Targeted calcium influx boosts cytotoxic T lymphocyte function in the tumour microenvironment

Kyun-Do Kim, Seyeon Bae, Tara Capece, Hristina Nedelkovska, Rafael G. de Rubio, Alan V. Smrcka, Chang-Duk Jun, Woojin Jung, Byeonghak Park, Tae-il Kim and Minsoo Kim ()
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Kyun-Do Kim: David H. Smith Center for Vaccine Biology and Immunology, University of Rochester
Seyeon Bae: David H. Smith Center for Vaccine Biology and Immunology, University of Rochester
Tara Capece: David H. Smith Center for Vaccine Biology and Immunology, University of Rochester
Hristina Nedelkovska: David H. Smith Center for Vaccine Biology and Immunology, University of Rochester
Rafael G. de Rubio: University of Rochester
Alan V. Smrcka: University of Rochester
Chang-Duk Jun: School of Life Sciences, Immune Synapse and Cell Therapy Research Center, Gwangju Institute of Science and Technology
Woojin Jung: School of Chemical Engineering, Sungkyunkwan University
Byeonghak Park: School of Chemical Engineering, Sungkyunkwan University
Tae-il Kim: School of Chemical Engineering, Sungkyunkwan University
Minsoo Kim: David H. Smith Center for Vaccine Biology and Immunology, University of Rochester

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: Abstract Adoptive cell transfer utilizing tumour-targeting cytotoxic T lymphocytes (CTLs) is one of the most effective immunotherapies against haematological malignancies, but significant clinical success has not yet been achieved in solid tumours due in part to the strong immunosuppressive tumour microenvironment. Here, we show that suppression of CTL killing by CD4+CD25+Foxp3+ regulatory T cell (Treg) is in part mediated by TGFβ-induced inhibition of inositol trisphosphate (IP3) production, leading to a decrease in T cell receptor (TCR)-dependent intracellular Ca2+ response. Highly selective optical control of Ca2+ signalling in adoptively transferred CTLs enhances T cell activation and IFN-γ production in vitro, leading to a significant reduction in tumour growth in mice. Altogether, our findings indicate that the targeted optogenetic stimulation of intracellular Ca2+ signal allows for the remote control of cytotoxic effector functions of adoptively transferred T cells with outstanding spatial resolution by boosting T cell immune responses at the tumour sites.

Date: 2017
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DOI: 10.1038/ncomms15365

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