Full Text:   <527>

Summary:  <187>

CLC number: 

On-line Access: 2023-05-15

Received: 2022-10-17

Revision Accepted: 2023-02-19

Crosschecked: 2023-05-16

Cited: 0

Clicked: 705

Citations:  Bibtex RefMan EndNote GB/T7714

-   Go to

Article info.
Open peer comments

Journal of Zhejiang University SCIENCE B 2023 Vol.24 No.5 P.387-396

http://doi.org/10.1631/jzus.B2200528


Double-negative T cells: a promising avenue of adoptive cell therapy in transplant oncology


Author(s):  Zhihang HU, Modan YANG, Hao CHEN, Chiyu HE, Zuyuan LIN, Xinyu YANG, Huigang LI, Wei SHEN, Di LU, Xiao XU

Affiliation(s):  Zhejiang University School of Medicine, Hangzhou 310058, China; more

Corresponding email(s):   zjxu@zju.edu.cn, zjuludi@zju.edu.cn

Key Words:  Double-negative T cell (DNT), Adoptive cell therapy (ACT), Liver cancer, Liver transplantation, Oncology


Zhihang HU, Modan YANG, Hao CHEN, Chiyu HE, Zuyuan LIN, Xinyu YANG, Huigang LI, Wei SHEN, Di LU, Xiao XU. Double-negative T cells: a promising avenue of adoptive cell therapy in transplant oncology[J]. Journal of Zhejiang University Science B, 2023, 24(5): 387-396.

@article{title="Double-negative T cells: a promising avenue of adoptive cell therapy in transplant oncology",
author="Zhihang HU, Modan YANG, Hao CHEN, Chiyu HE, Zuyuan LIN, Xinyu YANG, Huigang LI, Wei SHEN, Di LU, Xiao XU",
journal="Journal of Zhejiang University Science B",
volume="24",
number="5",
pages="387-396",
year="2023",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B2200528"
}

%0 Journal Article
%T Double-negative T cells: a promising avenue of adoptive cell therapy in transplant oncology
%A Zhihang HU
%A Modan YANG
%A Hao CHEN
%A Chiyu HE
%A Zuyuan LIN
%A Xinyu YANG
%A Huigang LI
%A Wei SHEN
%A Di LU
%A Xiao XU
%J Journal of Zhejiang University SCIENCE B
%V 24
%N 5
%P 387-396
%@ 1673-1581
%D 2023
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2200528

TY - JOUR
T1 - Double-negative T cells: a promising avenue of adoptive cell therapy in transplant oncology
A1 - Zhihang HU
A1 - Modan YANG
A1 - Hao CHEN
A1 - Chiyu HE
A1 - Zuyuan LIN
A1 - Xinyu YANG
A1 - Huigang LI
A1 - Wei SHEN
A1 - Di LU
A1 - Xiao XU
J0 - Journal of Zhejiang University Science B
VL - 24
IS - 5
SP - 387
EP - 396
%@ 1673-1581
Y1 - 2023
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2200528


Abstract: 
Tumor recurrence is one of the major life-threatening complications after liver transplantation for liver cancer. In addition to the common mechanisms underlying tumor recurrence, another unavoidable problem is that the immunosuppressive therapeutic regimen after transplantation could promote tumor recurrence and metastasis. Transplant oncology is an emerging field that addresses oncological challenges in transplantation. In this context, a comprehensive therapeutic management approach is required to balance the anti-tumor treatment and immunosuppressive status of recipients. Double-negative T cells (DNTs) are a cluster of heterogeneous cells mainly consisting of two subsets stratified by T cell receptor (TCR) type. Among them, TCRαβ+ DNTs are considered to induce immune suppression in immune-mediated diseases, while TCRγδ+ DNTs are widely recognized as tumor killers. As a composite cell therapy, healthy donor-derived DNTs can be propagated to therapeutic numbers in vitro and applied for the treatment of several malignancies without impairing normal tissues or being rejected by the host. In this work, we summarized the biological characteristics and functions of DNTs in oncology, immunology, and transplantation. Based on the multiple roles of DNTs, we propose that a new balance could be achieved in liver transplant oncology using them as an off-the-shelf adoptive cell therapy (ACT).

