ArticleCell2018
A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade.
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Article in Cell, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 935 papers, 1 of them a synthesis that pooled it.
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935citing papers in PubMed, 1 pooled it
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Who cites it
935 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Cellular Senescence and Immunosenescence in Melanoma: Insights From the Tumor Microenvironment.Cancer medicine · 2025Pooled it
- Cellular Neighborhoods Govern Antitumor T-cell Infiltration Following Anti-CTLA-4 in Melanoma with Primary Resistance to Anti-PD-1.Cancer discovery · 2026Trial
- Phase 2 study of palbociclib plus retifanlimab in patients with advanced dedifferentiated liposarcoma.Journal for immunotherapy of cancer · 2026Trial
- Tumor and Immune Dynamics Following Sequential CDK4/6 and PD-1 Inhibition: Results from a Phase 2 Study in Dedifferentiated Liposarcoma.Cancer research communications · 2026Trial
- 4-1BBCell reports. Medicine · 2025Trial
- Dynamic modulation of claudin18.2 expression and remodeling of the tumor microenvironment in gastric cancer during chemo-immunotherapy.Journal for immunotherapy of cancer · 2025Trial
- Distinct CD8Cancer cell · 2025Trial
- Dual metabolic checkpoint blockadeBioactive materials · 2027Article
- Multi-platform analysis of the tumor immune microenvironment associated with breast cancer subtypes.Oncoimmunology · 2026Article
- Inferring Phenotypes of Single Cells Based on the Expression Profiles of Phenotype-Associated Marker Genes in Bulks and Single Cells.Interdisciplinary sciences, computational life sciences · 2026Article
- Cell plasticity in cancer and therapy resistance.Experimental & molecular medicine · 2026Review
- BET Inhibition Synergizes with RLR Signaling to Enhance Tumor Immunogenicity and T-cell Recognition.Cancer immunology research · 2026Article
- Urine cell-free RNA for bladder cancer detection and treatment response prediction.Nature medicine · 2026Article
- The Impact of SF3B1 Mutations on the Tumor Microenvironment and Response to Immunotherapy.Cancer medicine · 2026Article
- CXCL14 is a novel biomarker for mast cell infiltration in the melanoma tumor microenvironment.Journal of dermatological science · 2026Article
- Immune-pressure redistribution in resistance to PD-1/PD-L1 blockade: mechanisms, biomarkers, and therapeutic design.Molecular cancer · 2026Review
- Cofilin1-driven cytoskeletal remodeling modulates pan-cancer CD8Cell reports. Medicine · 2026Article
- Clinical translation of senescence-related pan-cancer multi-omics: tools for assessment and immunotherapy prediction.Cancer gene therapy · 2026Article
- CD55 organizes lipid raft-LCK signaling to potentiate NK-cell antitumor immunity.Cell research · 2026Article
- CMTM3 links inflammation-related transcriptional dysregulation to immune and therapeutic stratification in gastric cancer.Translational oncology · 2026Article
875 more citing papers are in PubMed but not listed here.
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Authors and funding
52 authors.
Livnat Jerby-ArnonBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Parin ShahDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Michael S CuocoBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Christopher RodmanBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Mei-Ju SuDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Center for Cancer Precision Medicine of Dana-Farber Cancer Institute, Boston, MA, USA.
Johannes C MelmsDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Rachel LeesonDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Center for Cancer Precision Medicine of Dana-Farber Cancer Institute, Boston, MA, USA.
Abhay KanodiaDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Center for Cancer Precision Medicine of Dana-Farber Cancer Institute, Boston, MA, USA.
Shaolin MeiDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Laboratory for Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
Jia-Ren LinLaboratory for Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
Shu WangLaboratory for Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
Bokang RabashaDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
David LiuDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Gao ZhangMolecular & Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
Claire MargolaisDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Orr AshenbergBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Patrick A OttDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Elizabeth I BuchbinderDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Rizwan HaqDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
F Stephen HodiDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Genevieve M BolandMassachusetts General Hospital Cancer Center, Boston, MA, USA.
Ryan J SullivanMassachusetts General Hospital Cancer Center, Boston, MA, USA.
Dennie T FrederickMassachusetts General Hospital Cancer Center, Boston, MA, USA.
Benchun MiaoMassachusetts General Hospital Cancer Center, Boston, MA, USA.
Tabea MollMassachusetts General Hospital Cancer Center, Boston, MA, USA.
Keith T FlahertyMassachusetts General Hospital Cancer Center, Boston, MA, USA.
Meenhard HerlynMolecular & Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
Russell W JenkinsDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Massachusetts General Hospital Cancer Center, Boston, MA, USA.
Rohit ThummalapalliDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Monika S KowalczykBroad Institute of MIT and Harvard, Cambridge, MA, USA; Celsius Therapeutics, Cambridge, MA, USA.
Israel CañadasDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Bastian SchillingDepartment of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium, Essen, Germany; Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany.
