Effern, Maike ORCID: 0000-0002-1766-9881, Glodde, Nicole, Braun, Matthias, Liebing, Jana, Boll, Helena N., Yong, Michelle, Bawden, Emma ORCID: 0000-0002-4772-7675, Hinze, Daniel, Van den Boorn-Konijnenberg, Debby, Daoud, Mila, Aymans, Pia, Landsberg, Jennifer, Smyth, Mark J., Flatz, Lukas, Tueting, Thomas, Bald, Tobias, Gebhardt, Thomas and Hoelzel, Michael (2020). Adoptive T Cell Therapy Targeting Different Gene Products Reveals Diverse and Context-Dependent Immune Evasion in Melanoma. Immunity, 53 (3). S. 564 - 590. CAMBRIDGE: CELL PRESS. ISSN 1097-4180

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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 CDK4(R24C )(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 CDK4(R24C), promoted melanoma dedifferentiation, and increased myeloid cell infiltration. CDK4(R24C) antigen persistence was associated with an interferon-high and T-cell-rich tumor microenvironment, allowing for immune checkpoint inhibition as salvage therapy. Thus, the choice of target antigen determines the phenotype and immune contexture of recurrent melanomas, with implications to the design of cancer immunotherapies.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Effern, MaikeUNSPECIFIEDorcid.org/0000-0002-1766-9881UNSPECIFIED
Glodde, NicoleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braun, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liebing, JanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boll, Helena N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yong, MichelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bawden, EmmaUNSPECIFIEDorcid.org/0000-0002-4772-7675UNSPECIFIED
Hinze, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Van den Boorn-Konijnenberg, DebbyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Daoud, MilaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aymans, PiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Landsberg, JenniferUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smyth, Mark J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Flatz, LukasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tueting, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bald, TobiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gebhardt, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoelzel, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-319105
DOI: 10.1016/j.immuni.2020.07.007
Journal or Publication Title: Immunity
Volume: 53
Number: 3
Page Range: S. 564 - 590
Date: 2020
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1097-4180
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PD-1 BLOCKADE; ANTIGEN; IDENTIFICATION; LYMPHOCYTES; CANCER; RESISTANCE; ERADICATION; MUTATIONS; INDUCTION; RESPONSESMultiple languages
ImmunologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/31910

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