Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma
Open accessAbstract
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.
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A recent melanoma study found that on-treatment biopsies had increases in several mediators of dendritic cell and T cell recruitment with nivolumab and/or ipilimumab therapy.
“These findings are corroborated by a recent study in melanoma in which on-treatment biopsies had increases in several of these mediators of dendritic cell and T cell recruitment with nivolumab and/or ipilimumab therapy30.”
From Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial (2022) · cites this paper as [30]
CD8+ T-cell infiltration and IFNγ signaling signatures predict benefit from combined anti-PD-1 and anti-CTLA-4 in solid tumors or anti-PD-L1 alone in breast cancer.
“Both CD8+ T-cell infiltration and IFNγ signaling signatures are indicative of benefit from combined anti-PD-1 and anti-CTLA-4 in patients with solid tumors (71) or anti-PD-L1 alone in BC (72).”
Multiple studies reported that tumors with high expression of IFN-gamma-related gene signatures have better clinical responses to immune checkpoint therapy.
“Multiple studies have reported that tumors identified as having”
From The Next Decade of Immune Checkpoint Therapy (2021) · cites this paper as [162]
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References 61 · Cited by 390
- 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., 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.
- Affiliations
- Cedars-Sinai Medical Center (US)
- University of California, Los Angeles (US)
- University of Lausanne (CH)
- University of Chicago (US)
- Memorial Sloan Kettering Cancer Center (US)
- Vanderbilt University (US)
- Parker Institute for Cancer Immunotherapy (US)
- University of Washington (US)
- Johns Hopkins University (US)
- Providence Portland Medical Center (US)
- University of Virginia Health System (US)
- The University of Texas MD Anderson Cancer Center (US)
- The Netherlands Cancer Institute (NL)
- Corresponding author
- Grasso, Catherine S.
- Ribas, Antoni
- ORCID
- Grasso, Catherine S.
- Tsoi, Jennifer
- Onyshchenko, Mykola
- Champhekar, Ameya
- Medina, Egmidio
- Torrejon, Davis Y.
- Shin, Daniel Sanghoon
- Tran, Phuong
- Kim, Yeon Joo
- Puig-Saus, Cristina
- Campbell, Katie
- Vega-Crespo, Agustin
- Martignier, Christophe
- Luke, Jason J.
- Wolchok, Jedd D.
- Johnson, Douglas B.
- Chmielowski, Bartosz
- Hodi, F. Stephen
- Bhatia, Shailender
- Sharfman, William
- Urba, Walter J.
- Slingluff, Craig L.
- Diab, Adi
- Haanen, John B.A.G.
- Pardoll, Drew M.
- Anagnostou, Valsamo
- Topalian, Suzanne L.
- Velculescu, Victor E.
- Speiser, Daniel E.
- Kalbasi, Anusha
- Ribas, Antoni
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2020-10
- Volume
- 38
- Issue
- 4
- Pages
- 500-515.e3
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC7872287
- OpenAlex
- W3085427829
- Cited by
- 390
- References
- 61
- Citations by year
- 2026: 54 · 2025: 69 · 2024: 61 · 2023: 71 · 2022: 67 · 2021: 67 · 2020: 1
- FWCI
- 19.05
- Type
- journal article
- Language
- en
- Update notices
- erratum (2021-01-11)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- Tower Cancer Research Foundation
- Incyte
- Sanofi
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- AstraZeneca
- Radiological Society of North America (P01 CA244118, P30 CA016042, R35 CA197633)
- Astellas Pharma US
- Bristol-Myers Squibb
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
- Clinical and Translational Science Institute, University of California, Los Angeles
- Melanoma Research Alliance
- Takeda Pharmaceuticals U.S.A.
- Kyowa Hakko Kirin
- LUNGevity Foundation
- V Foundation for Cancer Research
- Boston Pharmaceuticals (9402905, 20170022275, 20100111973, 10279021, 20160046716, 20170008962, 7250291, 10106611, 20160340407, 20140004112, 20170343552, 20170248603)
- Genentech
- Merck (15/612,657, PCT/US18/36052)
- AbbVie
- American Society of Clinical Oncology
- Cancer Research Institute (CA233259, CA006973)
- Entertainment Industry Foundation
- American Association for Cancer Research
- Eli Lilly and Company
- Swim Across America
- Tizona Therapeutics
- Mark Foundation For Cancer Research
- Roche
- GlaxoSmithKline (3M)
- Commonwealth Foundation
- Bayer Fund
- EMD Serono
- National Institutes of Health (T32-CA009120)
- Johns Hopkins University
- National Cancer Institute (R35 CA197633, R01 CA142779)
- Parker Institute for Cancer Immunotherapy
- Novartis
- Jounce Therapeutics
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- interferon-gamma signaling, immune checkpoint blockade, melanoma, nivolumab, ipilimumab, PD-1, CTLA-4, T cell infiltration, tumor transcriptome, cell cycle signaling, Wnt signaling, antitumor immunity, treatment response prediction, IFN-gamma receptor, melanoma cell lines
- MeSH terms
- Ipilimumab, Nivolumab, Immune Checkpoint Inhibitors, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Cell Line, Female, Humans, Interferon-gamma, Male, Melanoma, Middle Aged, T-Lymphocytes, Gene Expression Profiling, Cell Line, Tumor, Young Adult, Transcriptome
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