Conserved interferon-γ signaling drives clinical response to immune checkpoint blockade therapy in melanoma Journal Article
| Authors: | Grasso, C. S.; 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, F. S.; Bhatia, S.; Sharfman, W.; Urba, W. J.; Slingluff, C. L. Jr; Diab, A.; Haanen, J. B. A. G.; Algarra, S. M.; Pardoll, D. M.; Anagnostou, V.; Topalian, S. L.; Velculescu, V. E.; Speiser, D. E.; Kalbasi, A.; Ribas, A. |
| Article Title: | Conserved interferon-γ signaling drives clinical response to immune checkpoint blockade therapy in melanoma |
| Abstract: | 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-γ (IFN-γ) 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-γ in vitro exposure leads to a conserved transcriptome response unless cells have IFN-γ receptor alterations. This conserved IFN-γ 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-γ signaling are the main drivers of clinical response or resistance to immune checkpoint blockade therapy. © 2020 Elsevier Inc. Analyzing the transcriptome of biopsies of patients during immune checkpoint blockade therapy, Grasso et al. show that the increase of T cell infiltration and the downstream IFN-γ signaling drive clinical responses. © 2020 Elsevier Inc. |
| Keywords: | clinical trial; transcriptomics; response; resistance; anti-ctla-4; rna-seq; biopsies; immune checkpoint blockade; interferon-γ; anti-pd-1; immune exclusion |
| Journal Title: | Cancer Cell |
| Volume: | 38 |
| Issue: | 4 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2020-10-12 |
| Start Page: | 500 |
| End Page: | 515.e3 |
| Language: | English |
| DOI: | 10.1016/j.ccell.2020.08.005 |
| PUBMED: | 32916126 |
| PROVIDER: | scopus |
| PMCID: | PMC7872287 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 November 2020 -- Source: Scopus |
