Complementarity-determining region clustering may cause CAR-T cell dysfunction

Tina Sarén, Giulia Saronio, Paula Marti Torrell, Xu Zhu, Josefin Thelander, Yasmin Andersson, Camilla Hofström, Marika Nestor, Anna Dimberg, Helena Persson, Mohanraj Ramachandran, Di Yu () and Magnus Essand ()
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Tina Sarén: Pathology, Science for Life Laboratory
Giulia Saronio: Pathology, Science for Life Laboratory
Paula Marti Torrell: Pathology, Science for Life Laboratory
Xu Zhu: Pathology, Science for Life Laboratory
Josefin Thelander: Pathology, Science for Life Laboratory
Yasmin Andersson: Science for Life Laboratory
Camilla Hofström: Science for Life Laboratory
Marika Nestor: Pathology, Science for Life Laboratory
Anna Dimberg: Pathology, Science for Life Laboratory
Helena Persson: Science for Life Laboratory
Mohanraj Ramachandran: Pathology, Science for Life Laboratory
Di Yu: Pathology, Science for Life Laboratory
Magnus Essand: Pathology, Science for Life Laboratory

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract Chimeric antigen receptor (CAR)-T cell therapy is rapidly advancing as cancer treatment, however, designing an optimal CAR remains challenging. A single-chain variable fragment (scFv) is generally used as CAR targeting moiety, wherein the complementarity-determining regions (CDRs) define its specificity. We report here that the CDR loops can cause CAR clustering, leading to antigen-independent tonic signalling and subsequent CAR-T cell dysfunction. We show via CARs incorporating scFvs with identical framework and varying CDR sequences that CARs may cluster on the T cell surface, which leads to antigen-independent CAR-T cell activation, characterized by increased cell size and interferon (IFN)-γ secretion. This results in CAR-T cell exhaustion, activation-induced cell death and reduced responsiveness to target-antigen-expressing tumour cells. CDR mutagenesis confirms that the CAR-clustering is mediated by CDR-loops. In summary, antigen-independent tonic signalling can be induced by CDR-mediated CAR clustering, which could not be predicted from the scFv sequences, but could be tested for by evaluating the activity of unstimulated CAR-T cells.

Date: 2023
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DOI: 10.1038/s41467-023-40303-z

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