Potential role of brachyury in HLA class I antigen processing machinery component downregulation in chordoma cells

Brachyury 在脊索瘤细胞 HLA I 类抗原加工机制成分下调中的潜在作用

• 批准号: 10908087
• 负责人: Cristina R. Ferrone
• 金额: $ 7.74万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10908087
• 关键词: Potential; role; brachyury; HLA; class

ABSTRACT Chordomas are spinal neoplasms uniquely characterized by their overexpression of the transcription factor brachyury. Beyond its role as a biomarker, brachyury is critical for disease pathogenesis and therefore appears to be an attractive target for therapy. However, development of strategies targeting brachyury has had slow progress. Complete surgical resection, the current gold standard treatment, is not always feasible. Radiotherapy is the main adjuvant treatment, but unfortunately brachyury is known to mediate radio-resistance, as well as chemo- resistance. Thus, interest in novel T cell-based immunotherapies arose, but they too yielded poor results. We hypothesize that the latter is due to defective HLA class I antigen processing machinery (APM) component expression in chordoma cells. Indeed, T cell-based immunotherapies are dependent on the presentation of tumor antigen peptides to the host’s immune system, requiring that HLA class I APM is fully functional. Our analysis of a small number of surgically removed chordoma tumors has shown that HLA class I APM expression defects are frequent in chordoma cells. The underlying molecular mechanisms behind these defects have been poorly characterized. Our goal is therefore to investigate the mechanisms underlying HLA class I APM component expression defects in chordoma cells. We focus on brachyury and the protein tyrosine phosphatase SHP2 which we have previously shown to play a role in HLA class I APM component downregulation in other cancer types. We have found that higher SHP2 expression is associated with lower HLA class I APM component expression in chordoma cell lines, and that SHP2 expression is positively correlated with brachyury expression. Furthermore, YAP1, a direct target of brachyury in chordoma which is associated with HLA class I APM component downregulation in other tumor types, was found to interact with SHP2. This was demonstrated by the presence of a YAP1 binding site on conserved regions of the SHP2 promoter. In turn, SHP2 has been shown to suppress HLA class I APM component expression by inhibiting phosphorylation of STAT1, a transcription factor required for HLA class I APM component expression. Overall, these data support the model Brachyury YAP1 SHP2 pSTAT1 HLA class I APM, demonstrating a potential role of brachyury in HLA class I APM component downregulation in chordoma cells, via upregulation of SHP2. Therefore, we aim to: i) delineate the potential role of brachyury in HLA class I APM component downregulation in chordoma cells; ii) assess the in vivo ability of small molecule SHP2 inhibitor SHP099 to restore HLA class I APM component expression and functional activity in chordoma cells; and iii) assess the clinical significance of the hypothesized model by determining the association of HLA class I APM component expression with the expression of brachyury, YAP1 and SHP2 in surgically removed tumors. The results obtained will contribute to the rational design of strategies to restore HLA class I APM component expression in chordoma cells which will likely improve the efficacy of T cell-based immunotherapies for this disease.

摘要 脊索瘤是以转录因子过度表达为特征的脊椎肿瘤。 太短促了。除了作为生物标记物的作用外，短视对于疾病的发病机制也是至关重要的，因此似乎 成为有吸引力的治疗对象。然而，针对短兵相接战略的开发进展缓慢。 完全手术切除是目前的金标准治疗方法，但并不总是可行的。放射治疗是主要的 辅助治疗，但不幸的是，短兵相接是已知的调解放射抵抗，以及化疗- 抵抗。因此，出现了对基于T细胞的新型免疫疗法的兴趣，但它们也产生了糟糕的结果。我们 假设后者是由于人类白细胞抗原I类抗原处理机制(APM)组件缺陷所致 在脊索瘤细胞中表达。事实上，基于T细胞的免疫疗法依赖于肿瘤的表现 抗原肽到宿主的免疫系统，要求人类白细胞抗原I类APM具有完全的功能。我们的分析 少数经手术切除的脊索瘤肿瘤已显示出人类白细胞抗原I类APM表达缺陷 在脊索瘤细胞中很常见。这些缺陷背后的潜在分子机制一直很差。 特色化的。因此，我们的目标是研究人类白细胞抗原I类APM组件的潜在机制 脊索瘤细胞中的表达缺陷。我们的重点是短吻和蛋白酪氨酸磷酸酶SHP2，它是 我们之前已经证明，在其他癌症类型中，人类白细胞抗原I类APM组分的下调起到了作用。 我们发现SHP2的高表达与HLAI类APM成分的低表达相关。 SHP2的表达与短缩蛋白的表达呈正相关。此外， 脊索瘤短缩的直接靶点YAP1与人类白细胞抗原I类APM组分相关 在其他肿瘤类型中下调，被发现与SHP2相互作用。这一点从在场的人身上可见一斑 在SHP2启动子的保守区有一个YAP1结合位点。反过来，SHP2被证明抑制了 通过抑制转录因子STAT1的磷酸化来表达HL A-I类APM成分 对于HLAI类APM组分的表达。总体而言，这些数据支持模型BrachyuryYAP1 Shp2HLAPSTAT1HLAIAPM，显示短暂性在IAPM中的潜在作用 脊索瘤细胞的成分下调，通过上调SHP2。因此，我们的目标是：i)划定 短臂在脊索瘤细胞中HLAI类APM组分下调中的潜在作用；ii)评估 小分子SHP2抑制剂SHP099恢复人类白细胞抗原I类APM组分表达的体内能力 脊索瘤细胞的功能活性；以及iii)通过以下方式评估假设模型的临床意义 人类白细胞抗原I类APM组分表达与短缩蛋白YAP1表达的相关性研究 和SHP2在手术切除的肿瘤中的表达。所得到的结果将有助于战略的合理设计 在脊索瘤细胞中恢复人类白细胞抗原I类APM组分的表达，可能会提高 以T细胞为基础的免疫疗法治疗这种疾病。

项目成果

The SPPL3-Defined Glycosphingolipid Repertoire Orchestrates HLA Class I-Mediated Immune Responses.

• DOI: 10.1016/j.immuni.2020.11.003
• 发表时间: 2021-01-12
• 期刊: Immunity
• 影响因子: 32.4
• 作者: Jongsma MLM;de Waard AA;Raaben M;Zhang T;Cabukusta B;Platzer R;Blomen VA;Xagara A;Verkerk T;Bliss S;Kong X;Gerke C;Janssen L;Stickel E;Holst S;Plomp R;Mulder A;Ferrone S;Claas FHJ;Heemskerk MHM;Griffioen M;Halenius A;Overkleeft H;Huppa JB;Wuhrer M;Brummelkamp TR;Neefjes J;Spaapen RM
• 通讯作者: Spaapen RM