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| Item Type: | Article |
|---|---|
| Title: | CAR affinity modulates the sensitivity of CAR-T cells to PD-1/PD-L1-mediated inhibition |
| Creators: |
Andreu-Saumell, I.  ORCID: https://orcid.org/0009-0006-8897-0846, Rodriguez-Garcia, A. ORCID: https://orcid.org/0000-0003-0906-1793, Mühlgrabner, V., Gimenez-Alejandre, M., Marzal, B., Castellsagué, J., Brasó-Maristany, F. ORCID: https://orcid.org/0000-0001-5440-9643, Calderon, H. ORCID: https://orcid.org/0000-0002-8902-4302, Angelats, L., Colell, S. ORCID: https://orcid.org/0000-0002-2132-2856, Nuding, M., Soria-Castellano, M. ORCID: https://orcid.org/0000-0002-0746-417X, Barbao, P. ORCID: https://orcid.org/0000-0001-7139-4420, Prat, A. ORCID: https://orcid.org/0000-0003-2377-540X, Urbano-Ispizua, A., Huppa, J.B. ORCID: https://orcid.org/0000-0003-2634-8198 and Guedan, S. ORCID: https://orcid.org/0000-0002-9605-0760
|
| 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. |
| Keywords: | B7-H1 Antigen, CRISPR-Cas Systems, Tumor Cell Line, Adoptive Immunotherapy, Inbred NOD Mice, Programmed Cell Death 1 Receptor, ErbB-2 Receptor, Chimeric Antigen Receptors, T-Lymphocytes, Xenograft Model Antitumor Assays, Animals, Mice |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 15 |
| Number: | 1 |
| Page Range: | 3552 |
| Date: | 26 April 2024 |
| Official Publication: | https://doi.org/10.1038/s41467-024-47799-z |
| PubMed: | View item in PubMed |
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