Eggink Florine A, Van Gool Inge C, Leary Alexandra, Pollock Pamela M, Crosbie Emma J, Mileshkin Linda, Jordanova Ekaterina S, Adam Julien, Freeman-Mills Luke, Church David N, Creutzberg Carien L, De Bruyn Marco, Nijman Hans W, Bosse Tjalling
Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen , Groningen, the Netherlands.
Department of Pathology, Leiden University Medical Center , Leiden, the Netherlands.
Oncoimmunology. 2016 Dec 9;6(2):e1264565. doi: 10.1080/2162402X.2016.1264565. eCollection 2017.
High-risk endometrial cancer (EC) is an aggressive disease for which new therapeutic options are needed. Aims of this study were to validate the enhanced immune response in highly mutated ECs and to explore immune profiles in other EC subgroups. We evaluated immune infiltration in 116 high-risk ECs from the TransPORTEC consortium, previously classified into four molecular subtypes: (i) ultramutated exonuclease domain-mutant ECs (-mutant); (ii) hypermutated microsatellite unstable (MSI); (iii) p53-mutant; and (iv) no specific molecular profile (NSMP). Within The Cancer Genome Atlas (TCGA) EC cohort, significantly higher numbers of predicted neoantigens were demonstrated in -mutant and MSI tumors compared with NSMP and p53-mutants. This was reflected by enhanced immune expression and infiltration in -mutant and MSI tumors in both the TCGA cohort (mRNA expression) and the TransPORTEC cohort (immunohistochemistry) with high infiltration of CD8 (90% and 69%), PD-1 (73% and 69%) and PD-L1 immune cells (100% and 71%). Notably, a subset of p53-mutant and NSMP cancers was characterized by signs of an antitumor immune response (43% and 31% of tumors with high infiltration of CD8 cells, respectively), despite a low number of predicted neoantigens. In conclusion, the presence of enhanced immune infiltration, particularly high numbers of PD-1 and PD-L1 positive cells, in highly mutated, neoantigen-rich -mutant and MSI endometrial tumors suggests sensitivity to immune checkpoint inhibitors.
高危子宫内膜癌（EC）是一种侵袭性疾病，需要新的治疗选择。本研究的目的是验证高突变EC中增强的免疫反应，并探索其他EC亚组的免疫特征。我们评估了来自TransPORTEC联盟的116例高危EC中的免疫浸润情况，这些病例先前被分为四种分子亚型：（i）超突变外切核酸酶结构域突变型EC（-突变型）；（ii）高突变微卫星不稳定（MSI）型；（iii）p53突变型；以及（iv）无特定分子特征（NSMP）型。在癌症基因组图谱（TCGA）的EC队列中，与NSMP和p53突变型肿瘤相比，-突变型和MSI肿瘤中预测的新抗原数量显著更高。这在TCGA队列（mRNA表达）和TransPORTEC队列（免疫组织化学）中的-突变型和MSI肿瘤的免疫表达和浸润增强中得到体现，其中CD8（90%和69%）、PD-1（73%和69%）和PD-L1免疫细胞浸润率高（分别为100%和71%）。值得注意的是，尽管预测的新抗原数量较少，但一部分p53突变型和NSMP癌症具有抗肿瘤免疫反应的迹象（分别有43%和31%的肿瘤CD8细胞浸润率高）。总之，在高度突变、富含新抗原的-突变型和MSI子宫内膜肿瘤中存在增强的免疫浸润，尤其是大量的PD-1和PD-L1阳性细胞，提示对免疫检查点抑制剂敏感。
