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

Irene Andreu-Saumell, Alba Rodriguez-Garcia (), Vanessa Mühlgrabner, Marta Gimenez-Alejandre, Berta Marzal, Joan Castellsagué, Fara Brasó-Maristany, Hugo Calderon, Laura Angelats, Salut Colell, Mara Nuding, Marta Soria-Castellano, Paula Barbao, Aleix Prat, Alvaro Urbano-Ispizua, Johannes B. Huppa and Sonia Guedan ()
Additional contact information
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
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
Alvaro Urbano-Ispizua: Fundació Clínic Recerca Biomédica- IDIBAPS
Johannes B. Huppa: Institute for Hygiene and Applied Immunology
Sonia Guedan: Fundació Clínic Recerca Biomédica- IDIBAPS

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47799-z

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