Conserved interferon-g signaling drives clinical response to immune checkpoint blockade therapy in melanoma

Grasso, C.S. (Catherine S.); Tsoi, J. (Jennifer); Onyshchenko, M. (Mykola); Abril-Rodriguez, G. (Gabriel); Ross-Macdonald, P. (Petra); Wind-Rotolo, M. (Megan); Champhekar, A. (Ameya); Medina, E. (Egmidio); Torrejon, D.Y. (Davis Y.); Sanghoon-Shin, D. (Daniel); Tran, P. (Phuong); Joo-Kim, Y. (Yeon); Puig-Saus, C. (Cristina); Campbell, K. (Katie); Vega-Crespo, A. (Agustin); Quist, M. (Michael); Martignier, C. (Christophe); Luke, J.J. (Jason J.); Wolchok, J.D. (Jedd D.); Johnson, D.B. (Douglas B.); Chmielowski, B. (Bartosz); Hodi, F.S. (F. Stephen); Bhatia, S. (Shailender); Sharfman, W. (William); Urba, W.J. (Walter J.); Slingluff, C.L. (Craig L.); Diab, A. (Adi); Haanen, J. (J.); Martin-Algarra, S. (Salvador); Pardoll, D.M. (Drew M.); Anagnostou, V. (Valsamo); Topalian, S.L. (Suzanne L.); Velculescu, V.E. (Victor E.); Speiser, D.E. (Daniel E.); Kalbasi, A. (Anusha); Ribas, A. (Antoni)

Keywords:

RNA-seq
Anti-CTLA-4
Anti-PD-1
Biopsies
Clinical trial
Immune checkpoint blockade
Immune exclusion
Interferon-γ
Resistance
Response
Transcriptomics

Issue Date:

2020

Publisher:

Elsevier

ISSN:

1878-3686

Note:

All rights are reserved, including those for text and data mining, AI training, and similar technologies. For all open access content, the Creative Commons licensing terms apply.

Citation:

Grasso, C.S. (Catherine S.); Tsoi, J. (Jennifer); Onyshchenko, M. (Mykola); et al. "Conserved interferon-g signaling drives clinical response to immune checkpoint blockade therapy in melanoma". Cell press. 38 (4), 2020, 500 - 515.e3.

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.

URI:

https://hdl.handle.net/10171/68513

DOI:

10.1016/j.ccell.2020.08.005

Appears in Collections:

DA - CUN - Oncología médica - Artículos de revista

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