2017年3月8日,英国《自然》在线发表美国哈佛医学院、达纳法伯癌症研究所、布莱根女子医院、葛兰素史克马萨诸塞州剑桥研发中心的研究报告,发现新型肿瘤免疫疗法可逆转乳腺癌免疫系统,通过抑制IIa类组蛋白脱乙酰酶(HDAC),使肿瘤相关巨噬细胞逆转产生抗肿瘤作用,减少乳腺肿瘤细胞及其转移。
就目前新一代肿瘤免疫疗法成功案例而言,大多并不是指整个免疫系统,这些疗法主要作用于获得性免疫系统,即对外来和疾病细胞进行精准攻击。但是免疫系统还有另一面,即先天性免疫系统,该系统实际上有时也会促进肿瘤生长。 该研究发现一种能够逆转先天性免疫系统的新型化合物,将该免疫系统从肿瘤启动者逆转为肿瘤对抗者,使小鼠乳腺肿瘤缩小,并减少其远处转移。将该疗法与化疗或另一种免疫疗法结合,可显著延长肿瘤缓解时间。该发现提出一种能将整个免疫系统投入对抗肿瘤的方法。 当前大多数肿瘤免疫疗法都是通过诱导获得性免疫系统T细胞攻击肿瘤细胞,或消除攻击障碍。该策略已经有效对抗若干类型的癌症,但是通常只有部分患者获益。该研究希望通过免疫系统的两个方面获得更好结果。 该研究的靶标即肿瘤相关巨噬细胞,此类先天性免疫系统细胞通常深嵌于肿瘤,虽然是免疫系统的一部分,可帮助人体对抗疾病,但是这些细胞常常促进肿瘤生长,对肿瘤产生的信号做出应答。 巨噬细胞发挥的作用有时为保护性,有时为破坏性,这取决于来自周围环境的信号。例如在伤口愈合时,巨噬细胞调节免疫系统,清除受损组织并恢复受影响的区域。而肿瘤相关巨噬细胞则利用这些作用达到保护自己的目的,因此癌症有时被称为不愈合的伤口。 既往研究已经发现,选择性一流的IIa类HDAC抑制剂(TMP195)通过改变肿瘤相关巨噬细胞内的基因活性,转换巨噬细胞应答,可以将肿瘤相关巨噬细胞从帮助肿瘤生长转变为攻击肿瘤生长。 该研究发现TMP195可显著降低小鼠乳腺癌生长速度,随后将TMP195与各种化疗方案以及一种T细胞检查点抑制剂免疫疗法结合,发现在这两种联合疗法与单用TMP195相比,可使乳腺癌缓解时间显著延长。 因此,巨噬细胞一旦发生逆转,就会成为免疫系统攻击肿瘤的协调者,IIa类HDAC抑制剂(TMP195)就可能利用巨噬细胞有效对抗肿瘤。 未来的乳腺癌治疗可能需要先天性免疫系统、获得性免疫系统,以及作用于乳腺癌细胞本身的疗法组合,后者如化疗、放疗、内分泌疗法、靶向疗法。先天性免疫系统是一个令人兴奋的乳腺癌治疗新前线。
Nature. 2017 Mar 8. [Epub ahead of print] Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages. 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. Dana-Farber Cancer Institute; Brigham and Women's Hospital; Harvard Medical School, Boston, Massachusetts, USA; GlaxoSmithKline, Cambridge, Massachusetts, USA. 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. PMID: 28273064 DOI: 10.1038/nature21409 |
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