Pieper, Natalia and Zaremba, Anne and Leonardelli, Sonia and Harbers, Franziska Noelle and Schwamborn, Marion and Luebcke, Silke and Schroers, Barbara and Baingo, Jolanthe and Schramm, Alexander and Haferkamp, Sebastian and Seifert, Ulrike and Sucker, Antje and Lennerz, Volker and Woelfel, Thomas and Schadendorf, Dirk and Schilling, Bastian and Paschen, Annette and Zhao, Fang (2018) Evolution of melanoma cross-resistance to CD8(+) T cells and MAPK inhibition in the course of BRAFi treatment. ONCOIMMUNOLOGY, 7 (8): e1450127. ISSN 2162-402X,
Full text not available from this repository. (Request a copy)Abstract
The profound but frequently transient clinical responses to BRAF(V600) inhibitor (BRAFi) treatment in melanoma emphasize the need for combinatorial therapies. Multiple clinical trials combining BRAFi and immunotherapy are under way to further enhance therapeutic responses. However, to which extent BRAF(V600) inhibition may affect melanoma immunogenicity over time remains largely unknown. To support the development of an optimal treatment protocol, we studied the impact of prolonged BRAFi exposure on the recognition of melanoma cells by T cells in different patient models. We demonstrate that autologous CD8(+) tumor-infiltrating lymphocytes (TILs) efficiently recognized short-term (3, 7days) BRAFi-treated melanoma cells but were less responsive towards long-term (14, 21days) exposed tumor cells. Those long-term BRAFi-treated melanoma cells showed a non-proliferative dedifferentiated phenotype and were less sensitive to four out of five CD8(+) T cell clones, present in the preexisting TIL repertoire, of which three recognized shared antigens (Tyrosinase, Melan-A and CSPG4) and one being neoantigen-specific. Only a second neoantigen was steadily recognized independent of treatment duration. Notably, in all cases the impaired T cell activation was due to a time-dependent downregulation of their respective target antigens. Moreover, combinatorial treatment of melanoma cells with BRAFi and an inhibitor of its downstream kinase MEK had similar effects on T cell recognition. In summary, MAP kinase inhibitors (MAPKi) strongly alter the tumor antigen expression profile over time, favoring evolution of melanoma variants cross-resistant to both T cells and MAPKi. Our data suggest that simultaneous treatment with MAPKi and immunotherapy could be most effective for tumor elimination.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | METASTATIC MELANOMA; ANTITUMOR-ACTIVITY; VEMURAFENIB; RECOGNITION; IMMUNOTHERAPY; SURVIVAL; INFILTRATION; NEOANTIGENS; DABRAFENIB; TRAMETINIB; BRAF; CD8(+) T cells; MEK; antigens; inhibitor; melanoma; resistance |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Dermatologie und Venerologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 20 Mar 2020 09:25 |
| Last Modified: | 20 Mar 2020 09:25 |
| URI: | https://pred.uni-regensburg.de/id/eprint/15342 |
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