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Conserved Interferon-gamma Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma

Autores: Grasso, C. S. (Autor de correspondencia); Tsoi, J.; Onyshchenko, M.; Abril-Rodriguez, G. ; Ross-Macdonald, P.; Wind-Rotolo, M. ; Champhekar, A. ; Medina, E.; Torrejon, D. Y.; Shin, D. S.; Tran, P. ; Kim, Y. J.; Puig-Saus, C.; Campbell, K.; Vega-Crespo, A. ; Quist, M.; Martignier, C.; Luke, J. J. ; Wolchok, J. D. ; Johnson, D. B. ; Chmielowski, B.; Hodi, S.; Bhatia, S.; Sharfman, W. ; Urba, W. J.; Slingluff, C. L.; Diab, A.; Haanen, J. B. A. G.; Martín Algarra, Salvador; Pardoll, D. M.; Anagnostou, V.; Topalian, S. L.; Velculescu, V. E.; Speiser, D. E.; Kalbasi, A. ; Ribas, A. (Autor de correspondencia)
Título de la revista: CANCER CELL
ISSN: 1535-6108
Volumen: 38
Número: 4
Páginas: 500 - +
Fecha de publicación: 2020
Resumen:
We analyze the transcriptome of baseline and on-therapy tumor biopsies from 101 patients with advanced melanoma treated with nivolumab (anti-PD-1) alone or combined with ipilimumab (anti-CTLA-4). We find that T cell infiltration and interferon-gamma (IFN-gamma) signaling signatures correspond most highly with clinical response to therapy, with a reciprocal decrease in cell-cycle and WNT signaling pathways in responding biopsies. We model the interaction in 58 human cell lines, where IFN-gamma in vitro exposure leads to a conserved transcriptome response unless cells have IFN-gamma receptor alterations. This conserved IFN-gamma transcriptome response in melanoma cells serves to amplify the antitumor immune response. Therefore, the magnitude of the antitumor T cell response and the corresponding downstream IFN-gamma signaling are the main drivers of clinical response or resistance to immune checkpoint blockade therapy.
DOI: https://doi.org/10.1016/j.ccell.2020.08.005
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