Journal article
Adoptive T Cell Therapy Targeting Different Gene Products Reveals Diverse and Context-Dependent Immune Evasion in Melanoma
M Effern, N Glodde, M Braun, J Liebing, HN Boll, M Yong, E Bawden, D Hinze, D van den Boorn-Konijnenberg, M Daoud, P Aymans, J Landsberg, MJ Smyth, L Flatz, T Tüting, T Bald, T Gebhardt, M Hölzel
Immunity | CELL PRESS | Published : 2020
Abstract
Tumor immune escape limits durable responses to T cell therapy. Here, we examined how regulation and function of gene products that provide the target epitopes for CD8+ T cell anti-tumor immunity influence therapeutic efficacy and resistance. We used a CRISPR-Cas9-based method (CRISPitope) in syngeneic melanoma models to fuse the same model CD8+ T cell epitope to the C-termini of different endogenous gene products. Targeting melanosomal proteins or oncogenic CDK4R24C (Cyclin-dependent kinase 4) by adoptive cell transfer (ACT) of the same epitope-specific CD8+ T cells revealed diverse genetic and non-genetic immune escape mechanisms. ACT directed against melanosomal proteins, but not CDK4R24C..
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Awarded by Bristol-Myers Squibb
Funding Acknowledgements
We thank P. Wurst and An. Dolf for help with flow cytometry. We thank the UKB core facilities (flow cytometry and NGS). This work was supported by an NHMRC Early Career fellowship (grant number 1124690) and an EMBO Long Term Fellowship ALTF (grant number 945-2015) to T.B., the Deutsche Krebshilfe (German Cancer Aid) through a junior research group grant within the Mildred Scheel School of Oncology (MSSO) Cologne-Bonn (70113307) to N.G., a scholarship within the ``Mildred Scheel Stiftung f_ur Krebsforschung'' to M.B., the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) within GRK 2168 to M.H., scholarships by the University of Melbourne to M.E. and E.B., a scholarship to M.E. within GRK 2168, and the DFG under Germany's Excellence Strategy-EXC2151-390873048. M.J.S. was supported by NHMRC Investigator (1173958) and Program (1132519) grants. T.G. and M.H. are supervisors in the GRK 2168 international graduate school, Bonn-Melbourne. M.H. is a member of the DFG Excellence Cluster ImmunoSensation2 (EXC 2151).