双阴性T细胞:移植肿瘤学中一种颇具前景的过继细胞疗法

胡志航1,2,3,4,5,杨墨丹1,2,3,4,5,陈昊1,2,3,4,5,何驰宇1,3,4,5,6,林祖源1,2,3,4,5,阳新宇1,2,3,4,5,李辉港1,2,3,4,5,沈未1,2,3,4,5,鲁迪1,2,3,4,5,徐骁1,2,3,4,5
1浙江大学医学院,中国杭州市,310058
2浙江大学医学院附属杭州市第一人民医院肝胆胰外科,中国杭州市,310006
3浙江省肿瘤融合与智能医学重点实验室,中国杭州市,310006
4浙江大学器官移植研究所,中国杭州市,310003
5卫健委多器官联合移植重点实验室,中国杭州市,310003
6树兰(杭州)医院肝胆胰外科,中国杭州市,310004
摘要:肿瘤复发是肝癌肝移植术后危及生命的主要并发症之一。除了常见的肿瘤复发机制外,另一个不可避免的问题是移植后的免疫抑制治疗方案可能促进肿瘤复发和转移。移植肿瘤学是一个新兴领域以解决肝移植相关的肿瘤学问题。在此背景下,需要综合治疗管理方法来平衡受者的抗肿瘤治疗和免疫抑制状态。双阴性T细胞(DNTs)是一群异质性细胞,主要由T细胞受体(TCR)不同类型的两个亚群组成。其中,TCRαβ+ DNTs被认为在免疫性疾病中诱导免疫抑制,而TCRγδ+ DNTs被广泛认为是肿瘤杀伤细胞。作为一种复合细胞疗法,健康供体来源的DNTs可在体外增殖至治疗量级,并应用于多种恶性肿瘤的治疗,同时既不损伤正常组织,也不被宿主排斥。本文就DNTs的生物学特性及其在肿瘤学、免疫学和移植领域等方面的研究进展进行综述。基于DNTs的多重作用,我们建议将其作为一种现成的过继性细胞治疗(ACT),从而为移植肿瘤学提供一种新的平衡。

关键词:双阴性T细胞(DNT);过继细胞疗法(ACT);肝癌;肝移植;肿瘤学

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

Reference

[1]AchitaP, DervovicD, LyD, et al., 2018. Infusion of ex-vivo expanded human TCR-αβ+ double-negative regulatory T cells delays onset of xenogeneic graft-versus-host disease. Clin Exp Immunol, 193(3):386-399.

[2]AlmeidaCF, SmithDGM, ChengTY, et al., 2021. Benzofuran sulfonates and small self-lipid antigens activate type II NKT cells via CD1d. Proc Natl Acad Sci USA, 118(34):e2104420118.

[3]BaforEE, ValenciaJC, YoungHA, 2022. Double negative T regulatory cells: an emerging paradigm shift in reproductive immune tolerance? Front Immunol, 13:886645.

[4]BroutierL, MastrogiovanniG, VerstegenMMA, et al., 2017. Human primary liver cancer-derived organoid cultures for disease modeling and drug screening. Nat Med, 23(12):1424-1435.

[5]CapsomidisA, BenthallG, van AckerHH, et al., 2018. Chimeric antigen receptor-engineered human gamma delta T cells: enhanced cytotoxicity with retention of cross presentation. Mol Ther, 26(2):354-365.

[6]ChakravertyR, TeshimaT, 2021. Graft-versus-host disease: a disorder of tissue regeneration and repair. Blood, 138(18):1657-1665.

[7]ChenB, LeeJB, KangH, et al., 2018. Targeting chemotherapy-resistant leukemia by combining DNT cellular therapy with conventional chemotherapy. J Exp Clin Cancer Res, 37:88.

