巨噬细胞成癌症帮凶:组蛋白去乙酰化酶抑制剂可破!
  • 肿瘤相关巨噬细胞(TAM)在肿瘤微环境中扮演双面角色:促癌 VS 抗癌;
  • TMP195( IIa类组蛋白去乙酰化酶抑制剂),影响人单核细胞包括巨噬细胞的分化、募集;
  • 注射TMP195到乳腺癌老鼠模型中,肿瘤体积缩小、肺转移减少、肿瘤微环境中TAM朝向抗癌的、具有吞噬功能的M1型巨噬细胞分化;
  • TMP195联合化疗,或联合免疫检查点抑制剂,治疗乳腺癌小鼠,效果更佳;
  • IIa型组蛋白去乙酰化酶抑制剂,未来或将成为肿瘤免疫治疗理想的联合对象。
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Nature [IF:42.778]

Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages

Nature:抑制IIa类组蛋白去乙酰化酶可诱导抗肿瘤巨噬细胞分化募集从而抑制乳腺癌生长和转移扩散

10.1038/nature21409

2017-03-08, Letter

Abstract & Authors:展开

Abstract:收起
Although the main focus of immuno-oncology has been manipulating the adaptive immune system, harnessing both the innate and adaptive arms of the immune system might produce superior tumour reduction and elimination. Tumour-associated macrophages often have net pro-tumour effects, but their embedded location and their untapped potential provide impetus to discover strategies to turn them against tumours. Strategies that deplete (anti-CSF-1 antibodies and CSF-1R inhibition) or stimulate (agonistic anti-CD40 or inhibitory anti-CD47 antibodies) tumour-associated macrophages have had some success. We hypothesized that pharmacologic modulation of macrophage phenotype could produce an anti-tumour effect. We previously reported that a first-in-class selective class IIa histone deacetylase (HDAC) inhibitor, TMP195, influenced human monocyte responses to the 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 tumour microenvironment and reduces tumour burden and pulmonary metastases by modulating macrophage phenotypes. TMP195 induces the recruitment and differentiation of highly phagocytic and stimulatory macrophages within tumours. Furthermore, combining TMP195 with chemotherapy regimens or T-cell checkpoint blockade in this model significantly enhances the durability of tumour reduction. These data introduce class IIa HDAC inhibition as a means to harness the anti-tumour potential of macrophages to enhance cancer therapy.

First Authors:
Michael A Nolan,Anthony Letai

Correspondence Authors:
Michael A Nolan,Anthony Letai

All Authors:
Jennifer L Guerriero,Alaba Sotayo,Holly E Ponichtera,Jessica A Castrillon,Alexandra L Pourzia,Sara Schad,Shawn F Johnson,Ruben D Carrasco,Suzan Lazo,Roderick T Bronson,Scott P Davis,Mercedes Lobera,Michael A Nolan,Anthony Letai

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