TY - JOUR
T1 - αβ-T Cells Engineered to Express γδ-T Cell Receptors Can Kill Neuroblastoma Organoids Independent of MHC-I Expression
AU - Strijker, Josephine G. M.
AU - Pscheid, Ronja
AU - Drent, Esther
AU - van der Hoek, Jessica J. F.
AU - Koopmans, Bianca
AU - Ober, Kimberley
AU - van Hooff, Sander R.
AU - Kholosy, Waleed M.
AU - Cornel, Annelisa M.
AU - Coomans, Chris
AU - Bisso, Andrea
AU - van Loenen, Marleen M.
AU - Molenaar, Jan J.
AU - Wienke, Judith
N1 - Funding Information: Funding: This work is part of the research programme Vernieuwingsimpuls Vidi (Combining targeted compounds in neuroblastoma tumours; is two better than one?) with project number 91716482, which is partly financed by the Dutch Research Council (NWO). In addition, this project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 716079 Predict. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/9/1
Y1 - 2021/9/1
N2 - Currently ~50% of patients with a diagnosis of high-risk neuroblastoma will not survive due to relapsing or refractory disease. Recent innovations in immunotherapy for solid tumors are highly promising, but the low MHC-I expression of neuroblastoma represents a major challenge for T cell-mediated immunotherapy. Here, we propose a novel T cell-based immunotherapy approach for neuroblastoma, based on the use of TEG002, αβ-T cells engineered to express a defined γδ-T cell receptor, which can recognize and kill target cells independent of MHC-I. In a co-culture killing assay, we showed that 3 out of 6 neuroblastoma organoids could activate TEG002 as measured by IFNγ production. Transcriptional profiling showed this effect correlates with an increased activity of processes involved in interferon signaling and extracellular matrix organization. Analysis of the dynamics of organoid killing by TEG002 over time confirmed that organoids which induced TEG002 activation were efficiently killed independent of their MHC-I expression. Of note, efficacy of TEG002 treatment was superior to donor-matched untransduced αβ-T cells or endogenous γδ-T cells. Our data suggest that TEG002 may be a promising novel treatment option for a subset of neuroblastoma patients.
AB - Currently ~50% of patients with a diagnosis of high-risk neuroblastoma will not survive due to relapsing or refractory disease. Recent innovations in immunotherapy for solid tumors are highly promising, but the low MHC-I expression of neuroblastoma represents a major challenge for T cell-mediated immunotherapy. Here, we propose a novel T cell-based immunotherapy approach for neuroblastoma, based on the use of TEG002, αβ-T cells engineered to express a defined γδ-T cell receptor, which can recognize and kill target cells independent of MHC-I. In a co-culture killing assay, we showed that 3 out of 6 neuroblastoma organoids could activate TEG002 as measured by IFNγ production. Transcriptional profiling showed this effect correlates with an increased activity of processes involved in interferon signaling and extracellular matrix organization. Analysis of the dynamics of organoid killing by TEG002 over time confirmed that organoids which induced TEG002 activation were efficiently killed independent of their MHC-I expression. Of note, efficacy of TEG002 treatment was superior to donor-matched untransduced αβ-T cells or endogenous γδ-T cells. Our data suggest that TEG002 may be a promising novel treatment option for a subset of neuroblastoma patients.
KW - Immunotherapy
KW - MHC-I
KW - Neuroblastoma
KW - TEG002
KW - γδ-T cells
UR - http://www.scopus.com/inward/record.url?scp=85115803435&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/jpm11090923
DO - https://doi.org/10.3390/jpm11090923
M3 - Article
C2 - 34575700
SN - 2075-4426
VL - 11
JO - Journal of Personalized Medicine
JF - Journal of Personalized Medicine
IS - 9
M1 - 923
ER -