9p21 loss confers a cold tumor immune microenvironment and primary resistance to immune checkpoint therapy

被引:134
作者
Han, Guangchun [1 ]
Yang, Guoliang [2 ]
Hao, Dapeng [1 ]
Lu, Yang [3 ]
Thein, Kyaw [4 ]
Simpson, Benjamin S. [5 ]
Chen, Jianfeng [2 ]
Sun, Ryan [6 ]
Alhalabi, Omar [2 ]
Wang, Ruiping [1 ]
Dang, Minghao [1 ]
Dai, Enyu [1 ]
Zhang, Shaojun [1 ]
Nie, Fengqi [2 ]
Zhao, Shuangtao [1 ]
Guo, Charles [7 ]
Hamza, Ameer [7 ]
Czerniak, Bogdan [7 ]
Cheng, Chao [8 ]
Siefker-Radtke, Arlene [2 ]
Bhat, Krishna [9 ]
Futreal, Andrew [1 ]
Peng, Guang [10 ]
Wargo, Jennifer [11 ]
Peng, Weiyi [12 ]
Kadara, Humam [9 ]
Ajani, Jaffer [13 ]
Swanton, Charles [14 ,15 ]
Litchfield, Kevin [5 ,15 ]
Ahnert, Jordi Rodon [1 ,4 ]
Gao, Jianjun [2 ]
Wang, Linghua [1 ,16 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA
[2] Univ Texas MD Anderson Canc Ctr, Dept Genitourinary Med Oncol, Houston, TX 77030 USA
[3] Univ Texas MD Anderson Canc Ctr, Dept Nucl Med, Houston, TX 77030 USA
[4] Univ Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, Houston, TX 77030 USA
[5] UCL, Canc Inst, Tumour Immunogen & Immunosurveillance Lab, London, England
[6] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA
[7] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA
[8] Baylor Coll Med, Dept Med Epidemiol & Populat Sci, Houston, TX 77030 USA
[9] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA
[10] Univ Texas MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX 77030 USA
[11] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA
[12] Univ Houston, Dept Biol & Biochem, Houston, TX USA
[13] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA
[14] Francis Crick Inst, Canc Evolut & Genome Instabil Lab, London, England
[15] UCL, Canc Inst, Canc Res UK Lung Canc Ctr Excellence, London, England
[16] Univ Texas MD Anderson Canc Ctr, UTHlth Grad Sch Biomed Sci GSBS, Houston, TX 77030 USA
关键词
MUTATIONAL LANDSCAPE; PD-L1; BLOCKADE; CANCER; CELLS; EXCLUSION; DELETION; BIOLOGY;
D O I
10.1038/s41467-021-25894-9
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Immune checkpoint therapy (ICT) provides substantial clinical benefits to cancer patients, but a large proportion of cancers do not respond to ICT. To date, the genomic underpinnings of primary resistance to ICT remain elusive. Here, we performed immunogenomic analysis of data from TCGA and clinical trials of anti-PD-1/PD-L1 therapy, with a particular focus on homozygous deletion of 9p21.3 (9p21 loss), one of the most frequent genomic defects occurring in similar to 13% of all cancers. We demonstrate that 9p21 loss confers "cold" tumor-immune phenotypes, characterized by reduced abundance of tumor-infiltrating leukocytes (TILs), particularly, T/B/NK cells, altered spatial TILs patterns, diminished immune cell trafficking/activation, decreased rate of PD-L1 positivity, along with activation of immunosuppressive signaling. Notably, patients with 9p21 loss exhibited significantly lower response rates to ICT and worse outcomes, which were corroborated in eight ICT trials of >1,000 patients. Further, 9p21 loss synergizes with PD-L1/TMB for patient stratification. A "response score" was derived by incorporating 9p21 loss, PD-L1 expression and TMB levels in pre-treatment tumors, which outperforms PD-L1, TMB, and their combination in identifying patients with high likelihood of achieving sustained response from otherwise non-responders. Moreover, we describe potential druggable targets in 9p21-loss tumors, which could be exploited to design rational therapeutic interventions.
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页数:19
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共 73 条
[1]   Pyruvate Kinase M2: A Potential Target for Regulating inflammation [J].
Alves-Filho, Jose C. ;
Palsson-McDermott, Eva M. .
FRONTIERS IN IMMUNOLOGY, 2016, 7
[2]   Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma [J].
Amaria, Rodabe N. ;
Reddy, Sangeetha M. ;
Tawbi, Hussein A. ;
Davies, Michael A. ;
Ross, Merrick, I ;
Glitza, Isabella C. ;
Cormier, Janice N. ;
Lewis, Carol ;
Hwu, Wen-Jen ;
Hanna, Ehab ;
Diab, Adi ;
Wong, Michael K. ;
Royal, Richard ;
Gross, Neil ;
Weber, Randal ;
Lai, Stephen Y. ;
Ehlers, Richard ;
Blando, Jorge ;
Milton, Denai R. ;
Woodman, Scott ;
Kageyama, Robin ;
Wells, Daniel K. ;
Hwu, Patrick ;
Patel, Sapna P. ;
Lucci, Anthony ;
Hessel, Amy ;
Lee, Jeffrey E. ;
Gershenwald, Jeffrey ;
Simpson, Lauren ;
Burton, Elizabeth M. ;
Posada, Liberty ;
Haydu, Lauren ;
Wang, Linghua ;
Zhang, Shaojun ;
Lazar, Alexanderj ;
Hudgens, Courtney W. ;
Gopalakrishnan, Vancheswaran ;
Reuben, Alexandre ;
Andrews, Miles C. ;
Spencer, Christine N. ;
Prieto, Victor ;
Sharma, Padmanee ;
Allison, James ;
Tetzlaff, Michael T. ;
Wargo, Jennifer A. .
