High-grade serous ovarian cancer (HGSC), the principal cause of death from gynecological malignancies in the world, has not significantly benefited from advances in cancer immunotherapy. Although HGSC infiltration by lymphocytes correlates with superior survival, the nature of antigens that can elicit anti-HGSC immune responses is unknown. The goal of this study was to establish the global landscape of HGSC tumor-specific antigens (TSAs) using a mass spectrometry pipeline that interrogated all reading frames of all genomic regions. In 23 HGSC tumors, we identified 103 TSAs. Classic TSA discovery approaches focusing only on mutated exonic sequences would have uncovered only three of these TSAs. Other mutated TSAs resulted from out-of-frame exonic translation (n=2) or from noncoding sequences (n=7). One group of TSAs (n=91) derived from aberrantly expressed unmutated genomic sequences, which were not expressed in normal tissues. These aberrantly expressed TSAs (aeTSAs) originated primarily from non-exonic sequences, in particular intronic (29%) and intergenic (22%) sequences. Their expression was regulated at the transcriptional level by variations in gene copy number and DNA methylation. Although mutated TSAs were unique to individual tumors, aeTSAs were shared by a large proportion of HGSCs. Taking into account the frequency of aeTSA expression and HLA allele frequencies, we calculated that, in Caucasians, the median number of aeTSAs per tumor would be five. We conclude that, in view of their number and the fact that they are shared by many tumors, aeTSAs may be the most attractive targets for HGSC immunotherapy.

中文翻译：

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蛋白质组学揭示了卵巢癌中大量的肿瘤特异性抗原。

高级别浆液性卵巢癌（HGSC）是世界上妇科恶性肿瘤致死的主要原因，并没有从癌症免疫治疗的进展中显着受益。尽管淋巴细胞向HGSC的浸润与存活率较高有关，但可引发抗HGSC免疫应答的抗原的性质尚不清楚。这项研究的目的是使用质询所有基因组区域的所有阅读框的质谱管线来建立HGSC肿瘤特异性抗原（TSA）的全球格局。在23种HGSC肿瘤中，我们鉴定出103种TSAs。仅关注突变外显子序列的经典TSA发现方法将只发现其中三个TSA。其他突变的TSA是由帧外外显子翻译（n = 2）或非编码序列（n = 7）引起的。一组源自异常表达的未突变基因组序列的TSA（n = 91），在正常组织中不表达。这些异常表达的TSA（aeTSA）主要源自非外显子序列，尤其是内含子（29％）和基因间（22％）序列。它们的表达在转录水平上通过基因拷贝数和DNA甲基化的变化来调节。尽管突变的TSA对于单个肿瘤是独特的，但是aeTSA被大部分HGSC共享。考虑到aeTSA表达的频率和HLA等位基因频率，我们计算出，在白种人中，每个肿瘤的aeTSA的中位数为5。我们得出结论，鉴于它们的数量以及许多肿瘤所共有的事实，aeTSA可能是HGSC免疫疗法最有吸引力的靶标。