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.
Highlights
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
Our study revealed that highly selective optical control of Ca2 þ signalling in adoptively transferred CTLs was sufficient to overcome Treg-mediated immunosuppression at the tumour site, leading to a significant reduction in tumour growth in the mouse melanoma model
To determine the mechanisms of Treg-mediated immune suppression at the tumour site, we first measured the kinetics of Treg responses in a mouse melanoma model
Summary
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. Our findings indicate that the targeted optogenetic stimulation of intracellular Ca2 þ 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. T cell-based immunotherapy has emerged as a powerful treatment option for several types of cancer[1] This success has not yet been transferred to solid tumours, due in part to the strong immunosuppressive tumour microenvironment[2,3,4,5,6]. Our study revealed that highly selective optical control of Ca2 þ signalling in adoptively transferred CTLs was sufficient to overcome Treg-mediated immunosuppression at the tumour site, leading to a significant reduction in tumour growth in the mouse melanoma model
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