NATURE MEDICINE, 2018, 24 (11) :1649-+
[3]   HTSeq-a Python']Python framework to work with high-throughput sequencing data [J].
Anders, Simon ;
Pyl, Paul Theodor ;
Huber, Wolfgang .
BIOINFORMATICS, 2015, 31 (02) :166-169
[4]   Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression [J].
Becht, Etienne ;
Giraldo, Nicolas A. ;
Lacroix, Laetitia ;
Buttard, Benedicte ;
Elarouci, Nabila ;
Petitprez, Florent ;
Selves, Janick ;
Laurent-Puig, Pierre ;
Sautes-Fridman, Catherine ;
Fridman, Wolf H. ;
de Reynies, Aurelien .
GENOME BIOLOGY, 2016, 17
[5]   The landscape of somatic copy-number alteration across human cancers [J].
Beroukhim, Rameen ;
Mermel, Craig H. ;
Porter, Dale ;
Wei, Guo ;
Raychaudhuri, Soumya ;
Donovan, Jerry ;
Barretina, Jordi ;
Boehm, Jesse S. ;
Dobson, Jennifer ;
Urashima, Mitsuyoshi ;
Mc Henry, Kevin T. ;
Pinchback, Reid M. ;
Ligon, Azra H. ;
Cho, Yoon-Jae ;
Haery, Leila ;
Greulich, Heidi ;
Reich, Michael ;
Winckler, Wendy ;
Lawrence, Michael S. ;
Weir, Barbara A. ;
Tanaka, Kumiko E. ;
Chiang, Derek Y. ;
Bass, Adam J. ;
Loo, Alice ;
Hoffman, Carter ;
Prensner, John ;
Liefeld, Ted ;
Gao, Qing ;
Yecies, Derek ;
Signoretti, Sabina ;
Maher, Elizabeth ;
Kaye, Frederic J. ;
Sasaki, Hidefumi ;
Tepper, Joel E. ;
Fletcher, Jonathan A. ;
Tabernero, Josep ;
Baselga, Jose ;
Tsao, Ming-Sound ;
Demichelis, Francesca ;
Rubin, Mark A. ;
Janne, Pasi A. ;
Daly, Mark J. ;
Nucera, Carmelo ;
Levine, Ross L. ;
Ebert, Benjamin L. ;
Gabriel, Stacey ;
Rustgi, Anil K. ;
Antonescu, Cristina R. ;
Ladanyi, Marc ;
Letai, Anthony .
NATURE, 2010, 463 (7283) :899-905
[6]   NK Cells Stimulate Recruitment of cDC1 into the Tumor Microenvironment Promoting Cancer Immune Control [J].
Boettcher, Jan P. ;
Bonavita, Eduardo ;
Chakravarty, Probir ;
Blees, Hanna ;
Cabeza-Cabrerizo, Mar ;
Sammicheli, Stefano ;
Rogers, Neil C. ;
Sahai, Erik ;
Zelenay, Santiago ;
Reis e Sousa, Caetano .
CELL, 2018, 172 (05) :1022-+
[7]   Cold Tumors: A Therapeutic Challenge for Immunotherapy [J].
Bonaventura, Paola ;
Shekarian, Tala ;
Alcazer, Vincent ;
Valladeau-Guilemond, Jenny ;
Valsesia-Wittmann, Sandrine ;
Amigorena, Sebastian ;
Caux, Christophe ;
Depil, Stephane .
FRONTIERS IN IMMUNOLOGY, 2019, 10
[8]   Landscape of Microsatellite Instability Across 39 Cancer Types [J].
Bonneville, Russell ;
Krook, Melanie A. ;
Kautto, Esko A. ;
Miya, Jharna ;
Wing, Michele R. ;
Chen, Hui-Zi ;
Reeser, Julie W. ;
Yu, Lianbo ;
Roychowdhury, Sameek .
JCO PRECISION ONCOLOGY, 2017, 1 :1-15
[9]   Direct and Indirect Modulation of T Cells by VEGF-A Counteracted by Anti-Angiogenic Treatment [J].
Bourhis, Morgane ;
Palle, Juliette ;
Galy-Fauroux, Isabelle ;
Terme, Magali .
FRONTIERS IN IMMUNOLOGY, 2021, 12
[10]   Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma [J].
Braun, David A. ;
Hou, Yue ;
Bakouny, Ziad ;
Ficial, Miriam ;
Sant' Angelo, Miriam ;
Forman, Juliet ;
Ross-Macdonald, Petra ;
Berger, Ashton C. ;
Jegede, Opeyemi A. ;
Elagina, Liudmilla ;
Steinharter, John ;
Sun, Maxine ;
Wind-Rotolo, Megan ;
Pignon, Jean-Christophe ;
Cherniack, Andrew D. ;
Lichtenstein, Lee ;
Neuberg, Donna ;
Catalano, Paul ;
Freeman, Gordon J. ;
Sharpe, Arlene H. ;
McDermott, David F. ;
Van Allen, Eliezer M. ;
Signoretti, Sabina ;
Wu, Catherine J. ;
Shukla, Sachet A. ;
Choueiri, Toni K. .
NATURE MEDICINE, 2020, 26 (06) :909-+