[8]ChenJ, HuPB, WuGH, et al., 2019. Antipancreatic cancer effect of DNT cells and the underlying mechanism. Pancreatology, 19(1):105-113.

[9]ChenWH, ZhouDJ, TorrealbaJR, et al., 2005. Donor lymphocyte infusion induces long-term donor-specific cardiac xenograft survival through activation of recipient double-negative regulatory T cells. J Immunol, 175(5):3409-3416.

[10]ChowdharyVR, KrogmanA, TilahunAY, et al., 2017. Concomitant disruption of CD4 and CD8 genes facilitates the development of double negative αβTCR+ peripheral T cells that respond robustly to staphylococcal superantigen. J Immunol, 198(1):4413-4424.

[11]CrosbyCM, KronenbergM, 2018. Tissue-specific functions of invariant natural killer T cells. Nat Rev Immunol, 18(9):559-574.

[12]de GassartA, LeKS, BruneP, et al., 2021. Development of ICT01, a first-in-class, anti-BTN3A antibody for activating Vγ9Vδ2 T cell-mediated antitumor immune response. Sci Transl Med, 13(616):eabj0835.

[13]DepilS, DuchateauP, GruppSA, et al., 2020. ‘Off-the-shelf’ allogeneic CAR T cells: development and challenges. Nat Rev Drug Discov, 19(3):185-199.

[14]FangLN, LyD, WangSS, et al., 2019. Targeting late-stage non-small cell lung cancer with a combination of DNT cellular therapy and PD-1 checkpoint blockade. J Exp Clin Cancer Res, 38:123.

[15]FischerK, VoelklS, HeymannJ, et al., 2005. Isolation and characterization of human antigen-specific TCRαβ+ CD4-CD8- double-negative regulatory T cells. Blood, 105(7):2828-2835.

[16]FordMS, YoungKJ, ZhangZX, et al., 2002. The immune regulatory function of lymphoproliferative double negative T cells in vitro and in vivo. J Exp Med, 196(2):261-267.

[17]GalluzziL, ChanTA, KroemerG, et al., 2018. The hallmarks of successful anticancer immunotherapy. Sci Transl Med, 10(459):eaat7807.

[18]GálvezNMS, BohmwaldK, PachecoGA, et al., 2021. Type I natural killer T cells as key regulators of the immune response to infectious diseases. Clin Microbiol Rev, 34(2):e00232-20.

[19]HibiT, SapisochinG, 2019. What is transplant oncology? Surgery, 165(2):281-285.

[20]HibiT, ItanoO, ShinodaM, et al., 2017. Liver transplantation for hepatobiliary malignancies: a new era of “Transplant Oncology” has begun. Surg Today, 47(4):403-415.

[21]HoeresT, SmetakM, PretscherD, et al., 2018. Improving the efficiency of Vγ9Vδ2 T-Cell immunotherapy in cancer. Front Immunol, 9:800.

[22]HsuJ, KrishnanA, LeeSA, et al., 2021. CD3+CD4-CD8- double-negative αβ T cells attenuate lung ischemia-reperfusion injury. J Thorac Cardiovasc Surg, 161(1):E81-E90.

[23]HuSH, ZhangLH, GaoJ, et al., 2021. NKG2D enhances double-negative T cell regulation of B cells. Front Immunol, 12:650788.

[24]JuvetSC, ZhangL, 2012. Double negative regulatory T cells in transplantation and autoimmunity: recent progress and future directions. J Mol Cell Biol, 4(1):48-58.

[25]KabelitzD, SerranoR, KouakanouL, et al., 2020. Cancer immunotherapy with γδ T cells: many paths ahead of us. Cell Mol Immunol, 17(9):925-939.

[26]KhanAA, LiuZK, XuX, 2021. Recent advances in immunotherapy for hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int, 20(6):511-520.

