Hurtado López Ana María, Chen-Liang Tzu Hua, Zurdo María, Carrillo-Tornel Salvador, Panadero Joaquín, Salido Eduardo José, Beltrán Victor, Muiña Begoña, Amigo MariLuz, Navarro-Villamor Noelia, Cifuentes Rosa, Calabria Inés, Antón Ana Isabel, Teruel Raúl, Muro Manuel, Vicente Vicente, Jerez Andrés
Hematology and Medical Oncology Department, Hospital Universitario Morales Meseguer, IMIB, Murcia, Spain.
Genomics Unit, Health Research Institute La Fe, Valencia, Spain.
Oncoimmunology. 2020 Oct 1;9(1):1824642. doi: 10.1080/2162402X.2020.1824642.
Cancer-Testis antigens (CTA) are named after the tissues where they are mainly expressed: in germinal and in cancer cells, a process that mimics many gametogenesis features. Mapping accurately the CTA gene expression signature in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) is a prerequisite for downstream immune target-discovery projects. In this study, we take advantage of the use of azacitidine to treat high-risk MDS and CMML to draw the CTAs landscape, before and after treatment, using an targeted RNA sequencing (RNA-seq) design for this group of low transcript genes. In 19 patients, 196 CTAs were detected at baseline. Azacitidine did not change the number of CTAs expressed, but it significantly increased or decreased expression in nine and five CTAs, respectively. and , emerged as the main candidates for immunotherapeutic targeting, as they showed three main features: i) a significant derepression on day +28 of cycle one in those patients who achieved complete remission with hypomethylating treatment (FC = 6, = .008; FC = 2.1, = .008, respectively), ii) similar dynamics at the protein level to what was observed at the RNA layer, and iii) to elicit significant specific cytotoxic immune responses detected by TFDP3 and DDX53 HLA-A*0201 tetramers. Our study addresses the unmet landscape of CTAs expression in MDS and CMML and revealed a previously unrecognized and reactivation, detectable in plasma and able to elicit a specific immune response after one cycle of azacitidine.
癌-睾丸抗原（CTA）因其主要表达的组织而得名：在生殖细胞和癌细胞中表达，这一过程模拟了许多配子发生的特征。准确绘制骨髓增生异常综合征（MDS）和慢性粒单核细胞白血病（CMML）中CTA基因表达特征图谱是下游免疫靶点发现项目的前提条件。在本研究中，我们利用阿扎胞苷治疗高危MDS和CMML的机会，通过针对这组低转录本基因的靶向RNA测序（RNA-seq）设计，描绘治疗前后的CTA图谱。在19例患者中，基线时检测到196种CTA。阿扎胞苷并未改变CTA的表达数量，但分别使9种和5种CTA的表达显著增加或减少。TFDP3和DDX53作为免疫治疗靶向的主要候选者出现，因为它们具有三个主要特征：i）在接受低甲基化治疗实现完全缓解的患者中，在第1周期第28天显著去抑制（FC = 6，P = 0.008；FC = 2.1，P = 0.008）；ii）蛋白质水平的动态变化与RNA层面观察到的相似；iii）能引发由TFDP3和DDX53 HLA-A*0201四聚体检测到的显著特异性细胞毒性免疫反应。我们的研究解决了MDS和CMML中CTA表达未被满足的情况，并揭示了一种先前未被识别的TFDP3和DDX53激活，在血浆中可检测到，且在一个周期的阿扎胞苷治疗后能够引发特异性免疫反应。
