Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages.
Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages.
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DOI：
10.1038/nature21409
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发表时间：
2017-03-16
期刊：
影响因子：
64.8
通讯作者：
Letai A
中科院分区：
文献类型：
--
作者：
Guerriero JL;Sotayo A;Ponichtera HE;Castrillon JA;Pourzia AL;Schad S;Johnson SF;Carrasco RD;Lazo S;Bronson RT;Davis SP;Lobera M;Nolan MA;Letai A
尽管免疫肿瘤学的主要焦点一直是调控适应性免疫系统，但利用免疫系统的先天性和适应性两方面可能会更有效地缩小和消除肿瘤。肿瘤相关巨噬细胞（TAMs）通常具有促进肿瘤的净效应，但其所处的位置以及尚未开发的潜力促使人们去探索使其对抗肿瘤的策略。耗竭（抗CSF - 1、CSF - 1R抑制）或刺激（激动性抗CD40、抑制性抗CD47）TAMs的策略已经取得了一些成功。我们则假设对巨噬细胞表型进行药物调节可能具有抗肿瘤效应。我们最近报道了一种首创的选择性IIa类组蛋白去乙酰化酶抑制剂（TMP195）在体外影响人单核细胞对集落刺激因子CSF - 1和CSF - 2的反应。在此，我们利用一种依赖巨噬细胞的乳腺癌原位小鼠模型来证明，体内TMP195治疗可改变肿瘤微环境，并通过巨噬细胞调节减轻肿瘤负荷和肺转移。TMP195诱导肿瘤内高吞噬性和刺激性巨噬细胞的募集和分化。此外，在该模型中将TMP195与化疗方案或T细胞检查点阻断相结合，显著提高了肿瘤缩小的持久性。这些数据引入了IIa类组蛋白去乙酰化酶抑制作为一种利用巨噬细胞抗肿瘤潜力来增强癌症治疗的新方法。
Although the main focus of immuno-oncology has been on manipulating the adaptive immune system, harnessing both the innate and adaptive arms of the immune system might produce superior tumor reduction and elimination. Tumor-associated macrophages (TAMs) often have net pro-tumor effects, but their embedded location and their untapped potential provide impetus to discover strategies to turn them against tumors. Strategies that deplete (αCSF-1, CSF-1R inhibition) or stimulate (agonistic αCD40, inhibitory αCD47) TAMs have met with some success. We instead hypothesized that pharmacologic modulation of macrophage phenotype might have anti-tumor effect. We recently reported that a first-in-class selective class IIa HDAC inhibitor (TMP195) influenced human monocyte responses to colony stimulating factors CSF-1 and CSF-2 in vitro. Here, we utilize a macrophage-dependent autochthonous mouse model of breast cancer to demonstrate that in vivo TMP195 treatment alters the tumor microenvironment and reduces tumor burden and pulmonary metastases through macrophage modulation. TMP195 induces recruitment and differentiation of highly phagocytic and stimulatory macrophages within tumors. Furthermore, combining TMP195 with chemotherapy regimens or T-cell checkpoint blockade in this model significantly enhances the durability of tumor reduction. These data introduce class IIa HDAC inhibition as a novel means to harness the anti-tumor potential of macrophages to enhance cancer therapy.
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影响因子：
50.3
作者：
Jain RK
通讯作者：
Jain RK
影响因子：
15.9
作者：
Gul, Nuray;Babes, Liane;van Egmond, Marjolein
通讯作者：
van Egmond, Marjolein
DOI：
10.1084/jem.20130579
发表时间：
2013-08-26
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Simpson TR;Li F;Montalvo-Ortiz W;Sepulveda MA;Bergerhoff K;Arce F;Roddie C;Henry JY;Yagita H;Wolchok JD;Peggs KS;Ravetch JV;Allison JP;Quezada SA
通讯作者：
Quezada SA
肿瘤相关巨噬细胞的细胞和分子起源。
DOI：
10.1126/science.1252510
发表时间：
2014-05-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Franklin RA;Liao W;Sarkar A;Kim MV;Bivona MR;Liu K;Pamer EG;Li MO
通讯作者：
Li MO
DOI：
10.1084/jem.20130762
发表时间：
2013-10-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Bos PD;Plitas G;Rudra D;Lee SY;Rudensky AY
通讯作者：
Rudensky AY