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CAR affinity modulates the sensitivity of CAR-T cells to PD-1/PD-L1-mediated inhibition

Author

Listed:
  • Irene Andreu-Saumell

    (Fundació Clínic Recerca Biomédica- IDIBAPS)

  • Alba Rodriguez-Garcia

    (Fundació Clínic Recerca Biomédica- IDIBAPS)

  • Vanessa Mühlgrabner

    (Institute for Hygiene and Applied Immunology)

  • Marta Gimenez-Alejandre

    (Fundació Clínic Recerca Biomédica- IDIBAPS)

  • Berta Marzal

    (Fundació Clínic Recerca Biomédica- IDIBAPS)

  • Joan Castellsagué

    (Fundació Clínic Recerca Biomédica- IDIBAPS)

  • Fara Brasó-Maristany

    (Fundació Clínic Recerca Biomédica- IDIBAPS)

  • Hugo Calderon

    (Fundació Clínic Recerca Biomédica- IDIBAPS)

  • Laura Angelats

    (Fundació Clínic Recerca Biomédica- IDIBAPS
    University of Barcelona)

  • Salut Colell

    (Fundació Clínic Recerca Biomédica- IDIBAPS)

  • Mara Nuding

    (Fundació Clínic Recerca Biomédica- IDIBAPS)

  • Marta Soria-Castellano

    (Fundació Clínic Recerca Biomédica- IDIBAPS)

  • Paula Barbao

    (Fundació Clínic Recerca Biomédica- IDIBAPS)

  • Aleix Prat

    (Fundació Clínic Recerca Biomédica- IDIBAPS
    University of Barcelona
    Hospital Clínic de Barcelona)

  • Alvaro Urbano-Ispizua

    (Fundació Clínic Recerca Biomédica- IDIBAPS
    University of Barcelona)

  • Johannes B. Huppa

    (Institute for Hygiene and Applied Immunology)

  • Sonia Guedan

    (Fundació Clínic Recerca Biomédica- IDIBAPS)

Abstract

Chimeric antigen receptor (CAR)-T cell therapy for solid tumors faces significant hurdles, including T-cell inhibition mediated by the PD-1/PD-L1 axis. The effects of disrupting this pathway on T-cells are being actively explored and controversial outcomes have been reported. Here, we hypothesize that CAR-antigen affinity may be a key factor modulating T-cell susceptibility towards the PD-1/PD-L1 axis. We systematically interrogate CAR-T cells targeting HER2 with either low (LA) or high affinity (HA) in various preclinical models. Our results reveal an increased sensitivity of LA CAR-T cells to PD-L1-mediated inhibition when compared to their HA counterparts by using in vitro models of tumor cell lines and supported lipid bilayers modified to display varying PD-L1 densities. CRISPR/Cas9-mediated knockout (KO) of PD-1 enhances LA CAR-T cell cytokine secretion and polyfunctionality in vitro and antitumor effect in vivo and results in the downregulation of gene signatures related to T-cell exhaustion. By contrast, HA CAR-T cell features remain unaffected following PD-1 KO. This behavior holds true for CD28 and ICOS but not 4-1BB co-stimulated CAR-T cells, which are less sensitive to PD-L1 inhibition albeit targeting the antigen with LA. Our findings may inform CAR-T therapies involving disruption of PD-1/PD-L1 pathway tailored in particular for effective treatment of solid tumors.

Suggested Citation

  • Irene Andreu-Saumell & Alba Rodriguez-Garcia & Vanessa Mühlgrabner & Marta Gimenez-Alejandre & Berta Marzal & Joan Castellsagué & Fara Brasó-Maristany & Hugo Calderon & Laura Angelats & Salut Colell &, 2024. "CAR affinity modulates the sensitivity of CAR-T cells to PD-1/PD-L1-mediated inhibition," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47799-z
    DOI: 10.1038/s41467-024-47799-z
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    1. Mohit Sachdeva & Brian W. Busser & Sonal Temburni & Billal Jahangiri & Anne-Sophie Gautron & Alan Maréchal & Alexandre Juillerat & Alan Williams & Stéphane Depil & Philippe Duchateau & Laurent Poirot , 2019. "Repurposing endogenous immune pathways to tailor and control chimeric antigen receptor T cell functionality," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
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