[27]Kjer-NielsenL, CorbettAJ, ChenZJ, et al., 2018. An overview on the identification of MAIT cell antigens. Immunol Cell Biol, 96(6):573-587.

[28]LeeJB, MindenMD, ChenWC, et al., 2018. Allogeneic human double negative T cells as a novel immunotherapy for acute myeloid leukemia and its underlying mechanisms. Clin Cancer Res, 24(2):370-382.

[29]LeeJB, KangH, FangLN, et al., 2019. Developing allogeneic double-negative T cells as a novel off-the-shelf adoptive cellular therapy for cancer. Clin Cancer Res, 25(7):2241-2253.

[30]LegouxF, SalouM, LantzO, 2017. Unconventional or preset αβ T cells: evolutionarily conserved tissue-resident T cells recognizing nonpeptidic ligands. Annu Rev Cell Dev Biol, 33:511-535.

[31]LingSB, ZhanQF, JiangGJ, et al., 2022. E2F7 promotes mammalian target of rapamycin inhibitor resistance in hepatocellular carcinoma after liver transplantation. Am J Transplant, 22(10):2323-2336.

[32]LiuYX, ZhangC, 2020. The role of human γδ T cells in anti-tumor immunity and their potential for cancer immunotherapy. Cells, 9(5):1206.

[33]LuJQ, LiuJY, LiA, 2022. Roles of neutrophil reactive oxygen species (ROS) generation in organ function impairment in sepsis. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 23(6):437-450.

[34]LuY, HuPB, ZhouHB, et al., 2019. Double-negative T cells inhibit proliferation and invasion of human pancreatic cancer cells in co-culture. Anticancer Res, 39(11):5911-5918.

[35]MarabelleA, TselikasL, de BaereT, et al., 2017. Intratumoral immunotherapy: using the tumor as the remedy. Ann Oncol, 28:xii33-xii43.

[36]MazzaferroV, RegaliaE, DociR, et al., 1996. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med, 334(11):693-700.

[37]MerimsS, LiX, JoeB, et al., 2011. Anti-leukemia effect of ex vivo expanded DNT cells from AML patients: a potential novel autologous T-cell adoptive immunotherapy. Leukemia, 25(9):1415-1422.

[38]MizukoshiE, KanekoS, 2019. Immune cell therapy for hepatocellular carcinoma. J Hematol Oncol, 12:52.

[39]Newman-RiveraAM, KurzhagenJT, RabbH, 2022. TCRαβ+ CD4-/CD8- “double negative” T cells in health and disease-implications for the kidney. Kidney Int, 102(1):25-37.

[40]NordnessMF, HamelS, GodfreyCM, et al., 2020. Fatal hepatic necrosis after nivolumab as a bridge to liver transplant for HCC: are checkpoint inhibitors safe for the pretransplant patient? Am J Transplant, 20(3):879-883.

[41]PauzaCD, LiouML, LahusenT, et al., 2018. Gamma delta T cell therapy for cancer: it is good to be local. Front Immunol, 9:1305.

[42]PellicciDG, UldrichAP, 2018. Unappreciated diversity within the pool of CD1d-restricted T cells. Semin Cell Dev Biol, 84:42-47.

[43]PonzettaA, CarrieroR, CarnevaleS, et al., 2019. Neutrophils driving unconventional T cells mediate resistance against murine sarcomas and selected human tumors. Cell, 178(2):346-360.e24.

[44]RaoulJL, FornerA, BolondiL, et al., 2019. Updated use of TACE for hepatocellular carcinoma treatment: how and when to use it based on clinical evidence. Cancer Treat Rev, 72:28-36.

[45]RoncaV, WoottonG, MilaniC, et al., 2020. The immunological basis of liver allograft rejection. Front Immunol, 11:2155.

[46]SoaresF, ChenB, LeeJB, et al., 2021. CRISPR screen identifies genes that sensitize AML cells to double-negative T-cell therapy. Blood, 137(16):2171-2181.

