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Nasopharyngeal carcinoma cells promote regulatory T cell development and suppressive activity via CD70-CD27 interaction

Author

Listed:
  • Lanqi Gong

    (The University of Hong Kong
    The University of Hong Kong-Shenzhen Hospital)

  • Jie Luo

    (The University of Hong Kong)

  • Yu Zhang

    (Sun Yat-sen University Cancer Center
    Sun Yat-sen University Cancer Center
    Sun Yat-sen University Cancer Center)

  • Yuma Yang

    (The University of Hong Kong)

  • Shanshan Li

    (The University of Hong Kong-Shenzhen Hospital)

  • Xiaona Fang

    (The University of Hong Kong)

  • Baifeng Zhang

    (The University of Hong Kong)

  • Jiao Huang

    (The University of Hong Kong)

  • Larry Ka-Yue Chow

    (The University of Hong Kong)

  • Dittman Chung

    (The University of Hong Kong)

  • Jinlin Huang

    (The University of Hong Kong)

  • Cuicui Huang

    (The University of Hong Kong
    The University of Hong Kong-Shenzhen Hospital)

  • Qin Liu

    (The University of Hong Kong
    The University of Hong Kong-Shenzhen Hospital)

  • Lu Bai

    (The University of Hong Kong
    The University of Hong Kong-Shenzhen Hospital)

  • Yuen Chak Tiu

    (The University of Hong Kong)

  • Pingan Wu

    (The University of Hong Kong-Shenzhen Hospital)

  • Yan Wang

    (The University of Hong Kong-Shenzhen Hospital)

  • George Sai-Wah Tsao

    (The University of Hong Kong)

  • Dora Lai-wan Kwong

    (The University of Hong Kong
    The University of Hong Kong-Shenzhen Hospital)

  • Anne Wing-Mui Lee

    (The University of Hong Kong
    The University of Hong Kong-Shenzhen Hospital
    Advanced Energy Science and Technology Guangdong Laboratory)

  • Wei Dai

    (The University of Hong Kong
    The University of Hong Kong-Shenzhen Hospital)

  • Xin-Yuan Guan

    (The University of Hong Kong
    The University of Hong Kong-Shenzhen Hospital
    Sun Yat-sen University Cancer Center
    Sun Yat-sen University Cancer Center)

Abstract

Despite the intense CD8+ T-cell infiltration in the tumor microenvironment of nasopharyngeal carcinoma, anti-PD-1 immunotherapy shows an unsatisfactory response rate in clinical trials, hindered by immunosuppressive signals. To understand how microenvironmental characteristics alter immune homeostasis and limit immunotherapy efficacy in nasopharyngeal carcinoma, here we establish a multi-center single-cell cohort based on public data, containing 357,206 cells from 50 patient samples. We reveal that nasopharyngeal carcinoma cells enhance development and suppressive activity of regulatory T cells via CD70-CD27 interaction. CD70 blocking reverts Treg-mediated suppression and thus reinvigorate CD8+ T-cell immunity. Anti-CD70+ anti-PD-1 therapy is evaluated in xenograft-derived organoids and humanized mice, exhibiting an improved tumor-killing efficacy. Mechanistically, CD70 knockout inhibits a collective lipid signaling network in CD4+ naïve and regulatory T cells involving mitochondrial integrity, cholesterol homeostasis, and fatty acid metabolism. Furthermore, ATAC-Seq delineates that CD70 is transcriptionally upregulated by NFKB2 via an Epstein-Barr virus-dependent epigenetic modification. Our findings identify CD70+ nasopharyngeal carcinoma cells as a metabolic switch that enforces the lipid-driven development, functional specialization and homeostasis of Tregs, leading to immune evasion. This study also demonstrates that CD70 blockade can act synergistically with anti-PD-1 treatment to reinvigorate T-cell immunity against nasopharyngeal carcinoma.

Suggested Citation

  • Lanqi Gong & Jie Luo & Yu Zhang & Yuma Yang & Shanshan Li & Xiaona Fang & Baifeng Zhang & Jiao Huang & Larry Ka-Yue Chow & Dittman Chung & Jinlin Huang & Cuicui Huang & Qin Liu & Lu Bai & Yuen Chak Ti, 2023. "Nasopharyngeal carcinoma cells promote regulatory T cell development and suppressive activity via CD70-CD27 interaction," Nature Communications, Nature, vol. 14(1), pages 1-24, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37614-6
    DOI: 10.1038/s41467-023-37614-6
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