Authors' Affiliations: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency; Department of Biochemistry and Microbiology, University of Victoria, Victoria; Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver; Departments of Medical Genetics and Pathology and Laboratory Medicine, University of British Columbia, Vancouver; and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
Clin Cancer Res. 2014 Mar 1;20(5):1125-34. doi: 10.1158/1078-0432.CCR-13-2147. Epub 2013 Dec 9.
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.
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.
The vast majority of mutations (78/79) were not recognized by tumor-associated T cells; however, a highly specific CD8(+) 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.
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.
癌症会随着时间的推移积累突变，每一个突变都有可能被免疫系统识别。我们评估了正在接受标准治疗的卵巢癌患者的肿瘤突变组中 T 细胞的识别情况。
通过 ELISPOT 评估了 3 名卵巢癌患者的肿瘤相关 T 细胞对自体肿瘤外显子组测序鉴定的非同义突变的识别情况。在原发性手术和第一次及第二次复发时连续采集的肿瘤样本中监测突变和应答 T 细胞的相对水平。
绝大多数突变（78/79）未被肿瘤相关 T 细胞识别；然而，在一名患者中检测到针对突变羟固醇脱氢酶样蛋白 1（HSDL1）（L25V）的高度特异性 CD8+T 细胞反应。在原发性肿瘤中，HSDL1（L25V）突变的患病率和表达水平较低，无法检测到相应的 T 细胞反应。在第一次复发时，突变及其相应的 MHC Ⅰ类表位的丰度显著增加，同时出现了 HSDL1（L25V）特异性 CD8+T 细胞反应。在第二次复发时，HSDL1（L25V）突变和表位继续表达；然而，相应的 T 细胞反应不再可检测。
免疫系统可以对不断进化的卵巢癌基因组作出反应。然而，这里检测到的 T 细胞反应是罕见的、短暂的，最终未能阻止疾病进展。这些发现揭示了在标准治疗环境下自发肿瘤免疫的局限性，并表明对潜在可通过免疫疗法逆转的肿瘤突变存在高度的无知。
