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CD27 enhances the killing effect of CAR T cells targeting trophoblast cell surface antigen 2 in the treatment of solid tumors

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Abstract

Chimeric antigen receptor (CAR) T cell therapy, a type of adoptive cell therapy, has been successfully used when treating lymphoma malignancies, but not nearly as successful in treating solid tumors. Trophoblast cell surface antigen 2 (Trop2) is expressed in various solid tumors and plays a role in tumor growth, invasion, and metastasis. In this study, a CAR targeting Trop2 (T2-CAR) was developed with different co-stimulatory intercellular domains. T2-CAR T cells demonstrated a powerful killing ability in the presence of Trop2-positive cells following an in vitro assay. Moreover, T2-CAR T cells produced multiple effector cytokines under antigen stimulation. In tumor-bearing mouse models, the CD27-based T2-CAR T cells showed a higher antitumor activity. Additionally, more CD27-based T2-CAR T cells survived in tumor-bearing mice spleens as well as in the tumor tissue. CD27-based T2-CAR T cells were also found to upregulate IL-7Rα expression, while downregulating PD-1 expression. In conclusion, the CD27 intercellular domain can enhance the T2-CAR T cell killing effect via multiple mechanisms, thus indicating that a CD27-based T2-CAR T cell approach is suitable for clinical applications.

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All data generated during this study have included in this article.

Change history

  • 08 May 2024

    Missing supplementary file and the supplementary figure links which were wrongly linked to main text figures have been updated.

Abbreviations

ACT:

Adoptive cell transfer

Trop2:

Trophoblast cell surface antigen 2

CAR:

Chimeric antigen receptor

T2-CAR:

Trop2-specific CAR

TAA:

Tumor-associated antigen

FDA:

Food and Drug Administration

scFv:

Single-chain fragment variant

MHC:

Major histocompatibility complex

IL-2:

Interleukin-2

IL-7:

Interleukin-7

IL-15:

Interleukin-15

TNF-α:

Tumor necrosis factor-α

UTD:

Untransduced

IFN-γ:

Interferon-γ

PBMCs:

Peripheral blood mononuclear cells

IVIS:

In Vivo Imaging System

LDH:

Lactate dehydrogenase

TNBC:

Triple-negative breast cancer

TIL:

Tumor infiltrated lymphocyte

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Acknowledgements

We thank LetPub (www.letpub.com) for its linguistic assistance during the preparation of this manuscript.

Funding

This research was supported by the Science and Technology Department of Guangdong Province (2017A050501010 and 2016A050503023) and Guangzhou Science, Technology and Innovation Commission (201807010042).

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Authors and Affiliations

  1. Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, N1311 Rm, No. 10 Bld, 74 Zhongshan 2nd Rd, Guangzhou, 510080, China

    Huanpeng Chen, Fengjiao Wei & Zhaofeng Huang

  2. Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, China

    Huanpeng Chen, Fengjiao Wei & Zhaofeng Huang

  3. Sun Yat-Sen University Cancer Center, Guangzhou, China

    Meng Yin & Qingyu Zhao

  4. Laboratory Animal Center, South China Agricultural University, Guangzhou, China

    Zhonghua Liu

  5. Key Laboratory for Major Obstetric Diseases of Guangdong Province, BioResource Research Center, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

    Bolan Yu

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  1. Huanpeng Chen
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  3. Meng Yin
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  4. Qingyu Zhao
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  5. Zhonghua Liu
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Contributions

H.Z and C.H designed the study. C.H, Y.M, W.F, Z.Q, Y.B, and H.Z performed experiments, collected and analyzed data. L.Z provided technical support on the mouse model. C.H and H.Z drafted the manuscript. All authors revised and approved the manuscript.

Corresponding author

Correspondence to Zhaofeng Huang.

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The research was approved by the Zhongshan School of Medicine, Sun Yat-sen University (Guangzhou, China). This research was performed in accordance with the Declaration of Helsinki and according to national and international guidelines. Whole blood from anonymous healthy volunteer donors was obtained from Guangzhou Blood Center, Guangzhou, in which all volunteers had known and confirmed that the blood was going to be used for scientific research. All mouse experiments were approved by and followed to the ethical regulations of IACUC, SYSU.

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Chen, H., Wei, F., Yin, M. et al. CD27 enhances the killing effect of CAR T cells targeting trophoblast cell surface antigen 2 in the treatment of solid tumors. Cancer Immunol Immunother 70, 2059–2071 (2021). https://doi.org/10.1007/s00262-020-02838-8

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