TY - JOUR
T1 - 9p21 loss confers a cold tumor immune microenvironment and primary resistance to immune checkpoint therapy
AU - Han, Guangchun
AU - Yang, Guoliang
AU - Hao, Dapeng
AU - Lu, Yang
AU - Thein, Kyaw
AU - Simpson, Benjamin S.
AU - Chen, Jianfeng
AU - Sun, Ryan
AU - Alhalabi, Omar
AU - Wang, Ruiping
AU - Dang, Minghao
AU - Dai, Enyu
AU - Zhang, Shaojun
AU - Nie, Fengqi
AU - Zhao, Shuangtao
AU - Guo, Charles
AU - Hamza, Ameer
AU - Czerniak, Bogdan
AU - Cheng, Chao
AU - Siefker-Radtke, Arlene
AU - Bhat, Krishna
AU - Futreal, Andrew
AU - Peng, Guang
AU - Wargo, Jennifer
AU - Peng, Weiyi
AU - Kadara, Humam
AU - Ajani, Jaffer
AU - Swanton, Charles
AU - Litchfield, Kevin
AU - Ahnert, Jordi Rodon
AU - Gao, Jianjun
AU - Wang, Linghua
N1 - Funding Information:
We thank all the patients who generally provided their biospecimens and information for this research. We are grateful to Mariathasan S., Rizvi H., Riaz N., Gide T.N., Liu D. and their teams and the TCGA Pan-Cancer Analysis Working Groups for kindly sharing their genomic datasets. L.W. is supported in part by the start-up research fund and the institutional research grant (IRG) awards provided by U.T. MD Anderson Cancer Center, the Andrew Sabin Family Fellowship provided by the Andrew Sabin Family Foundation. This study was also supported by the Doris Duke Clinical Scientist Development Award (#2018097) to J.G. and L.W., the MD Anderson Physician Scientist Award, Khalifa Physician Scientist Award, Andrew Sabin Family Foundation Fellows Award, MD Anderson Faculty Scholar Award, the David H. Koch Center for Applied Research of Genitourinary Cancers, R01 CA254988, Wendy and Leslie Irvin Barnhart Fund and Joan and Herb Kelleher Charitable Foundation provided to J.G. Figs. 3a, 4a, e, and 6g were created with BioRender.com.
Funding Information:
J.G. serves as an Advisory Committee Member for CRISPR Therapeutics, Infiniti, Jounce Therapeutics, Polaris and Seagen, as a consultant for AstraZeneca, Janssen, Pfizer, and Symphogen. J.G. is supported by the Doris Duke Clinical Scientist Development Award (#2018097), the MD Anderson Physician Scientist Award, Khalifa Physician Scientist Award, Andrew Sabin Family Foundation Fellows Award, MD Anderson Faculty Scholar Award, the David H. Koch Center for Applied Research of Genitourinary Cancers, Wendy and Leslie Irvin Barnhart Fund, and Joan and Herb Kelleher Charitable Foundation. JAW reports compensation for speaker’s bureau and honoraria from Imedex, Dava Oncology, Omniprex, Illumina, Gilead, PeerView, Physician Education Resource, MedImmune, and Bristol–Myers Squibb. J.R.A. reports non-financial support and reasonable reimbursement for travel from European Journal of Cancer, Vall d’Hebron Institut of Oncology, Chinese University of Hong Kong, SOLTI, Elsevier, GLAX-OSMITHKLINE, receiving consulting and travel fees from Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharmaceuticals, Peptomyc, Merck Sharp & Dohme, Kelun Pharmaceutical/Klus Pharma, Spectrum Pharmaceuticals Inc, Pfizer, Roche Pharmaceuticals, Ellipses Pharma, NovellusDx, Ionctura and Molecular Partners (including serving on the scientific advisory board from 2015-present), receiving research funding from Blueprint Pharmaceuticals, Bayer and Novartis, and serving as investigator in clinical trials with Spectrum Pharmaceuticals, Tocagen, Symphogen, BioAtla, Pfizer, GenMab, CytomX, KELUN-BIOTECH, Takeda-Millenium, GLAXOSMITHKLINE, IPSEN and travel fees from ESMO, US Department of Defense, Louissiana State University, Hunstman Cancer Institute, Cancer Core Europe, Karolinska Cancer Institute and King Abdullah International Medical Research Center (KAIMRC), Molecular Partners. JAW serves as a consultant/advisory board member for Roche/Genentech, Novartis, AstraZeneca, GlaxoSmithKline, Bristol–Myers Squibb, Merck, Biothera Pharmaceuticals, Ella Therapeutics, and Microbiome DX. JAW also receives research support from GlaxoSmithKline, Roche/Genentech, Bristol–Myers Squibb, and Novartis, all outside of the submitted work. A.S.R. serves as an advisory board member for AstraZeneca, Bavarian Nordic, Genentech, Janssen, Merck Sharp and Dohme, Mirati, Nektar Therapeutics, and Seattle Genetics. A.S.R. receives research support from Bristol–Myers Squibb, Janssen, Merck Sharp and Dohme, Nektar Therapeutics. H.K. receives funding from Johnson and Johnson.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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 ~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.
AB - 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 ~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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U2 - 10.1038/s41467-021-25894-9
DO - 10.1038/s41467-021-25894-9
M3 - Article
C2 - 34556668
AN - SCOPUS:85115613365
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5606
ER -