27 July 2020

Scientists in Germany have made new discoveries into T cell receptor signalling which could improve immunotherapy for haematological cancers.

The work was jointly supervised by Dr Susana Minguet and Prof Wolgang Schamel at the University of Freiburg in Germany. In this study, the team examined various subunits of the T cell receptor using a combination of biochemistry, synthetic biology, and immunology.

In doing so, they found a previously undiscovered region of the CD3ε chain, which they called the receptor kinase (RK) motif. When a T cell recognises an infected or tumour cell, the researchers found that a molecule called Lymphocyte-specific kinase (Lck) binds to the T cell receptor at the RK motif. Once this happens, the T cell is activated and becomes a killer cell to tackle the threat.

Further experiments suggested that adding the RK motif to chimeric antigen receptors (CARs) may improve CAR-T cell therapy against cancer. Mice carrying a B-cell acute lymphoblastic leukaemia cell line survived for longer after treatment with CAR-T cells which incorporated the RK motif, compared to a standard CAR.

The team’s findings were published last week in Nature Immunology. Dr Minguet and Prof Schamel said: “We were astounded that this RK motive has never been described before. Immunologists have been studying the T-cell receptor for more than 30 years now.”

They found that the RK motif is normally hidden so that T cells are not activated inappropriately.

“This discovery allows us to control T cells more precisely,” explained Dr Minguet. “And now we can do this very specifically, because this is the only cell type to use this novel activation mechanism. In the future, this may not only help in the treatment of cancer but possibly also improve therapies for autoimmune diseases or even immunodeficiencies.”

Source: Hartl FA, Beck-Garcìa E, Woessner NM, Flachsmann LJ, Cárdenas RMV, Brandl SM, Taromi S, Fiala GJ, Morath A, Mishra P, Yousefi OS, Zimmermann J, Hoefflin N, Köhn M, Wöhrl BM, Zeiser R, Schweimer K, Günther S, Schamel WW, Minguet S (2020) “Noncanonical binding of Lck to CD3ε promotes TCR signaling and CAR function.” Nature Immunology, doi: 10.1038/s41590-020-0732-3


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