TY  - JOUR
AU  - Kropp, Korbinian N
AU  - Fatho, Martina
AU  - Huduti, Enes
AU  - Faust, Marilena
AU  - Lübcke, Silke
AU  - Lennerz, Volker
AU  - Paschen, Annette
AU  - Theobald, Matthias
AU  - Wölfel, Thomas
AU  - Wölfel, Catherine
TI  - Targeting the melanoma-associated antigen CSPG4 with HLA-C*07:01-restricted T-cell receptors.
JO  - Frontiers in immunology
VL  - 14
SN  - 1664-3224
CY  - Lausanne
PB  - Frontiers Media
M1  - DKFZ-2023-02103
SP  - 1245559
PY  - 2023
AB  - Chondroitin sulfate proteoglycan 4 (CSPG4), also known as high molecular weight-melanoma associated antigen, is expressed in melanoma but also other tumor entities and constitutes an attractive target for immunotherapeutic approaches. While recent preclinical reports focused on anti-CSPG4 chimeric antigen receptors (CAR), we here explore T-cell receptor (TCR)-based approaches targeting CSPG4.The TCRs of two CSPG4-reactive T-cell clones (11C/73 and 2C/165) restricted by the highly prevalent HLA-C*07:01 allele were isolated and the respective αβTCR pairs were retrovirally expressed in CRISPR/Cas9-edited TCR-knockout T cells for functional testing. We also combined alpha and beta TCR chains derived from 11C/73 and 2C/165 in a cross-over fashion to assess for hemichain dominance. CSPG4+ melanoma, glioblastoma and lung cancer cell lines were identified and, if negative, retrovirally transduced with HLA-C*07:01.Functional tests confirmed specific recognition of CSPG4+HLA-C*07:01+ target cells by the αβTCR retrieved from the parental T-cell clones and in part also by the cross-over TCR construct 2Cα-11Cβ. Despite high surface expression, the 11Cα-2Cβ combination, however, was not functional.Collectively, 11C/73- and 2C/165-expressing T cells specifically and efficiently recognized CSPG4+HLA-C*07:01+ cancer cells which warrants further preclinical and clinical evaluation of these TCRs.
KW  - CSPG4 (Other)
KW  - T cell receptor (TCR) (Other)
KW  - TCR hemichain dominance (Other)
KW  - chondroitin sulfate proteoglycan 4 (Other)
KW  - tumor immunotherapy (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37849763
C2  - pmc:PMC10577170
DO  - DOI:10.3389/fimmu.2023.1245559
UR  - https://inrepo02.dkfz.de/record/284800
ER  -