatment.
Depletion of tumor associated macrophages enhances local and systemic platelet-mediated anti-PD-1 delivery for post-surgery tumor recurrence treatment.
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DOI：
10.1038/s41467-022-29388-0
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发表时间：
2022-04-06
影响因子：
16.6
通讯作者：
Hu Q
中科院分区：
文献类型：
--
作者：
Li Z;Ding Y;Liu J;Wang J;Mo F;Wang Y;Chen-Mayfield TJ;Sondel PM;Hong S;Hu Q
驻留在肿瘤微环境中的免疫抑制细胞，特别是肿瘤相关巨噬细胞（TAM），阻碍T细胞的浸润和活化，限制了免疫检查点阻断的抗癌结果。在这里，我们报告了一种生物相容性的藻酸盐基水凝胶，其中载有Pexidartinib（PLX）包封的纳米颗粒，该纳米颗粒在肿瘤部位逐渐释放PLX，以阻断集落刺激因子1受体（CSF 1 R），从而耗尽TAM。受控的TAM消耗为促进抗程序性细胞死亡蛋白1（aPD-1）抗体缀合的血小板的局部和全身递送以抑制手术后肿瘤复发创造了有利的环境。肿瘤免疫抑制微环境也通过TAM消除而重新编程，进一步促进T细胞浸润到肿瘤组织中。此外，手术后的炎症环境可触发血小板活化以促进aPD-1的释放，伴随着血小板衍生的微粒与PD-1受体结合以重新活化T细胞。所有这些结果共同表明，局部和全身施用aPD-1抗体缀合的血小板两者的针对肿瘤复发的免疫功效可以通过经由水凝胶储库局部消耗TAM来加强。肿瘤相关巨噬细胞密度增加与手术后肿瘤复发相关。在本文中，作者设计了一种基于藻酸盐的水凝胶，该水凝胶包封抗PD-1缀合的血小板和装载有巨噬细胞消耗CSF-1 R抑制剂pexidartinib的纳米颗粒，在临床前模型中显示出对术后肿瘤复发的抑制。
Immunosuppressive cells residing in the tumor microenvironment, especially tumor associated macrophages (TAMs), hinder the infiltration and activation of T cells, limiting the anti-cancer outcomes of immune checkpoint blockade. Here, we report a biocompatible alginate-based hydrogel loaded with Pexidartinib (PLX)-encapsulated nanoparticles that gradually release PLX at the tumor site to block colony-stimulating factor 1 receptors (CSF1R) for depleting TAMs. The controlled TAM depletion creates a favorable milieu for facilitating local and systemic delivery of anti-programmed cell death protein 1 (aPD-1) antibody-conjugated platelets to inhibit post-surgery tumor recurrence. The tumor immunosuppressive microenvironment is also reprogrammed by TAM elimination, further promoting the infiltration of T cells into tumor tissues. Moreover, the inflammatory environment after surgery could trigger the activation of platelets to facilitate the release of aPD-1 accompanied with platelet-derived microparticles binding to PD-1 receptors for re-activating T cells. All these results collectively indicate that the immunotherapeutic efficacy against tumor recurrence of both local and systemic administration of aPD-1 antibody-conjugated platelets could be strengthened by local depletion of TAMs through the hydrogel reservoir. Increased density of tumor associated macrophages has been correlated with tumor recurrence following surgery. Here the authors design an alginate-based hydrogel encapsulating anti-PD-1-conjugated platelets and nanoparticles loaded with the macrophage-depleting CSF-1R inhibitor pexidartinib, showing inhibition of post-surgery tumor recurrence in preclinical models.
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影响因子：
3.3
作者：
Haldar, Rita;Ben-Eliyahu, Shamgar
通讯作者：
Ben-Eliyahu, Shamgar
影响因子：
10.9
作者：
Bakos O;Lawson C;Rouleau S;Tai LH
通讯作者：
Tai LH
影响因子：
--
作者：
GILLIES, RJ;LIU, Z;BHUJWALLA, Z
通讯作者：
BHUJWALLA, Z
影响因子：
3.8
作者：
Kim, Hyera;Kwon, Minsuk;Ahn, Myung-Ju
通讯作者：
Ahn, Myung-Ju
肿瘤微环境产生的酸度驱动局部侵袭。
影响因子：
11.2
作者：
Estrella V;Chen T;Lloyd M;Wojtkowiak J;Cornnell HH;Ibrahim-Hashim A;Bailey K;Balagurunathan Y;Rothberg JM;Sloane BF;Johnson J;Gatenby RA;Gillies RJ
通讯作者：
Gillies RJ