A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade

被引：988

作者：

Jerby-Arnon, Livnat ^{[1
]}

Shah, Parin ^{[2
]}

Cuoco, Michael S. ^{[1
]}

Rodman, Christopher ^{[1
]}

Su, Mei-Ju ^{[2
,3
]}

Melms, Johannes C. ^{[2
]}

Leeson, Rachel ^{[2
,3
]}

Kanodia, Abhay ^{[2
,3
]}

Mei, Shaolin ^{[2
,4
]}

Lin, Jia-Ren ^{[4
]}

Wang, Shu ^{[4
]}

Rabasha, Bokang ^{[2
]}

Liu, David ^{[2
]}

Zhang, Gao ^{[5
,6
]}

Margolais, Claire ^{[2
]}

Ashenberg, Orr ^{[1
]}

Ott, Patrick A. ^{[2
]}

Buchbinder, Elizabeth I. ^{[2
]}

Haq, Rizwan ^{[2
]}

Hodi, F. Stephen ^{[2
]}

Boland, Genevieve M. ^{[7
]}

Sullivan, Ryan J. ^{[7
]}

Frederick, Dennie T. ^{[7
]}

Miao, Benchun ^{[7
]}

Moll, Tabea ^{[7
]}

Flaherty, Keith T. ^{[7
]}

Herlyn, Meenhard ^{[5
,6
]}

Jenkins, Russell W. ^{[2
,7
]}

Thummalapalli, Rohit ^{[2
]}

Kowalczyk, Monika S. ^{[1
,8
]}

Canadas, Israel ^{[2
]}

Schilling, Bastian ^{[9
,10
,11
]}

Cartwright, Adam N. R. ^{[12
]}

Luoma, Adrienne M. ^{[12
]}

Malu, Shruti ^{[2
]}

Hwu, Patrick ^{[13
]}

Bernatchez, Chantale ^{[13
]}

Forget, Marie-Andree ^{[13
]}

Barbie, David A. ^{[2
]}

Shalek, Alex K. ^{[1
]}

Tirosh, Itay ^{[1
]}

Sorger, Peter K. ^{[4
]}

Wucherpfennig, Kai ^{[12
]}

Van Allen, Eliezer M. ^{[2
]}

Schadendorf, Dirk ^{[9
,10
]}

Johnson, Bruce E. ^{[2
,3
]}

Rotem, Asaf ^{[1
,2
,3
]}

Rozenblatt-Rosen, Orit ^{[1
]}

Garraway, Levi A. ^{[1
,2
,3
,14
,15
]}

Yoon, Charles H. ^{[2
,16
]}

机构：

[1] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[2] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[3] Dana Farber Canc Inst, Ctr Canc Precis Med, Boston, MA 02115 USA

[4] Harvard Med Sch, Lab Syst Pharmacol, Boston, MA 02115 USA

[5] Wistar Inst Anat & Biol, Mol & Cellular Oncogenesis Program, 3601 Spruce St, Philadelphia, PA 19104 USA

[6] Wistar Inst Anat & Biol, Melanoma Res Ctr, 3601 Spruce St, Philadelphia, PA 19104 USA

[7] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA

[8] Celsius Therapeut, Cambridge, MA USA

[9] Univ Duisburg Essen, West German Canc Ctr, Univ Hosp Essen, Dept Dermatol, Essen, Germany

[10] German Canc Consortium, Essen, Germany

[11] Univ Hosp Wurzburg, Dept Dermatol Venereol & Allergol, Wurzburg, Germany

[12] Dana Farber Canc Inst, Ctr Immunol & Virol, Boston, MA 02115 USA

[13] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Houston, TX 77030 USA

[14] Harvard, Ludwig Ctr Canc Res, Boston, MA 02115 USA

[15] Howard Hughes Med Inst, Chevy Chase, MD USA

[16] Brigham & Womens Hosp, Dept Surg Oncol, 75 Francis St, Boston, MA 02115 USA

[17] MIT, Ludwig Ctr Canc Res, Boston, MA USA

[18] MIT, Dept Biol, Cambridge, MA USA

来源：

CELL | 2018年 / 175卷 / 04期

关键词：

IDENTIFICATION; SENSITIVITY; MELANOMA;

D O I：

10.1016/j.cell.2018.09.006

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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 over-come immunotherapy resistance.

