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Immunity . 2020 Jul 22

Adoptive T Cell Therapy Targeting Different Gene Products Reveals Diverse and Context-Dependent Immune Evasion in Melanoma

Sonali Pechlivanis, Susanne Moebus, Nils Lehmann, Raimund Erbel, Amir A Mahabadi, Per Hoffmann, Karl-Heinz Jöckel, Markus M Nöthen, Hagen S Bachmann, Heinz Nixdorf Recall Study Investigative Group, Tina Meller, Simon Schmitt, Frederike Stein, Katharina Brosch, Johannes Mosebach, Dilara Yüksel, Dario Zaremba, Dominik Grotegerd, Katharina Dohm, Susanne Meinert, Katharina Förster, Ronny Redlich, Nils Opel, Jonathan Repple, Tim Hahn, Andreas Jansen, Till F M Andlauer, Andreas J Forstner, Stefanie Heilmann-Heimbach, Fabian Streit, Stephanie H Witt, Marcella Rietschel, Bertram Müller-Myhsok, Markus M Nöthen, Udo Dannlowski, Axel Krug, Tilo Kircher, Igor Nenadić, Michael Praktiknjo, Caroline Clees, Alessandra Pigliacelli, Stefan Fischer, Christian Jansen, Jennifer Lehmann, Alessandra Pohlmann, Barbara Lattanzi, Viktoria Katharina Krabbe, Christian P Strassburg, Vicente Arroyo, Manuela Merli, Carsten Meyer, Jonel Trebicka, Maike Effern, Nicole Glodde, Matthias Braun, Jana Liebing, Helena N Boll, Michelle Yong, Emma Bawden, Daniel Hinze, Debby van den Boorn-Konijnenberg, Mila Daoud, Pia Aymans, Jennifer Landsberg, Mark J Smyth, Lukas Flatz, Thomas Tüting, Tobias Bald, Thomas Gebhardt, Michael Hölzel

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, promoted melanoma dedifferentiation, and increased myeloid cell infiltration. CDK4R24C 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.

PMID: 32750334