TY - JOUR
T1 - A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade
AU - Jerby-Arnon, Livnat
AU - Shah, Parin
AU - Cuoco, Michael S.
AU - Rodman, Christopher
AU - Su, Mei Ju
AU - Melms, Johannes C.
AU - Leeson, Rachel
AU - Kanodia, Abhay
AU - Mei, Shaolin
AU - Lin, Jia Ren
AU - Wang, Shu
AU - Rabasha, Bokang
AU - Liu, David
AU - Zhang, Gao
AU - Margolais, Claire
AU - Ashenberg, Orr
AU - Ott, Patrick A.
AU - Buchbinder, Elizabeth I.
AU - Haq, Rizwan
AU - Hodi, F. Stephen
AU - Boland, Genevieve M.
AU - Sullivan, Ryan J.
AU - Frederick, Dennie T.
AU - Miao, Benchun
AU - Moll, Tabea
AU - Flaherty, Keith T.
AU - Herlyn, Meenhard
AU - Jenkins, Russell W.
AU - Thummalapalli, Rohit
AU - Kowalczyk, Monika S.
AU - Cañadas, Israel
AU - Schilling, Bastian
AU - Cartwright, Adam N.R.
AU - Luoma, Adrienne M.
AU - Malu, Shruti
AU - Hwu, Patrick
AU - Bernatchez, Chantale
AU - Forget, Marie Andrée
AU - Barbie, David A.
AU - Shalek, Alex K.
AU - Tirosh, Itay
AU - Sorger, Peter K.
AU - Wucherpfennig, Kai
AU - Van Allen, Eliezer M.
AU - Schadendorf, Dirk
AU - Johnson, Bruce E.
AU - Rotem, Asaf
AU - Rozenblatt-Rosen, Orit
AU - Garraway, Levi A.
AU - Yoon, Charles H.
AU - Izar, Benjamin
AU - Regev, Aviv
N1 - Funding Information:
We thank Meromit Singer for discussions; Leslie Gaffney for help with artwork; and Laura Dellostritto, Karla Helvie, Nichole Straub, and the CCPM members at DFCI. L.J.-A. is a CRI Irvington Fellow supported by the CRI and a fellow of the Eric and Wendy Schmidt postdoctoral program. B.I. was supported by NCI grant K08-CA222663 , DFCI Claudia Adams Barr Program for Innovative Cancer Research, the Burroughs Wellcome Fund Career Award for Medical Scientists, and the SITC Translational Fellowship. A. Regev is an HHMI Investigator. Work was supported by the Klarman Cell Observatory , STARR Cancer Consortium , NCI grants 1U24CA180922 and R33-CA202820 , Koch Institute NCI Support (core) grant P30-CA14051 , Ludwig Centers at Harvard and MIT , AMRF , and the Broad Institute . Processed scRNA-seq data are available at https://portals.broadinstitute.org/single_cell/study/melanoma-immunotherapy-resistance and under accession number GEO: GSE115978 . Raw scRNA-seq data will be deposited in dbGAP.
Funding Information:
We thank Meromit Singer for discussions; Leslie Gaffney for help with artwork; and Laura Dellostritto, Karla Helvie, Nichole Straub, and the CCPM members at DFCI. L.J.-A. is a CRI Irvington Fellow supported by the CRI and a fellow of the Eric and Wendy Schmidt postdoctoral program. B.I. was supported by NCI grant K08-CA222663, DFCI Claudia Adams Barr Program for Innovative Cancer Research, the Burroughs Wellcome Fund Career Award for Medical Scientists, and the SITC Translational Fellowship. A. Regev is an HHMI Investigator. Work was supported by the Klarman Cell Observatory, STARR Cancer Consortium, NCI grants 1U24CA180922 and R33-CA202820, Koch Institute NCI Support (core) grant P30-CA14051, Ludwig Centers at Harvard and MIT, AMRF, and the Broad Institute. Processed scRNA-seq data are available at https://portals.broadinstitute.org/single_cell/study/melanoma-immunotherapy-resistance and under accession number GEO: GSE115978. Raw scRNA-seq data will be deposited in dbGAP.
Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/11/1
Y1 - 2018/11/1
N2 - 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. Single-cell sequencing of checkpoint-inhibitor-resistant melanomas identifies predictive signatures to guide therapeutic approaches to overcome immunotherapy resistance.
AB - 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. Single-cell sequencing of checkpoint-inhibitor-resistant melanomas identifies predictive signatures to guide therapeutic approaches to overcome immunotherapy resistance.
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U2 - 10.1016/j.cell.2018.09.006
DO - 10.1016/j.cell.2018.09.006
M3 - Article
C2 - 30388455
AN - SCOPUS:85055549585
SN - 0092-8674
VL - 175
SP - 984-997.e24
JO - Cell
JF - Cell
IS - 4
ER -