引用

页码：984 / +

页数：38

共 39 条

[1]

Genomic Classification of Cutaneous Melanoma [J].

Akbani, Rehan ;

Akdemir, Kadir C. ;

Aksoy, B. Arman ;

Albert, Monique ;

Ally, Adrian ;

Amin, Samirkumar B. ;

Arachchi, Harindra ;

Arora, Arshi ;

Auman, J. Todd ;

Ayala, Brenda ;

Baboud, Julien ;

Balasundaram, Miruna ;

Balu, Saianand ;

Barnabas, Nandita ;

Bartlett, John ;

Bartlett, Pam ;

Bastian, Boris C. ;

Baylin, Stephen B. ;

Behera, Madhusmita ;

Belyaev, Dmitry ;

Benz, Christopher ;

Bernard, Brady ;

Beroukhim, Rameen ;

Bir, Natalie ;

Black, Aaron D. ;

Bodenheimer, Tom ;

Boice, Lori ;

Boland, Genevieve M. ;

Bono, Riccardo ;

Bootwalla, Moiz S. ;

Bosenberg, Marcus ;

Bowen, Jay ;

Bowlby, Reanne ;

Bristow, Christopher A. ;

Brockway-Lunardi, Laura ;

Brooks, Denise ;

Brzezinski, Jakub ;

Bshara, Wiam ;

Buda, Elizabeth ;

Burns, William R. ;

Butterfield, Yaron S. N. ;

Button, Michael ;

Calderone, Tiffany ;

Cappellini, Giancarlo Antonini ;

Carter, Candace ;

Carter, Scott L. ;

Cherney, Lynn ;

Cherniack, Andrew D. ;

Chevalier, Aaron ;

Chin, Lynda .

CELL, 2015, 161 (07) :1681-1696

[2]

Ayers, Mark ;

Lunceford, Jared ;

Nebozhyn, Michael ;

Murphy, Erin ;

Loboda, Andrey ;

Kaufman, David R. ;

Albright, Andrew ;

Cheng, Jonathan D. ;

Kang, S. Peter ;

Shankaran, Veena ;

Piha-Paul, Sarina A. ;

Yearley, Jennifer ;

Seiwert, Tanguy Y. ;

Ribas, Antoni ;

McClanahan, Terrill K. .

JOURNAL OF CLINICAL INVESTIGATION, 2017, 127 (08) :2930-2940

[3]

CONTROLLING THE FALSE DISCOVERY RATE - A PRACTICAL AND POWERFUL APPROACH TO MULTIPLE TESTING [J].

BENJAMINI, Y ;

HOCHBERG, Y .

JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-STATISTICAL METHODOLOGY, 1995, 57 (01) :289-300

[4]

Integrating single-cell transcriptomic data across different conditions, technologies, and species [J].

Butler, Andrew ;

Hoffman, Paul ;

Smibert, Peter ;

Papalexi, Efthymia ;

Satija, Rahul .

NATURE BIOTECHNOLOGY, 2018, 36 (05) :411-+

[5]

Absolute quantification of somatic DNA alterations in human cancer [J].

Carter, Scott L. ;

Cibulskis, Kristian ;

Helman, Elena ;

McKenna, Aaron ;

Shen, Hui ;

Zack, Travis ;

Laird, Peter W. ;

Onofrio, Robert C. ;

Winckler, Wendy ;

Weir, Barbara A. ;

Beroukhim, Rameen ;

Pellman, David ;

Levine, Douglas A. ;

Lander, Eric S. ;

Meyerson, Matthew ;

Getz, Gad .

