Surveillance of the Tumor Mutanome by T Cells during Progression from Primary to Recurrent Ovarian Cancer
Surveillance of the Tumor Mutanome by T Cells during Progression from Primary to Recurrent Ovarian Cancer
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DOI：
10.1158/1078-0432.ccr-13-2147
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发表时间：
2014-03-01
影响因子：
11.5
通讯作者：
Nelson, Brad H.
中科院分区：
文献类型：
--
作者：
Wick, Darin A.;Webb, John R.;Nelson, Brad H.
目的：癌症随着时间的推移积累突变，每个突变都有可能被免疫系统识别。我们评估了接受标准治疗的卵巢癌患者的T细胞对肿瘤突变组的识别。实验设计：通过ELISPOT评估来自3名卵巢癌患者的肿瘤相关T细胞对通过自体肿瘤全外显子组测序鉴定的非同义突变的识别。结果：绝大多数突变（78/79）不被肿瘤相关T细胞识别;然而，在1例患者中检测到对突变的羟类固醇脱氢酶样蛋白1（HSDL 1）（L25 V）的高度特异性CD 8（+）T细胞应答。在原发性肿瘤中，HSDL 1（L25 V）突变的发生率和表达率较低，相应的T细胞反应检测不到。在第一次复发时，突变和相应的MHC I类表位的丰度显著增加，并且这伴随着HSDL 1（L25 V）特异性CD 8（+）T细胞应答的出现。在第二次复发，HSDL 1（L25 V）突变和表位继续表达，然而，相应的T细胞反应不再detected.Conclusion：免疫系统可以响应不断发展的卵巢癌基因组。然而，这里检测到的T细胞反应是罕见的，是短暂的，最终未能阻止疾病进展。这些发现揭示了自发肿瘤免疫在标准治疗中的局限性，并表明对可能通过免疫治疗逆转的肿瘤突变的高度忽视。(C)2013年AACR。
Purpose: Cancers accumulate mutations over time, each of which brings the potential for recognition by the immune system. We evaluated T-cell recognition of the tumor mutanome in patients with ovarian cancer undergoing standard treatment.Experimental Design: Tumor-associated T cells from 3 patients with ovarian cancer were assessed by ELISPOT for recognition of nonsynonymous mutations identified by whole exome sequencing of autologous tumor. The relative levels of mutations and responding T cells were monitored in serial tumor samples collected at primary surgery and first and second recurrence.Results: The vast majority of mutations (78/79) were not recognized by tumor-associated T cells; however, a highly specificCD8(+) T-cell response to the mutation hydroxysteroid dehydrogenase-like protein 1 (HSDL1)(L25V) was detected in one patient. In the primary tumor, the HSDL1(L25V) mutation had low prevalence and expression, and a corresponding T-cell response was undetectable. At first recurrence, there was a striking increase in the abundance of the mutation and corresponding MHC class I epitope, and this was accompanied by the emergence of the HSDL1(L25V) -specific CD8(+) T-cell response. At second recurrence, the HSDL1(L25V) mutation and epitope continued to be expressed; however, the corresponding T-cell response was no longer detectable.Conclusion: The immune system can respond to the evolving ovarian cancer genome. However, the T-cell response detected here was rare, was transient, and ultimately failed to prevent disease progression. These findings reveal the limitations of spontaneous tumor immunity in the setting of standard treatments and suggest a high degree of ignorance of tumor mutations that could potentially be reversed by immunotherapy. (C) 2013 AACR.