ArticleThe New England journal of medicine2016
Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma.
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In one paragraph
Article in The New England journal of medicine, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1,989 papers, 2 of them syntheses that pooled it.
0numbers the graph read from it
0cells of the map it votes in
1,989citing papers in PubMed, 2 pooled it
159.0field-weighted citation impact, top 1% of its field
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
1,989 citing papers in PubMed, 2 syntheses or guidelines pooled it, 3,099 citations in OpenAlex.
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- Heating the Cold: Overcoming Immunotherapy Resistance in Microsatellite-Stable Colorectal Cancer: A Systematic Review.Molecules (Basel, Switzerland) · 2026Pooled it
- Cellular Neighborhoods Govern Antitumor T-cell Infiltration Following Anti-CTLA-4 in Melanoma with Primary Resistance to Anti-PD-1.Cancer discovery · 2026Trial
- Extracellular Matrix-MYCAF Signatures Correlate with Resistance to Neoadjuvant aPD-L1 Immune Checkpoint Inhibition with Durvalumab + Metformin in HPV+ HNSCC.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Trial
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- Overcoming melanoma drug resistance: Mechanisms and clinical progress of oncolytic viruses combined with immune checkpoint inhibitors (Review).Oncology reports · 2026Review
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- Molecular classification and precision therapy in gastric cancer: Current advances and future perspectives (Review).Oncology reports · 2026Review
- Evidence-steered medicine in oncology: network-aware micro-combinations that safeguard standard of care and potentially improve benefit-risk.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Post‑translational modification‑governed immune states in cancer immunity: Biomarker implications for checkpoint competence, tumor visibility and immunotherapy resistance (Review).International journal of oncology · 2026Review
- Advances in γδ T Cells: Cutaneous Biology and Therapeutic Potential for Skin Neoplasms.The Journal of dermatology · 2026Review
- Resistance to PD-1/PD-L1 blockade: Mechanism and pharmacological strategies.Pharmacological research · 2026Review
- High ZFP36 Family Expression in Exhausted T Cells Is Associated With Impaired Antitumor Effector Function.Cancer science · 2026Article
- Local delivery of interferon restores antigen presentation and sensitizes medulloblastoma to T cell killing.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Immune-pressure redistribution in resistance to PD-1/PD-L1 blockade: mechanisms, biomarkers, and therapeutic design.Molecular cancer · 2026Review
1,929 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
29 authors at 2 institutions in 1 country.
Jesse M ZaretskyFrom the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
Angel Garcia-DiazFrom the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
Daniel S ShinFrom the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
Helena Escuin-OrdinasFrom the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
Willy HugoFrom the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
Siwen Hu-LieskovanFrom the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
Davis Y TorrejonFrom the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
Gabriel Abril-RodriguezFrom the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
Salemiz SandovalFrom the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
Lucas BarthlyFrom the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
Justin SacoFrom the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
Blanca Homet MorenoFrom the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
Riccardo MezzadraFrom the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
Bartosz ChmielowskiFrom the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
Kathleen RuchalskiFrom the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
I Peter ShintakuFrom the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
Phillip J SanchezFrom the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
Cristina Puig-SausFrom the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
Grace CherryFrom the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
Elizabeth SejaFrom the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
Xiangju KongFrom the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
Jia PangFrom the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
Beata Berent-MaozFrom the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
Begoña Comin-AnduixFrom the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
