Conserved interferon-gamma signaling and decreased immune exclusion programs in responses to immune checkpoint blockade therapy

We analyzed 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). Analysis of whole transcriptome data showed that T cell infiltration and interferon-gamma signaling signatures corresponded most highly with clinical response to therapy, with a reciprocal decrease in cell cycle and WNT signaling pathways in responding biopsies. Clinical outcome differences were likely not due to differential melanoma cell responses to interferon-gamma, as 57 human melanoma cell lines exposed in vitro to this cytokine showed a conserved interferon-gamma transcriptome response unless they had mutations that precluded signaling from the interferon-gamma receptor. Therefore, the magnitude of the antitumor T cell response and the corresponding downstream interferon-gamma signaling are the main drivers of clinical response or resistance to immune checkpoint blockade therapy.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

1 Dataset 4 Publications

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Dataset ID	Description	Technology	Samples
EGAD00001006282	We analyzed 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). Analysis of whole transcriptome data showed that T cell infiltration and interferon-gamma signaling signatures corresponded most highly with clinical response to therapy, with a reciprocal decrease in cell cycle and WNT signaling pathways in responding biopsies. Clinical outcome differences were likely not due to differential melanoma cell responses to interferon-gamma, as 57 human melanoma cell lines exposed in vitro to this cytokine showed a conserved interferon-gamma transcriptome response unless they had mutations that precluded signaling from the interferon-gamma receptor. Therefore, the magnitude of the antitumor T cell response and the corresponding downstream interferon-gamma signaling are the main drivers of clinical response or resistance to immune checkpoint blockade therapy.	Illumina HiSeq 2000	54

Publications	Citations
Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma. Grasso CS, Tsoi J, Onyshchenko M, Abril-Rodriguez G, Ross-Macdonald P, Wind-Rotolo M, Champhekar A, Medina E, Torrejon DY, Shin DS, Tran P, Kim YJ, Puig-Saus C, Campbell K, Vega-Crespo A, Quist M, Martignier C, Luke JJ, Wolchok JD, Johnson DB, Chmielowski B, Hodi FS, Bhatia S, Sharfman W, Urba WJ, Slingluff CL, Diab A, Haanen JBAG, Algarra SM, Pardoll DM, Anagnostou V, Topalian SL, Velculescu VE, Speiser DE, Kalbasi A, Ribas A. Cancer Cell 38: 2020 500-515.e3	166
Integrative Tumor and Immune Cell Multi-omic Analyses Predict Response to Immune Checkpoint Blockade in Melanoma. Anagnostou V, Bruhm DC, Niknafs N, White JR, Shao XM, Sidhom JW, Stein J, Tsai HL, Wang H, Belcaid Z, Murray J, Balan A, Ferreira L, Ross-Macdonald P, Wind-Rotolo M, Baras AS, Taube J, Karchin R, Scharpf RB, Grasso C, Ribas A, Pardoll DM, Topalian SL, Velculescu VE. Cell Rep Med 1: 2020 100139	42
Nanoparticle Delivery of Immunostimulatory Alu RNA for Cancer Immunotherapy. Garland KM, Kwiatkowski AJ, Tossberg JT, Crooke PS, Aune TM, Wilson JT. Cancer Res Commun 3: 2023 1800-1809	1
CAR-T cell therapy targeting surface expression of TYRP1 to treat cutaneous and rare melanoma subtypes. Jilani S, Saco JD, Mugarza E, Pujol-Morcillo A, Chokry J, Ng C, Abril-Rodriguez G, Berger-Manerio D, Pant A, Hu J, Gupta R, Vega-Crespo A, Baselga-Carretero I, Chen JM, Shin DS, Scumpia P, Radu RA, Chen Y, Ribas A, Puig-Saus C. Nat Commun 15: 2024 1244	5