Adam N R CartwrightCenter for Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
Adrienne M LuomaCenter for Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
Shruti MaluDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Patrick HwuDepartment of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Chantale BernatchezDepartment of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Marie-Andrée ForgetDepartment of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
David A BarbieDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Alex K ShalekBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Itay TiroshBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Peter K SorgerLaboratory for Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
Kai WucherpfennigCenter for Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
Eliezer M Van AllenDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Dirk SchadendorfDepartment of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium, Essen, Germany.
Bruce E JohnsonDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Center for Cancer Precision Medicine of Dana-Farber Cancer Institute, Boston, MA, USA.
Asaf RotemBroad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Center for Cancer Precision Medicine of Dana-Farber Cancer Institute, Boston, MA, USA.
Orit Rozenblatt-RosenBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Levi A GarrawayBroad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Center for Cancer Precision Medicine of Dana-Farber Cancer Institute, Boston, MA, USA; Ludwig Center for Cancer Research at Harvard, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
Charles H YoonDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Brigham and Women's Hospital, Department of Surgical Oncology, Boston, MA, USA.
Benjamin IzarBroad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Center for Cancer Precision Medicine of Dana-Farber Cancer Institute, Boston, MA, USA; Laboratory for Systems Pharmacology, Harvard Medical School, Boston, MA, USA; Center for Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Ludwig Center for Cancer Research at Harvard, Boston, MA, USA. Electronic address: benjamin_izar@dfci.harvard.edu.
Aviv RegevBroad Institute of MIT and Harvard, Cambridge, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA; Ludwig Center for Cancer Research at MIT, Boston, MA, USA; Massachusetts Institute of Technology, Department of Biology, Cambridge, MA, USA.
Funding
VIRUS PRODUCTION COREP30CA014051 · NCI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI MATTHEW G. VANDER HEIDEN · 1985 to 2026
$93.9MTumor Microenvironment and MetastasisP30CA010815 · NCI · WISTAR INSTITUTE · PI Aaron Robert Goldman · 1985 to 2026
$75.9MTrinity: Transcriptome assembly for genetic and functional analysis of cancerU24CA180922 · NCI · BROAD INSTITUTE, INC. · PI HAAS, BRIAN · 2013 to 2022
$7.5MReprogramming of T cells for the Treatment of MelanomaR01CA173750 · NCI · DANA-FARBER CANCER INST · PI GOTTSCHALK, STEPHEN, WUCHERPFENNIG, KAI W · 2012 to 2016
$5.0MCancer Immunology Training GrantT32CA207021 · NCI · DANA-FARBER CANCER INST · PI WUCHERPFENNIG, KAI W · 2016 to 2020
$2.4MClinical implementation of single cell tumor transcriptome analysisR33CA202820 · NCI · BROAD INSTITUTE, INC. · PI GOLUB, TODD R., JOHNSON, BRUCE E. · 2016 to 2018
$1.3MDissecting mechanisms of immunotherapy resistance in melanoma patientsK08CA222663 · NCI · DANA-FARBER CANCER INST · PI IZAR, BENJAMIN · 2017 to 2021
$827kHoward Hughes Medical InstituteNCI NIH HHS K08 CA222663NCI NIH HHS P30 CA010815NCI NIH HHS P30 CA014051NCI NIH HHS R01 CA173750NCI NIH HHS R33 CA202820NCI NIH HHS T32 CA207021NCI NIH HHS U24 CA180922
Abstract
Immune checkpoint inhibitors (ICIs) produce durable responses in some melanoma patients, but many patients derive no clinical benefit, and the molecular underpinnings of such resistance remain elusive. Here, we leveraged single-cell RNA sequencing (scRNA-seq) from 33 melanoma tumors and computational analyses to interrogate malignant cell states that promote immune evasion. We identified a resistance program expressed by malignant cells that is associated with T cell exclusion and immune evasion. The program is expressed prior to immunotherapy, characterizes cold niches in situ, and predicts clinical responses to anti-PD-1 therapy in an independent cohort of 112 melanoma patients. CDK4/6-inhibition represses this program in individual malignant cells, induces senescence, and reduces melanoma tumor outgrowth in mouse models in vivo when given in combination with immunotherapy. Our study provides a high-resolution landscape of ICI-resistant cell states, identifies clinically predictive signatures, and suggests new therapeutic strategies to overcome immunotherapy resistance.
Indexed as
Tumor EscapeAgedAged, 80 and overAnimalsAntineoplastic AgentsCell Line, TumorCyclin-Dependent Kinase 4Cyclin-Dependent Kinase 6FemaleHumansImmunotherapyMaleMelanomaMiceMice, Inbred C57BLMiddle AgedAntineoplastic AgentsCDK4 protein, humanCDK6 protein, humanCyclin-Dependent Kinase 4Cyclin-Dependent Kinase 6Programmed Cell Death 1 ReceptorProtein Kinase Inhibitors
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