Mixed T cell receptor dimers harbor potentially harmful neoreactivity.
Adoptive transfer of T cell receptor (TCR)-transduced T cells may be an attractive strategy to target both hematological malignancies and solid tumors. By introducing a TCR, large numbers of T cells with defined antigen (Ag) specificity can be obtained. However, by introduction of a TCR, mixed TCR dimers can be formed. Besides the decrease in TCR expression of the introduced and endogenous TCR, these mixed TCR dimers could harbor potentially harmful specificities. In this study, we demonstrate that introduction of TCRs resulted in formation of neoreactive mixed TCR dimers, composed of the introduced TCR chains pairing with either the endogenous TCR alpha or beta chain. Neoreactivities observed were HLA class I or class II restricted. Most neoreactive mixed TCR dimers were allo-HLA reactive; however, neoreactive mixed TCR dimers with autoreactive activity were also observed. We demonstrate that inclusion of an extra disulfide bond between the constant domains of the introduced TCR markedly reduced neoreactivity, whereas enhanced effectiveness of the introduced TCR was observed. In conclusion, TCR transfer results in the formation of neoreactive mixed TCR dimers with the potential to generate off-target effects, underlining the importance of searching for techniques to facilitate preferential pairing.
Department of Hematology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. M.M.van_Loenen@LUMC.nl
Marleen M
MM
van Loenen
Renate
R
de Boer
Avital L
AL
Amir
Renate S
RS
Hagedoorn
Gerdien L
GL
Volbeda
Roelof
R
Willemze
Johannes J
JJ
van Rood
J H Frederik
JH
Falkenburg
Mirjam H M
MH
Heemskerk
D019264:Adoptive Transfer; D002460:Cell Line; D003545:Cysteine / Q000737:chemistry; D019281:Dimerization; D006680:HLA Antigens / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D055503:Protein Multimerization; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D014161:Transduction, Genetic
D006680:HLA Antigens; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; D003545:Cysteine