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Kirschner, Andreas; Thiede, Melanie; Blaeschke, Franziska; Richter, Günther H. S.; Gerke, Julia S.; Baldauf, Michaela C.; Grünewald, Thomas G. P.; Busch, Dirk H.; Burdach, Stefan and Thiel, Uwe (2016): Lysosome-associated membrane glycoprotein 1 predicts fratricide amongst T cell receptor transgenic CD8(+) T cells directed against tumor-associated antigens. In: Oncotarget, Vol. 7, No. 35: pp. 56584-56597

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Aim: Autologous as well as allogeneic CD8(+) T cells transduced with tumor antigen specific T cell receptors (TCR) may cause significant tumor lysis upon adoptive transfer. Besides unpredictable life-threatening off-target effects, these TCRs may unexpectedly commit fratricide. We hypothesized lysosome-associated membrane glycoprotein 1 (LAMP1, CD107a) to be a marker for fratricide in TCR transgenic CD8(+) T cells. Methods: We identified HLA-A*02:01/peptide-restricted T cells directed against ADRB3(295). After TCR identification, we generated HLA-A*02:01/peptide restricted TCR transgenic T cells by retroviral transduction and tested T cell expansion rates as well as A*02:01/peptide recognition and ES killing in ELISpot and xCELLigence assays. Expansion arrest was analyzed via Annexin and CD107a staining. Results were compared to CHM1(319)-TCR transgenic T cells. Results: Beta-3-adrenergic receptor (ADRB3) as well as chondromodulin-1 (CHM1) are over-expressed in Ewing Sarcoma (ES) but not on T cells. TCR transgenic T cells demonstrated HLA-A*02:01/ADRB3(295) mediated ES recognition and killing in ELISpot and xCELLigence assays. 24h after TCR transduction, CD107a expression correlated with low expansion rates due to apoptosis of ADRB3 specific T cells in contrast to CHM1 specific transgenic T cells. Amino-acid exchange scans clearly indicated the cross-reactive potential of HLA-A*02:01/ADRB3(295)- and HLA-A*02:01/CHM1(319)-TCR transgenic T cells. Comparison of peptide motive binding affinities revealed extended fratricide among ADRB3(295) specific TCR transgenic T cells in contrast to CHM1(319). Conclusion: Amino-acid exchange scans alone predict TCR cross-reactivity with little specificity and thus require additional assessment of potentially cross-reactive HLA-A*02:01 binding candidates. CD107a positivity is a marker for fratricide of CD8(+) TCR transgenic T cells.

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