[47]StrippoliS, FanizziA, NegriA, et al., 2021. Examining the relationship between circulating CD4-CD8- double-negative T cells and outcomes of immuno-checkpoint inhibitor therapy—looking for biomarkers and therapeutic targets in metastatic melanoma. Cells, 10(2):406.

[48]SunH, CaoS, MashlRJ, et al., 2021. Comprehensive characterization of 536 patient-derived xenograft models prioritizes candidatesfor targeted treatment. Nat Commun, 12:5086.

[49]TakadaY, ItoT, UedaM, et al., 2007. Living donor liver transplantation for patients with HCC exceeding the Milan criteria: a proposal of expanded criteria. Dig Dis, 25(4):299-302.

[50]ThommenDS, SchumacherTN, 2018. T cell dysfunction in cancer. Cancer Cell, 33(4):547-562.

[51]TuvesonD, CleversH, 2019. Cancer modeling meets human organoid technology. Science, 364(6444):952-955.

[52]VasicD, LeeJB, LeungY, et al., 2022. Allogeneic double-negative CAR-T cells inhibit tumor growth without off-tumor toxicities. Sci Immunol, 7(70):eabl3642.

[53]VelikkakamT, GollobKJ, DutraWO, 2022. Double-negative T cells: setting the stage for disease control or progression. Immunology, 165(4):371-385.

[54]VernaEC, PatelYA, AggarwalA, et al., 2020. Liver transplantation for hepatocellular carcinoma: management after the transplant. Am J Transplant, 20(2):333-347.

[55]VoelklS, MooreTV, RehliM, et al., 2009. Characterization of MHC class-I restricted TCRαβ+ CD4- CD8- double negative T cells recognizing the gp100 antigen from a melanoma patient after gp100 vaccination. Cancer Immunol Immunother, 58(5):709-718.

[56]XuH, ZhuXX, ChenJ, 2016. DNT cell inhibits the growth of pancreatic carcinoma via abnormal expressions of NKG2D and MICA in vivo. Biochem Biophys Res Commun, 469(2):145-150.

[57]XuX, LuD, LingQ, et al., 2016. Liver transplantation for hepatocellular carcinoma beyond the Milan criteria. Gut, 65(6):1035-1041.

[58]YangXY, LuD, WangR, et al., 2021. Single-cell profiling reveals distinct immune phenotypes that contribute to ischaemia-reperfusion injury after steatotic liver transplantation. Cell Prolif, 54(10):e13116.

[59]YaoFY, FerrellL, BassNM, et al., 2001. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology, 33(6):1394-1403.

[60]YaoJL, LyD, DervovicD, et al., 2019. Human double negative T cells target lung cancer via ligand-dependent mechanisms that can be enhanced by IL-15. J Immunother Cancer, 7(1):17.

[61]YeQW, LingSB, ZhengSS, et al., 2019. Liquid biopsy in hepatocellular carcinoma: circulating tumor cells and circulating tumor DNA. Mol Cancer, 18:114.

[62]YoungKJ, YangLM, PhillipsMJ, et al., 2002. Donor-lymphocyte infusion induces transplantation tolerance by activating systemic and graft-infiltrating double-negative regulatory T cells. Blood, 100(9):3408-3414.

[63]YoungKJ, KayLS, PhillipsMJ, et al., 2003. Antitumor activity mediated by double-negative T cells. Cancer Res, 63(22):8014-8021.

[64]ZhangYJ, KongDR, WangH, 2020. Mucosal-associated invariant T cell in liver diseases. Int J Biol Sci, 16(3):460-470.

[65]ZhuoJY, SuRY, TanWY, et al., 2020. The ongoing trends of patient-derived xenograft models in oncology. Cancer Commun (Lond), 40(11):559-563.

Open peer comments: Debate/Discuss/Question/Opinion

<1>

Please provide your name, email address and a comment





Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - 2024 Journal of Zhejiang University-SCIENCE