Single-cell genomic approaches for developing the next generation of immunotherapies.
Animals
B7-H1 Antigen
/ immunology
Biomarkers
/ metabolism
CD8-Positive T-Lymphocytes
/ immunology
CTLA-4 Antigen
/ immunology
Clinical Trials as Topic
Drug Design
Drug Industry
/ trends
Drug Therapy, Combination
Genomics
Humans
Immunologic Factors
Immunotherapy
/ methods
Neoplasms
/ therapy
Phenotype
Single-Cell Analysis
/ methods
T-Lymphocytes
/ metabolism
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
03
09
2019
accepted:
10
12
2019
pubmed:
6
2
2020
medline:
22
4
2020
entrez:
5
2
2020
Statut:
ppublish
Résumé
Recent progress in single-cell genomics urges its application in drug development, particularly of cancer immunotherapies. Current immunotherapy pipelines are focused on functional outcome and simple cellular and molecular readouts. A thorough mechanistic understanding of the cells and pathways targeted by immunotherapy agents is lacking, which limits the success rate of clinical trials. A large leap forward can be made if the immunotherapy target cells and pathways are characterized at high resolution before and after treatment, in clinical cohorts and model systems. This will enable rapid development of effective immunotherapies and data-driven design of synergistic drug combinations. In this Perspective, we discuss how emerging single-cell genomic technologies can serve as an engine for target identification and drug development.
Identifiants
pubmed: 32015555
doi: 10.1038/s41591-019-0736-4
pii: 10.1038/s41591-019-0736-4
doi:
Substances chimiques
B7-H1 Antigen
0
Biomarkers
0
CD274 protein, human
0
CTLA-4 Antigen
0
CTLA4 protein, human
0
Immunologic Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
171-177Références
Keener, A. B. Single-cell sequencing edges into clinical trials. Nat. Med. 25, 1322–1326 (2019).
doi: 10.1038/d41591-019-00017-6
Regev, A. et al. The Human Cell Atlas. eLife 6, e27041 (2017).
doi: 10.7554/eLife.27041
Giladi, A. & Amit, I. Single-cell genomics: a stepping stone for future immunology discoveries. Cell 172, 14–21 (2018).
doi: 10.1016/j.cell.2017.11.011
Ziegenhain, C. et al. Comparative analysis of single-cell RNA sequencing methods. Mol. Cell 65, 631–643.e4 (2017).
doi: 10.1016/j.molcel.2017.01.023
Zheng, C. et al. Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing. Cell 169, 1342–1356.e16 (2017).
doi: 10.1016/j.cell.2017.05.035
Azizi, E. et al. Single-cell map of diverse immune phenotypes in the breast tumor microenvironment. Cell 174, 1293–1308.e36 (2018).
doi: 10.1016/j.cell.2018.05.060
Li, H. et al. Dysfunctional CD8 T cells form a proliferative, dynamically regulated compartment within human melanoma. Cell 176, 775–789.e18 (2019).
doi: 10.1016/j.cell.2018.11.043
Gubin, M. M. et al. High-dimensional analysis delineates myeloid and lymphoid compartment remodeling during successful immune-checkpoint cancer therapy. Cell 175, 1014–1030.e19 (2018).
doi: 10.1016/j.cell.2018.09.030
Yost, K. E. et al. Clonal replacement of tumor-specific T cells following PD-1 blockade. Nat. Med. 25, 1251–1259 (2019).
doi: 10.1038/s41591-019-0522-3
Savage, P. et al. A Targetable EGFR-dependent tumor-initiating program in breast cancer. Cell Rep. 21, 1140–1149 (2017).
doi: 10.1016/j.celrep.2017.10.015
Zitvogel, L., Pitt, J. M., Daillère, R., Smyth, M. J. & Kroemer, G. Mouse models in oncoimmunology. Nat. Rev. Cancer 16, 759–773 (2016).
doi: 10.1038/nrc.2016.91
Lavin, Y. et al. Innate immune landscape in early lung adenocarcinoma by paired single-cell analyses. Cell 169, 750–765.e17 (2017).
doi: 10.1016/j.cell.2017.04.014
Zilionis, R. et al. Single-cell transcriptomics of human and mouse lung cancers reveals conserved myeloid populations across individuals and species. Immunity 50, 1317–1334.e10 (2019).
