高亲和力新抗原与更好的预后相关，并通过激活CD39 + CD8 + T细

StephenW

High-affinity neoantigens correlate with better prognosis and trigger potent antihepatocellular carcinoma (HCC) activity by activating CD39+CD8+ T cells

    Ting Liu1, Jizhou Tan1, Minhao Wu2, Wenzhe Fan1, Jialiang Wei1, Bowen Zhu1, Jian Guo1, Shutong Wang1, Penghui Zhou3, Hui Zhang2, Liangrong Shi4, http://orcid.org/0000-0003-2927-8877Jiaping Li1

Author affiliations

    Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
    Department of Immunology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
    State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
    Radiological Intervention Center, Department of Radiology, Xiangya Hospital, Central South University, Changsha, Hunan, China

    Correspondence to Dr Jiaping Li; [email protected]

Abstract

Objective 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.

Design 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.

Results 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.

Conclusions 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.
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
View Full Text

http://dx.doi.org/10.1136/gutjnl-2020-322196

StephenW

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

    刘婷1，谭州洲1，吴敏浩2，范文哲1，魏家亮1，祝文1，简国1，王树彤1，周鹏辉3，张辉2，石良荣4，http：//orcid.org/0000-0003-2927-8877

作者单位

    中山大学附属第一医院介入肿瘤科，广东广州
    中山大学中山医学院免疫学教研室，广州
    中南大学肿瘤医学合作创新中心，华南肿瘤学国家重点实验室，广州
    中南大学湘雅医院放射科放射干预中心，湖南长沙

    通讯作者李加平博士； [email protected]

抽象

目的肿瘤突变负担（TMB）或新抗原是肝细胞癌（HCC）的预后标志物仍存在争议。这项研究旨在确定TMB或新抗原在抗肿瘤免疫治疗中的功能。

使用具有主要组织相容性复合物1（MHC-I）算法的pVAC工具，基于全外显子组测序分析患者（n = 56）的设计新抗原，并将IC50 <50 <nM突变型的新抗原定义为高亲和力新抗原（HANs） 。根据HAN值的中位数将患者分为HAN高/低组，并分析了总生存期（OS）。建立自体类器官杀伤模型以阐明HANs的抗肿瘤活性。

结果肝癌患者中HAN值与OS（p = 0.0199）的相关性高于TMB（p = 0.7505）或新抗原（p = 0.2297），并且与CD39 + CD8 +肿瘤浸润淋巴细胞（TILs）的频率呈正相关。此外，在CD39 + CD8 + TILs中鉴定出HAN特异性CD8 + T细胞，与HAN-low组相比，HAN-high组具有更好的抗肿瘤活性。另外，在高HAN组与低HAN组中鉴定出更有效的HAN肽。此外，流式细胞仪数据显示，在新鲜肿瘤中，高表达组与低表达组相比，CD39 + PD-1intCD8 + TILs具有效应表型和更强的抗肿瘤活性。更重要的是，抗-PD-1治疗后，高HAN组与低HAN组的患者预后较好。

结论我们的研究首先证明，HAN值与HCC患者的OS呈正相关。 HAN通过激活肿瘤反应性CD39 + CD8 + T细胞来触发抗肿瘤活性，高HAN组的患者比低HAN组受益于抗PD-1治疗。这些发现可能为肝癌的个性化抗肿瘤治疗提供一种新颖的策略。
http://creativecommons.org/licenses/by-nc/4.0/

这是根据非商业知识共享署名（CC BY-NC 4.0）许可分发的开放获取文章，该许可允许其他人以非商业方式分发，重新混合，改编，基于该作品并在不同的作品上许可其衍生作品条款，前提是正确引用了原始作品，给予了适当的信誉，指出了所做的任何更改，并且此使用是非商业用途。请参阅：http：//creativecommons.org/licenses/by-nc/4.0/。
查看全文

http://dx.doi.org/10.1136/gutjnl-2020-322196

StephenW

https://gut.bmj.com/content/gutj ... 020-322196.full.pdf