Wilms tumor reveals DNA repair gene hyperexpression is linked to lack of tumor immune infiltration.
Wilms tumor reveals DNA repair gene hyperexpression is linked to lack of tumor immune infiltration.
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DOI：
10.1136/jitc-2022-004797
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发表时间：
2022-06
影响因子：
10.9
通讯作者：
Gajewski, Thomas F.
中科院分区：
文献类型：
--
作者：
Higgs, Emily F.;Bao, Riyue;Hatogai, Ken;Gajewski, Thomas F.
在几种成人癌症中，富含T细胞的肿瘤微环境与改善的临床结果和对免疫检查点阻断疗法的反应相关。了解肿瘤中缺乏免疫细胞浸润的机制对于扩大免疫治疗疗效至关重要。为了获得对肿瘤免疫原性差的机制的新见解，我们转向儿科癌症，这些癌症通常对检查点阻断无反应。肾母细胞瘤、横纹肌样瘤、骨肉瘤和神经母细胞瘤的RNA测序和临床数据来自产生有效治疗的治疗适用研究（TARGET）数据库，成人癌症来自癌症基因组图谱（TCGA）。使用代表活化的CD 8 + T细胞的18基因肿瘤炎症标记（TIS），我们鉴定了与标记负相关的基因。基于这些结果，还分析了成人肿瘤，并对转移性黑色素瘤样品进行免疫荧光分析，以评估MSH 2与抗程序性细胞死亡蛋白-1（PD-1）疗效的关系。在四种儿科癌症中，我们观察到Wilms肿瘤的TIS评分最低。与匹配的正常肾组织相比，肾母细胞瘤的TIS评分较低，这表明内源性T细胞浸润丧失。对肾母细胞瘤中上调的基因进行通路分析，并与TIS反相关，发现激活的通路涉及DNA修复。TCGA中的大多数成人肿瘤也显示出与低TIS相关的高DNA修复评分。来自独立队列的黑色素瘤样品揭示了MSH 2+肿瘤细胞和CD 8 + T细胞之间的负相关性。此外，具有高MSH 2+肿瘤细胞数量的黑色素瘤在很大程度上对抗PD-1治疗无应答。DNA修复基因的肿瘤表达增加与Wilms肿瘤和大多数TCGA肿瘤类型中较不稳健的免疫应答相关。令人惊讶的是，当校正突变计数时，DNA修复评分和TIS之间的负相关在TCGA中仍然很强，表明DNA修复基因在防止突变积累之外的潜在作用。虽然DNA修复机制的丧失与致癌作用和突变抗原的产生有关，但我们的研究结果表明，DNA修复基因的过表达可能会抑制抗肿瘤免疫力，因此认为DNA修复的药理学靶向是一种潜在的治疗策略。
A T cell-rich tumor microenvironment has been associated with improved clinical outcome and response to immune checkpoint blockade therapies in several adult cancers. Understanding the mechanisms for lack of immune cell infiltration in tumors is critical for expanding immunotherapy efficacy. To gain new insights into the mechanisms of poor tumor immunogenicity, we turned to pediatric cancers, which are generally unresponsive to checkpoint blockade. RNA sequencing and clinical data were obtained for Wilms tumor, rhabdoid tumor, osteosarcoma, and neuroblastoma from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database, and adult cancers from The Cancer Genome Atlas (TCGA). Using an 18-gene tumor inflammation signature (TIS) representing activated CD8+ T cells, we identified genes inversely correlated with the signature. Based on these results, adult tumors were also analyzed, and immunofluorescence was performed on metastatic melanoma samples to assess the MSH2 relationship to anti-programmed cell death protein-1 (PD-1) efficacy. Among the four pediatric cancers, we observed the lowest TIS scores in Wilms tumor. TIS scores were lower in Wilms tumors compared with matched normal kidney tissues, arguing for loss of endogenous T cell infiltration. Pathway analysis of genes upregulated in Wilms tumor and anti-correlated with TIS revealed activated pathways involved DNA repair. The majority of adult tumors in TCGA also showed high DNA repair scores associated with low TIS. Melanoma samples from an independent cohort revealed an inverse correlation between MSH2+ tumor cells and CD8+ T cells. Additionally, melanomas with high MSH2+ tumor cell numbers were largely non-responders to anti-PD-1 therapy. Increased tumor expression of DNA repair genes is associated with a less robust immune response in Wilms tumor and the majority of TCGA tumor types. Surprisingly, the negative relationship between DNA repair score and TIS remained strong across TCGA when correcting for mutation count, indicating a potential role for DNA repair genes outside of preventing the accumulation of mutations. While loss of DNA repair machinery has been associated with carcinogenesis and mutational antigen generation, our results suggest that hyperexpression of DNA repair genes might be prohibitive for antitumor immunity, arguing for pharmacologic targeting of DNA repair as a potential therapeutic strategy.
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