Evolution of melanoma cross-resistance to CD8+ T cells and MAPK inhibition in the course of BRAFi treatment

OncoImmunology

Ulrike Seifert¹  Fang Zhao²  Jolanthe Baingo²  Sonia Leonardelli²  Antje Sucker²  Franziska Noelle Harbers²  Dirk Schadendorf²  Natalia Pieper²  Anne Zaremba²  Marion Schwamborn²  Annette Paschen²  Alexander Schramm³  Sebastian Haferkamp⁴  Silke Lübcke⁵  Barbara Schrörs⁵  Thomas Wölfel⁵  Volker Lennerz⁵  Bastian Schilling⁶ 

[1] Friedrich Loeffler Institute of Medical Microbiology, University Medicine Greifswald;University Hospital Essen, University Duisburg-Essen and German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf;University Hospital Essen;University Hospital Regensburg;University Medical Center, Johannes Gutenberg University;Venerology and Allergology, University Hospital Würzburg;

关键词: braf;    cd8+ t cells;    mek;    antigens;    inhibitor;    melanoma;    resistance;   

DOI  :  10.1080/2162402X.2018.1450127

来源: DOAJ

【 摘 要 】

The profound but frequently transient clinical responses to BRAFV600 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 BRAFV600 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, 7 days) BRAFi-treated melanoma cells but were less responsive towards long-term (14, 21 days) 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.

【 授权许可】

Unknown