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,Sonia Guedan

Nature Communications(2024)

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摘要
AbstractChimeric 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.
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