NATURE BIOTECHNOLOGY, 2012, 30 (05) :413-+

[6]

CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation [J].

Deng, Jiehui ;

Wang, Eric S. ;

Jenkins, Russell W. ;

Li, Shuai ;

Dries, Ruben ;

Yates, Kathleen ;

Chhabra, Sandeep ;

Huang, Wei ;

Liu, Hongye ;

Aref, Amir R. ;

Ivanova, Elena ;

Paweletz, Cloud P. ;

Bowden, Michaela ;

Zhou, Chensheng W. ;

Herter-Sprie, Grit S. ;

Sorrentino, Jessica A. ;

Bisi, John E. ;

Lizotte, Patrick H. ;

Merlino, Ashley A. ;

Quinn, Max M. ;

Bufe, Lauren E. ;

Yang, Annan ;

Zhang, Yanxi ;

Zhang, Hua ;

Gao, Peng ;

Chen, Ting ;

Cavanaugh, Megan E. ;

Rode, Amanda J. ;

Haines, Eric ;

Roberts, Patrick J. ;

Strum, Jay C. ;

Richards, William G. ;

Lorch, Jochen H. ;

Parangi, Sareh ;

Gunda, Viswanath ;

Boland, Genevieve M. ;

Bueno, Raphael ;

Palakurthi, Sangeetha ;

Freeman, Gordon J. ;

Ritz, Jerome ;

Haining, W. Nicholas ;

Sharpless, Norman E. ;

Arthanari, Haribabu ;

Shapiro, Geoffrey I. ;

Barbie, David A. ;

Gray, Nathanael S. ;

Wong, Kwok-Kin .

CANCER DISCOVERY, 2018, 8 (02) :216-233

[7]

Ester M., 1996, P 2 INT C KNOWL DISC, V96, P226

[8]

Fan J, 2016, NAT METHODS, V13, P241, DOI [10.1038/NMETH.3734, 10.1038/nmeth.3734]

[9]

The immune contexture in human tumours: impact on clinical outcome [J].

Fridman, Wolf Herman ;

Pages, Franck ;

Sautes-Fridman, Catherine ;

Galon, Jerome .

NATURE REVIEWS CANCER, 2012, 12 (04) :298-306

[10]

Systematic identification of genomic markers of drug sensitivity in cancer cells [J].

Garnett, Mathew J. ;

Edelman, Elena J. ;

Heidorn, Sonja J. ;

Greenman, Chris D. ;

Dastur, Anahita ;

Lau, King Wai ;

Greninger, Patricia ;

Thompson, I. Richard ;

Luo, Xi ;

Soares, Jorge ;

Liu, Qingsong ;

Iorio, Francesco ;

Surdez, Didier ;

Chen, Li ;

Milano, Randy J. ;

Bignell, Graham R. ;

Tam, Ah T. ;

Davies, Helen ;

Stevenson, Jesse A. ;

Barthorpe, Syd ;

Lutz, Stephen R. ;

Kogera, Fiona ;

Lawrence, Karl ;

McLaren-Douglas, Anne ;

Mitropoulos, Xeni ;

Mironenko, Tatiana ;

Thi, Helen ;

Richardson, Laura ;

Zhou, Wenjun ;

Jewitt, Frances ;

Zhang, Tinghu ;

O'Brien, Patrick ;

Boisvert, Jessica L. ;

Price, Stacey ;

Hur, Wooyoung ;

Yang, Wanjuan ;

Deng, Xianming ;

Butler, Adam ;

Choi, Hwan Geun ;

Chang, JaeWon ;

Baselga, Jose ;

Stamenkovic, Ivan ;

Engelman, Jeffrey A. ;

Sharma, Sreenath V. ;

Delattre, Olivier ;

Saez-Rodriguez, Julio ;

Gray, Nathanael S. ;

Settleman, Jeffrey ;

Futreal, P. Andrew ;

Haber, Daniel A. .

NATURE, 2012, 483 (7391) :570-U87

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