Thomas G GraeberFrom the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
Paul C TumehFrom the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
Ton N M SchumacherFrom the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
Roger S LoFrom the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
Antoni RibasFrom the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
UCLA Jonsson Comprehensive Cancer CenterOncode Institute · NL
Funding
Women's CancersP30CA016042 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Samuel Wheeler French · 1985 to 2026
$134.5MUCLA Clinical Translational Science InstituteUL1TR001881 · NCATS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI ARLEEN F. BROWN, ARASH NAEIM · 2016 to 2026
$118.1MUCLA Clinical and Translational Science InstituteUL1TR000124 · NCATS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI DUBINETT, STEVEN M. · 2012 to 2015
$57.0MUCLA-Caltech Medical Scientist Training ProgramT32GM008042 · NIGMS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI AJIJOLA, OLUJIMI A, DAWSON, DAVID WAYNE · 1985 to 2023
$29.9MRepurposing of cancer therapeutics for treatment of patients with COVID-19 diseaseU54CA199090 · NCI · INSTITUTE FOR SYSTEMS BIOLOGY · PI HEATH, JAMES R., RIBAS, ANTONI · 2015 to 2020
$11.4MNext Generation Cancer Immunotherapies to Defeat MelanomaR35CA197633 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI ANTONI RIBAS · 2015 to 2026
$10.4MUCLA Tumor Immunology Training ProgramT32CA009120 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Steven M. Dubinett, MICHAEL A TEITELL · 1985 to 2026
$10.3MTARGETED COMBINATORIAL TREATMENT OF BRAF MELANOMASP01CA168585 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI RIBAS, ANTONI · 2013 to 2017
$8.4MACADEMIC TRAINING IN MEDICAL ONCOLOGYT32CA009297 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI RIBAS, ANTONI · 1985 to 2013
$3.3MStrategies for Distinguishing Success in Immunotherapy Treatments (PQ20)R01CA170689 · NCI · CALIFORNIA INSTITUTE OF TECHNOLOGY · PI HEATH, JAMES R., RIBAS, ANTONI · 2012 to 2015
$2.5MDermatology Scientist Training ProgramT32AR058921 · NIAMS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI MODLIN, ROBERT L · 2010 to 2014
$877kNCATS NIH HHS UL1 TR000124NCATS NIH HHS UL1 TR001881NCI NIH HHS 1U54 CA199090NCI NIH HHS 5T32CA009120-39NCI NIH HHS 5T32CA009297-30NCI NIH HHS P01 CA168585NCI NIH HHS P30 CA016042NCI NIH HHS R01 CA170689NCI NIH HHS R35 CA197633NCI NIH HHS T32 CA009120NCI NIH HHS T32 CA009297NCI NIH HHS U54 CA199090NIAMS NIH HHS 5T32AR058921-05NIAMS NIH HHS T32 AR058921NIGMS NIH HHS GM08042NIGMS NIH HHS T32 GM008042
Abstract
backgroundApproximately 75% of objective responses to anti-programmed death 1 (PD-1) therapy in patients with melanoma are durable, lasting for years, but delayed relapses have been noted long after initial objective tumor regression despite continuous therapy. Mechanisms of immune escape in this context are unknown.
methodsWe analyzed biopsy samples from paired baseline and relapsing lesions in four patients with metastatic melanoma who had had an initial objective tumor regression in response to anti-PD-1 therapy (pembrolizumab) followed by disease progression months to years later.
resultsWhole-exome sequencing detected clonal selection and outgrowth of the acquired resistant tumors and, in two of the four patients, revealed resistance-associated loss-of-function mutations in the genes encoding interferon-receptor-associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion of the wild-type allele. A truncating mutation in the gene encoding the antigen-presenting protein beta-2-microglobulin (B2M) was identified in a third patient. JAK1 and JAK2 truncating mutations resulted in a lack of response to interferon gamma, including insensitivity to its antiproliferative effects on cancer cells. The B2M truncating mutation led to loss of surface expression of major histocompatibility complex class I.
conclusionsIn this study, acquired resistance to PD-1 blockade immunotherapy in patients with melanoma was associated with defects in the pathways involved in interferon-receptor signaling and in antigen presentation. (Funded by the National Institutes of Health and others.).
Indexed as
ImmunotherapyMutationAntibodies, Monoclonal, HumanizedAntineoplastic Agentsbeta 2-MicroglobulinBiopsyDrug Resistance, NeoplasmExomeGene Expression Regulation, NeoplasticGenes, MHC Class IHumansInterferon-gammaJanus Kinase 1Janus Kinase 2MelanomaProgrammed Cell Death 1 ReceptorAntibodies, Monoclonal, HumanizedAntineoplastic Agentsbeta 2-MicroglobulinInterferon-gammaJanus Kinase 1Janus Kinase 2PDCD1 protein, humanpembrolizumabProgrammed Cell Death 1 Receptor
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