鉴定DNA错配修复损失的遗传决定因素,预测对免疫检查点封锁的反应

Charlotte Smith, D. Cucchi, Amy Gibson, Kirsten Brooksbank, S. Martin
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摘要

尽管具有很大的临床前景,但免疫检查点阻断(ICB)的应答率差异很大,而且缺乏应答的生物标志物。最近一项针对DNA错配修复(MMR)途径缺陷患者的II期临床试验表明,MMR状态预示着PD-1抑制剂派姆单抗的临床益处。这些发现导致了抗PD-1治疗MMR缺乏症不可切除或转移性实体瘤的首次组织不可知批准。然而,越来越清楚的是,许多mmr缺陷肿瘤对ICBs没有反应,约50%的肿瘤难以治疗。此外,应答者的临床获益差异很大。然而,为什么会出现这种情况,以及如何将其临床转化,在很大程度上仍然未知。我们激动人心的初步数据表明,特异性MMR基因的缺失导致免疫检查点分子PD-L1表达的差异增加。值得注意的是,我们观察到在MMR基因MLH1、MSH2、PMS2和MSH3沉默的细胞中PD-L1表达上调,正如预期的那样。然而,我们没有观察到MSH6缺失后PD-L1的表达增加。在RNA和细胞表面水平上进一步验证了MMR基因缺失之间的差异表达。通过研究MMR缺失后调控PD-L1表达的分子机制,我们发现STAT1的磷酸化与PD-L1的表达呈正相关,而STAT3的磷酸化与PD-L1的表达呈负相关,因此在MLH1和PMS2缺失的细胞中,STAT1的磷酸化增加,而在MSH6缺失的细胞中没有,而STAT3的磷酸化仅在MSH6缺失的细胞中观察到。值得注意的是,在药理学和遗传学上,抑制STAT3可以恢复msh6缺陷细胞中PD-L1的表达。因此,我们有证据表明特异性MMR基因的缺失可以通过STAT1/STAT3介导的途径触发PD-L1的差异表达,我们假设正是这种差异表达可能在一定程度上决定了对ICB治疗的敏感性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Identification of genetic determinants of DNA mismatch repair loss that predict response to immune checkpoint blockade
Despite showing great clinical promise, response rates to immune checkpoint blockade (ICB) vary greatly and biomarkers of response are lacking. A recent Phase II clinical trial in patients with deficiency in the DNA mismatch repair (MMR) pathway indicated that MMR status predicted clinical benefit with the PD-1 inhibitor, pembrolizumab. These findings have led to the first tissue-agnostic approval for anti PD-1 therapy for unresectable or metastatic solid tumours with MMR deficiency. However, it is becoming increasingly clear that many MMR-deficient tumours fail to respond to ICBs with ~50% refractory to treatment. Furthermore, there is a wide diversity of clinical benefit among responders. However why this is the case and how this can be clinically translated remains largely unknown. Our exciting preliminary data suggest that loss of specific MMR genes results in a differential increased expression of the immune checkpoint molecule, PD-L1. Significantly, we observed an upregulation of PD-L1 expression in cells silenced for the MMR genes, MLH1, MSH2, PMS2 and MSH3, as expected. However, we did not observe an increased expression of PD-L1 upon MSH6 loss. This differential expression amongst MMR gene loss was further validated at both RNA and cell surface level. Upon investigation of the molecular mechanism regulating PD-L1 expression after MMR loss, we observed that that phosphorylation of STAT1 positively correlates with PD-L1 expression whilst STAT3 phosphorylation was negatively correlated, such that increased STAT1 phosphorylation was observed upon MLH1 and PMS2 loss and not in MSH6-deficient cells whilst STAT3 phosphorylation was only observed upon MSH6 loss. Significantly, inhibition of STAT3, both pharmacologically and genetically, reinstated PD-L1 expression in MSH6-deficient cells. Therefore, we have evidence that loss of specific MMR genes can trigger differential expression of PD-L1 through a STAT1/STAT3 mediated pathway and we hypothesize that it is this differential expression that may in part determine sensitivity to treatment with ICB.
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