High-affinity neoantigens correlate with better prognosis and trigger potent antihepatocellular carcinoma (HCC) activity by activating CD39(+)CD8(+) T cells.
High-affinity neoantigens correlate with better prognosis and trigger potent antihepatocellular carcinoma (HCC) activity by activating CD39(+)CD8(+) T cells.
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高亲和力新抗原与更好的预后相关，并通过激活 CD39 CD8 T 细胞触发有效的抗肝细胞癌 (HCC) 活性
作者：
Liu T;Tan J;Wu M;Fan W;Wei J;Zhu B;Guo J;Wang S;Zhou P;Zhang H;Shi L;Li J
肿瘤突变负荷（TMB）或新抗原是否是肝细胞癌（HCC）的预后标志物仍有争议。本研究旨在确定TMB或新抗原在抗肿瘤免疫治疗中的功能。使用基于全外显子组测序的主要组织相容性复合体-I（MHC-I）算法通过pVAC工具分析患者（n=56）的新抗原，并且将突变型IC 50 <50 nM的新抗原定义为高亲和力新抗原（HAN）。根据HAN值的中位数将患者分为HAN高/低组，并分析总生存期（OS）。开发了自体类器官杀伤模型以阐明HAN的抗肿瘤活性。在HCC患者中，HAN值与OS（p=0.0199）的相关性优于TMB（p=0.7505）或新抗原（p=0.2297），并且与CD 39 + CD 8+肿瘤浸润淋巴细胞（TIL）的频率呈正相关。此外，在CD 39 + CD 8 + TIL中鉴定出HAN特异性CD 8 + T细胞，其在HAN高组中比HAN低组显示出更好的抗肿瘤活性。此外，在HAN高组与HAN低组中鉴定出更有效的HAN肽。流式细胞术结果显示，在新鲜肿瘤中，HAN高表达组的CD 39 +PD-1 intCD 8 + TILs表现出效应表型，其抗肿瘤活性强于HAN低表达组。更重要的是，HAN高组患者与HAN低组患者在抗PD-1治疗后显示出更好的预后。我们的研究首次证明了HAN值与HCC患者的较好OS呈正相关。HAN通过激活肿瘤反应性CD 39 + CD 8 + T细胞来触发抗肿瘤活性，并且HAN高组患者比HAN低组患者从抗PD-1治疗中获益更多。这些发现可能为HCC的个性化抗肿瘤治疗提供新的策略。
It remains controversial whether tumour mutational burden (TMB) or neoantigens are prognostic markers in hepatocellular carcinoma (HCC). This study aimed to define the function of TMB or neoantigens in antitumour immunotherapy. Neoantigens of patients (n=56) were analysed by pVAC tools with major histocompatibility complex-1 (MHC-I) algorithms based on whole exome sequencing and neoantigens with mutant type IC50 <50 nM were defined as high-affinity neoantigens (HANs). Patients were segregated into HAN-high/low groups by median of HAN value, and overall survival (OS) was analysed. Autologous organoid killing model was developed to clarify the antitumour activity of HANs. The value of HAN showed a better correlation with OS (p=0.0199) than TMB (p=0.7505) or neoantigens (p=0.2297) in patients with HCC and positively correlated with the frequency of CD39+CD8+ tumour infiltrating lymphocytes (TILs). Furthermore, HAN-specific CD8+ T cells were identified in CD39+CD8+ TILs, which showed better antitumour activity in HAN-high versus HAN-low group. In addition, more effective HAN peptides were identified in HAN-high versus HAN-low group. Besides, flow cytometry data showed that in fresh tumour, CD39+PD-1intCD8+ TILs displayed an effector phenotype and stronger antitumour activity in HAN-high versus HAN-low group. More importantly, patients in HAN-high versus HAN-low group showed a better prognosis after anti-PD-1 therapy. Our study first demonstrates that HAN value positively correlates with better OS in patients with HCC. HANs trigger antitumour activity by activating tumour-reactive CD39+CD8+ T cells, and patients in HAN-high group benefited more from anti-PD-1 therapy than HAN-low group. These findings may provide a novel strategy for personalised antitumour therapies for HCC.
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影响因子：
13.6
作者：
Antonioli L;Pacher P;Vizi ES;Haskó G
通讯作者：
Haskó G
克服感染和癌症中的T细胞耗尽。
影响因子：
16.8
作者：
Pauken KE;Wherry EJ
通讯作者：
Wherry EJ
影响因子：
64.8
作者：
Simoni, Yannick;Becht, Etienne;Newell, Evan W.
通讯作者：
Newell, Evan W.
DOI：
10.1126/science.aaf1490
发表时间：
2016-03-25
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
McGranahan N;Furness AJ;Rosenthal R;Ramskov S;Lyngaa R;Saini SK;Jamal-Hanjani M;Wilson GA;Birkbak NJ;Hiley CT;Watkins TB;Shafi S;Murugaesu N;Mitter R;Akarca AU;Linares J;Marafioti T;Henry JY;Van Allen EM;Miao D;Schilling B;Schadendorf D;Garraway LA;Makarov V;Rizvi NA;Snyder A;Hellmann MD;Merghoub T;Wolchok JD;Shukla SA;Wu CJ;Peggs KS;Chan TA;Hadrup SR;Quezada SA;Swanton C
通讯作者：
Swanton C
DOI：
10.1056/nejmoa1801946
发表时间：
2018-05-31
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hellmann MD;Ciuleanu TE;Pluzanski A;Lee JS;Otterson GA;Audigier-Valette C;Minenza E;Linardou H;Burgers S;Salman P;Borghaei H;Ramalingam SS;Brahmer J;Reck M;O'Byrne KJ;Geese WJ;Green G;Chang H;Szustakowski J;Bhagavatheeswaran P;Healey D;Fu Y;Nathan F;Paz-Ares L
通讯作者：
Paz-Ares L