doi: 10.1016/j.immuni.2019.03.009
Stoeckius, M. et al. Simultaneous epitope and transcriptome measurement in single cells. Nat. Methods 14, 865–868 (2017).
doi: 10.1038/nmeth.4380
Wolchok, J. D. et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 377, 1345–1356 (2017).
doi: 10.1056/NEJMoa1709684
Mariathasan, S. et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544–548 (2018).
doi: 10.1038/nature25501
Christmas, B. J. et al. Entinostat converts immune-resistant breast and pancreatic cancers into checkpoint-responsive tumors by reprogramming tumor-infiltrating MDSCs. Cancer Immunol. Res. 6, 1561–1577 (2018).
doi: 10.1158/2326-6066.CIR-18-0070
Bibeau, F. et al. Impact of FcγRIIa-FcγRIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with cetuximab plus irinotecan. J. Clin. Oncol. 27, 1122–1129 (2009).
doi: 10.1200/JCO.2008.18.0463
Selby, M. J. et al. Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol. Res. 1, 32–42 (2013).
doi: 10.1158/2326-6066.CIR-13-0013
Arce Vargas, F. et al. Fc effector function contributes to the activity of human anti-CTLA-4 antibodies. Cancer Cell 33, 649–663.e4 (2018).
doi: 10.1016/j.ccell.2018.02.010
Dahan, R. et al. FcγRs Modulate the anti-tumor activity of antibodies targeting the PD-1/PD-L1 axis. Cancer Cell 28, 285–295 (2015).
doi: 10.1016/j.ccell.2015.08.004
Pincetic, A. et al. Type I and type II Fc receptors regulate innate and adaptive immunity. Nat. Immunol. 15, 707–716 (2014).
doi: 10.1038/ni.2939
Smith, P., DiLillo, D. J., Bournazos, S., Li, F. & Ravetch, J. V. Mouse model recapitulating human Fcγ receptor structural and functional diversity. Proc. Natl Acad. Sci. USA 109, 6181–6186 (2012).
doi: 10.1073/pnas.1203954109
Lux, A. & Nimmerjahn, F. Of mice and men: the need for humanized mouse models to study human IgG activity in vivo. J. Clin. Immunol. 33(Suppl 1), S4–S8 (2013).
doi: 10.1007/s10875-012-9782-0
Soerensen, M. M. et al. Safety, PK/PD, and anti-tumor activity of RO6874281, an engineered variant of interleukin-2 (IL-2v) targeted to tumor-associated fibroblasts via binding to fibroblast activation protein (FAP). J. Clin. Oncol. 36, e15155 (2018).
doi: 10.1200/JCO.2018.36.15_suppl.e15155
Peterson, V. M. et al. Multiplexed quantification of proteins and transcripts in single cells. Nat. Biotechnol. 35, 936–939 (2017).
doi: 10.1038/nbt.3973
Lareau, C. A. et al. Droplet-based combinatorial indexing for massive-scale single-cell chromatin accessibility. Nat. Biotechnol. 37, 916–924 (2019).
doi: 10.1038/s41587-019-0147-6
Satpathy, A. T. et al. Massively parallel single-cell chromatin landscapes of human immune cell development and intratumoral T cell exhaustion. Nat. Biotechnol. 37, 925–936 (2019).
doi: 10.1038/s41587-019-0206-z
Keren, L. et al. A structured tumor-immune microenvironment in triple negative breast cancer revealed by multiplexed ion beam imaging. Cell 174, 1373–1387.e19 (2018).
doi: 10.1016/j.cell.2018.08.039
Ståhl, P. L. et al. Visualization and analysis of gene expression in tissue sections by spatial transcriptomics. Science 353, 78–82 (2016).
doi: 10.1126/science.aaf2403
Pauken, K. E. et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354, 1160–1165 (2016).
doi: 10.1126/science.aaf2807
Scott, A. C. et al. TOX is a critical regulator of tumour-specific T cell differentiation. Nature 571, 270–274 (2019).
doi: 10.1038/s41586-019-1324-y
Simpson, T. R. et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J. Exp. Med. 210, 1695–1710 (2013).
doi: 10.1084/jem.20130579
Sharma, A. et al. Anti-CTLA-4 immunotherapy does not deplete FOXP3
doi: 10.1158/1078-0432.CCR-18-0762
Siddiqui, I. et al. Intratumoral Tcf1
doi: 10.1016/j.immuni.2018.12.021