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

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Hepatology
Original research
High-affinity neoantigens correlate with better prognosis and trigger potent antihepatocellular carcinoma (HCC) activity by activating CD39+CD8+ T cells
  1. Ting Liu1,
  2. Jizhou Tan1,
  3. Minhao Wu2,
  4. Wenzhe Fan1,
  5. Jialiang Wei1,
  6. Bowen Zhu1,
  7. Jian Guo1,
  8. Shutong Wang1,
  9. Penghui Zhou3,
  10. Hui Zhang2,
  11. Liangrong Shi4,
  12. Jiaping Li1
  1. 1 Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
  2. 2 Department of Immunology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
  3. 3 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
  4. 4 Radiological Intervention Center, Department of Radiology, Xiangya Hospital, Central South University, Changsha, Hunan, China
  1. Correspondence to Dr Jiaping Li; lijiap{at}mail.sysu.edu.cn

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.

  • hepatocellular carcinoma
  • immunotherapy
  • mutation screening
  • T lymphocytes

Data availability statement

Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. The data used to support the findings of this study are included within the article.

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/.

https://doi.org/10.1136/gutjnl-2020-322196

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    Data availability statement

    Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. The data used to support the findings of this study are included within the article.

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    Footnotes

    • TL, JT and MW contributed equally.

    • Contributors TL, JT and MW wrote the manuscript. TL, JT and JL designed experiments. TL and JT performed experiments, TL, JT, MW, WF, PZ, HZ and LS analysed and interpreted the data. BZ, JW, JG and SW collected clinical samples and data. JL supervised the project.

    • Funding This work was supported by grants from National Natural Science Foundation of China (No. 81671797, No. 81971719), the major scientific and technological project of Guangdong Province (No. 2017B030308006), the major programme for tackling key problems of Guangzhou city (No. 201704020144).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.