Journal
CANCER CELL
Volume 38, Issue 4, Pages 500-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2020.08.005
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Funding
- Parker Institute for Cancer Immunotherapy
- NIH Ruth L. Kirschstein Institutional National Research Service Award [T32-CA009120, T32CA009120]
- Isabel & Harvey Kibel Fellowship award
- Alan Ghitis Fellowship Award for Melanoma Research
- ASCO
- Spanish Society of Medical Oncology for Translational Research in Reference Centers
- V Foundation-Gil Nickel Family Endowed Fellowship in Melanoma Research
- Cancer Research Institute Irvington Postdoctoral Fellowship
- NIH [P30 CA008748]
- US NIH [CA121113, CA006973, CA233259]
- V Foundation
- Swim Across America
- Allegheny Health Network-Johns Hopkins Research Fund
- LUNGevity Foundation
- NCI [R01 CA142779]
- Bloomberg-Kimmel Institute for Cancer Immunotherapy
- Cancer Immunology Translational Cancer Research Grant from Cancer Research Institute-Stand Up 2 Cancer [SU2C-AACR-DT1012]
- Commonwealth Foundation
- BloombergKimmel Institute for Cancer Immunotherapy
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Mark Foundation for Cancer Research
- UCLA CTSI KL2 Award
- Sarcoma Alliance for Research through Collaboration Career Enhancement Program
- Tower Cancer Research Foundation Young Investigator Award
- Radiological Society for North America Research Scholar Grant
- Parker Institute for Cancer Immunotherapy, NIH [R35 CA197633, P01 CA244118, P30 CA016042]
- Ressler Family Fund
- Ken and Donna Schultz Fund
- Melanoma Research Alliance
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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.
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