Neoantigen load and HLA-class I expression identify a subgroup of tumors with a T-cell-inflamed phenotype and favorable prognosis in homologous recombination-proficient high-grade serous ovarian carcinoma
Neoantigen load and HLA-class I expression identify a subgroup of tumors with a T-cell-inflamed phenotype and favorable prognosis in homologous recombination-proficient high-grade serous ovarian carcinoma
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新抗原负载和 HLA-I 类表达鉴定出具有 T 细胞炎症表型的肿瘤亚组，并且在同源重组熟练的高级别浆液性卵巢癌中具有良好的预后
DOI：
10.1136/jitc-2019-000375
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发表时间：
2020
影响因子：
10.9
通讯作者：
K
中科院分区：
文献类型：
--
作者：
Matsushita Hirokazu;Hasegawa Kosei;Oda Katsutoshi;Yamamoto Shogo;Asada Kayo;Karasaki Takahiro;Yabuno Akira;Nishijima Akira;Nejo Takahide;Kobayashi Yukari;Sato Sho;Ikeda Yuji;Miyai Manami;Takahashi Yusuke;Yamaguchi Rui;Fujiwara Keiichi;Aburatani Hiroyuki;K
背景越来越多的证据表明，聚ADP核糖聚合酶（PARP）抑制剂对一部分高级别浆液性卵巢癌（HGSC）患者，尤其是那些同源重组（HR）缺陷型肿瘤患者有益。然而，新的治疗策略，如免疫检查点抑制，需要与HR熟练的肿瘤患者。方法对80例HGSC患者的临床资料进行分析。对这些肿瘤进行全外显子组和RNA测序。甲基化阵列也进行了检查BRCA 1和RAD 51 C启动子甲基化状态。研究了突变、新抗原负荷、抗原呈递机制和局部免疫特征，并分析了这些因素与临床结局的关系。结果与预期的一样，预测的neoAg的数量在HR熟练的肿瘤（n=46）中低于HR缺陷的肿瘤（n=34）。然而，40%的HR熟练肿瘤患者的neoAg数量仍高于中位数，并且比neoAg数量较低的患者生存率更高。将人类白细胞抗原（HLA）-I类表达状态纳入生存分析显示，具有高neoAg数量和高HLA-I类表达（neoAghiHLAhi）的患者在HR熟练的HGSC中具有最佳无进展生存期（PFS）（p=0.0087）。基因集富集分析表明，效应记忆CD 8 T细胞、TH 1 T细胞、干扰素-γ应答和其他免疫相关基因的基因在这些患者中富集。有趣的是，在HR缺陷型HGSC中，该患者亚组也具有更好的PFS（p=0.0015）和比具有相同表型（neoAghiHLAhi）的患者更多的T细胞发炎肿瘤表型。结论我们的研究结果表明，免疫检查点抑制剂可能是一种替代方案，以探索在HR熟练的情况下，目前没有受益于PARP抑制。
Background There is increasing evidence for the benefit of poly ADP ribose polymerase (PARP) inhibitors in a subset of high-grade serous ovarian carcinoma (HGSC) patients, especially those with homologous recombination (HR)-deficient tumors. However, new treatment strategies, such as immune checkpoint inhibition, are required for patients with HR-proficient tumors. Methods A total of 80 cases of HGSC were analyzed in this study. Whole exome and RNA sequencing was performed for these tumors. Methylation arrays were also carried out to examine BRCA1 and RAD51C promoter methylation status. Mutations, neoantigen load, antigen presentation machinery, and local immune profile were investigated, and the relationships of these factors with clinical outcome were also analyzed. Results As expected, the numbers of predicted neoAgs were lower in HR-proficient (n=46) than HR-deficient tumors (n=34). However, 40% of the patients with HR-proficient tumors still had higher than median numbers of neoAgs and better survival than patients with lower numbers of neoAgs. Incorporation of human leukocyte antigen (HLA)-class I expression status into the survival analysis revealed that patients with both high neoAg numbers and high HLA-class I expression (neoAghiHLAhi) had the best progression-free survival (PFS) in HR-proficient HGSC (p=0.0087). Gene set enrichment analysis demonstrated that the genes for effector memory CD8 T cells, TH1 T cells, the interferon-γ response, and other immune-related genes, were enriched in these patients. Interestingly, this subset of patients also had better PFS (p=0.0015) and a more T-cell-inflamed tumor phenotype than patients with the same phenotype (neoAghiHLAhi) in HR-deficient HGSC. Conclusions Our results suggest that immune checkpoint inhibitors might be an alternative to explore in HR-proficient cases which currently do not benefit from PARP inhibition.
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影响因子：
12.7
作者：
Nomura M;Mukasa A;Nagae G;Yamamoto S;Tatsuno K;Ueda H;Fukuda S;Umeda T;Suzuki T;Otani R;Kobayashi K;Maruyama T;Tanaka S;Takayanagi S;Nejo T;Takahashi S;Ichimura K;Nakamura T;Muragaki Y;Narita Y;Nagane M;Ueki K;Nishikawa R;Shibahara J;Aburatani H;Saito N
通讯作者：
Saito N
影响因子：
64.8
作者：
Patch, Ann-Marie;Christie, Elizabeth L.;Bowtell, David D. L.
通讯作者：
Bowtell, David D. L.
影响因子：
--
作者：
Ward JP;Gubin MM;Schreiber RD
通讯作者：
Schreiber RD
影响因子：
28.2
作者：
Konstantinopoulos PA;Ceccaldi R;Shapiro GI;D'Andrea AD
通讯作者：
D'Andrea AD
DOI：
10.1073/pnas.080469697
发表时间：
2000-05-09
影响因子：
11.1
作者：
Ouchi, T;Lee, SW;Horvath, CM
通讯作者：
Horvath, CM