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

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.

A calcium optimum for cytotoxic T lymphocyte and natural killer cell cytotoxicity

“…) and it has been recently shown that targeted Ca 2+ entry in CTLs increases cytotoxic functions against tumour cells (Kim et al . ). Thus, to fully understand the Ca 2+ dependence of LG release in CTLs and NK cells, local domains at the IS have to be analysed and potential Ca 2+ sensors need to be identified.…”

Impact of Lanthanide Nanomaterials on Photonic Devices and Smart Applications

“…a) Endoplasmic reticulum (ER)‐tethered OptoPBer with the induced reversible labeling of the plasma membrane (PM) contact sites; b) experimental design of the optical control of Ca 2+ signal in vivo . c) Wireless light‐delivery system and fully internal implants; d) multifunctional implantable optoelectronic device, in a tilted and expanded view .…”

“…c) Wireless light‐delivery system and fully internal implants; d) multifunctional implantable optoelectronic device, in a tilted and expanded view . Reproduced with permission . Panel (a), Copyright 2017, Royal Society of Chemistry, Panel (b), 2017 Macmillan Publishers Limited, Panel (c), 2015 Macmillan Publishers Limited, Panel (d), 2013 American Association for the Advancement of Science.…”

“…Optical control of Ca 2+ signaling in adoptively transferred CTLs enhances T‐cell activation and interferon (IFN‐γ) production in vitro, thereby leading to significant reduction of tumor growth in mice. Fluorescence imaging of (Ca 2+ ) i demonstrated that green‐light stimulation drives the prominent (Ca 2+ ) i signal in CatCh (a new variant of channel rhodopsin)‐expressing cells, thereby indicating functional expression (Figure b) …”

Activity – Stability Volcano Plots for the Investigation of Nano‐Sized Electrode Materials in Lithium‐Ion Batteries

“…[12] One shortcoming of predictive Volcano plots based on a priori computational screening, which may serve as an important precursor step to the synthesis of improved catalytic materials, [13] constitutes the fact that in most studies Volcano curves indicate the activity of the catalytic material only, while the stability of the catalyst is not accounted for. Since catalysts with an increased catalytic activity rather often suffer from a diminished stability, [14,15] which in turn limit the application of highly active materials in practice, it would be advantageous to tackle the stability issue within the concept of Volcano plots as considered in reference. [16] Herein, the present study aims at transferring the idea of Volcano plots from catalysis to battery research by considering both activity as well as stability.…”