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Low-dose radiotherapy combined with dual PD-L1 and VEGFA blockade elicits antitumor response in hepatocellular carcinoma mediated by activated intratumoral CD8+ exhausted-like T cells

Author

Listed:
  • Siqi Li

    (The Third Affiliated Hospital of Sun Yat-sen University
    The Third Affiliated Hospital of Sun Yat-sen University)

  • Kun Li

    (The Third Affiliated Hospital of Sun Yat-sen University
    The Third Affiliated Hospital of Sun Yat-sen University)

  • Kang Wang

    (Naval Medical University)

  • Haoyuan Yu

    (The Third Affiliated Hospital of Sun Yat-sen University
    The Third Affiliated Hospital of Sun Yat-sen University)

  • Xiangyang Wang

    (The Seventh Affiliated Hospital of Sun Yat-sen University)

  • Mengchen Shi

    (Sun Yat-sen University)

  • Zhixing Liang

    (The Third Affiliated Hospital of Sun Yat-sen University
    The Third Affiliated Hospital of Sun Yat-sen University)

  • Zhou Yang

    (The Third Affiliated Hospital of Sun Yat-sen University
    The Third Affiliated Hospital of Sun Yat-sen University)

  • Yongwei Hu

    (The Third Affiliated Hospital of Sun Yat-sen University
    The Third Affiliated Hospital of Sun Yat-sen University)

  • Yang Li

    (The Third Affiliated Hospital of Sun Yat-sen University)

  • Wei Liu

    (The Third Affiliated Hospital of Sun Yat-sen University)

  • Hua Li

    (The Third Affiliated Hospital of Sun Yat-sen University)

  • Shuqun Cheng

    (Naval Medical University)

  • Linsen Ye

    (The Third Affiliated Hospital of Sun Yat-sen University
    The Third Affiliated Hospital of Sun Yat-sen University)

  • Yang Yang

    (The Third Affiliated Hospital of Sun Yat-sen University)

Abstract

Atezolizumab (anti-PD-L1) combined with bevacizumab (anti-VEGFA) is the first-line immunotherapy for advanced hepatocellular carcinoma (HCC), but the number of patients who benefit from this regimen remains limited. Here, we combine dual PD-L1 and VEGFA blockade (DPVB) with low-dose radiotherapy (LDRT), which rapidly inflames tumors, rendering them vulnerable to immunotherapy. The combinatorial therapy exhibits superior antitumor efficacy mediated by CD8+ T cells in various preclinical HCC models. Treatment efficacy relies upon mobilizing exhausted-like CD8+ T cells (CD8+ Tex) with effector function and cytolytic capacity. Mechanistically, LDRT sensitizes tumors to DPVB by recruiting stem-like CD8+ Tpex, the progenitor exhausted CD8+ T cells, from draining lymph nodes (dLNs) into the tumor via the CXCL10/CXCR3 axis. Together, these results further support the rationale for combining LDRT with atezolizumab and bevacizumab, and its clinical translation.

Suggested Citation

  • Siqi Li & Kun Li & Kang Wang & Haoyuan Yu & Xiangyang Wang & Mengchen Shi & Zhixing Liang & Zhou Yang & Yongwei Hu & Yang Li & Wei Liu & Hua Li & Shuqun Cheng & Linsen Ye & Yang Yang, 2023. "Low-dose radiotherapy combined with dual PD-L1 and VEGFA blockade elicits antitumor response in hepatocellular carcinoma mediated by activated intratumoral CD8+ exhausted-like T cells," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43462-1
    DOI: 10.1038/s41467-023-43462-1
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    as
    1. Jocelyn E. Chau & Kimberly J. Vish & Titus J. Boggon & Amy L. Stiegler, 2022. "SH3 domain regulation of RhoGAP activity: Crosstalk between p120RasGAP and DLC1 RhoGAP," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Francesca Alfei & Kristiyan Kanev & Maike Hofmann & Ming Wu & Hazem E. Ghoneim & Patrick Roelli & Daniel T. Utzschneider & Madlaina von Hoesslin & Jolie G. Cullen & Yiping Fan & Vasyl Eisenberg & Dirk, 2019. "TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection," Nature, Nature, vol. 571(7764), pages 265-269, July.
    3. Paul C. Tumeh & Christina L. Harview & Jennifer H. Yearley & I. Peter Shintaku & Emma J. M. Taylor & Lidia Robert & Bartosz Chmielowski & Marko Spasic & Gina Henry & Voicu Ciobanu & Alisha N. West & M, 2014. "PD-1 blockade induces responses by inhibiting adaptive immune resistance," Nature, Nature, vol. 515(7528), pages 568-571, November.
    4. Massimo Andreatta & Jesus Corria-Osorio & Sören Müller & Rafael Cubas & George Coukos & Santiago J. Carmona, 2021. "Interpretation of T cell states from single-cell transcriptomics data using reference atlases," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    5. Caroline S. Jansen & Nataliya Prokhnevska & Viraj A. Master & Martin G. Sanda & Jennifer W. Carlisle & Mehmet Asim Bilen & Maria Cardenas & Scott Wilkinson & Ross Lake & Adam G. Sowalsky & Rajesh M. V, 2019. "An intra-tumoral niche maintains and differentiates stem-like CD8 T cells," Nature, Nature, vol. 576(7787), pages 465-470, December.
    6. M. E. Mikucki & D. T. Fisher & J. Matsuzaki & J. J. Skitzki & N. B. Gaulin & J. B. Muhitch & A. W. Ku & J. G. Frelinger & K. Odunsi & T. F. Gajewski & A. D. Luster & S. S. Evans, 2015. "Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints," Nature Communications, Nature, vol. 6(1), pages 1-14, November.
    7. Peter Bailey & David K. Chang & Katia Nones & Amber L. Johns & Ann-Marie Patch & Marie-Claude Gingras & David K. Miller & Angelika N. Christ & Tim J. C. Bruxner & Michael C. Quinn & Craig Nourse & L. , 2016. "Genomic analyses identify molecular subtypes of pancreatic cancer," Nature, Nature, vol. 531(7592), pages 47-52, March.
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