Systematic Immunotherapy Target Discovery Using Genome-Scale In Vivo CRISPR Screens in CD8 T Cells
Open accessAbstract
CD8 T cells play essential roles in anti-tumor immune responses. Here, we performed genome-scale CRISPR screens in CD8 T cells directly under cancer immunotherapy settings and identified regulators of tumor infiltration and degranulation. The in vivo screen robustly re-identified canonical immunotherapy targets such as PD-1 and Tim-3, along with genes that have not been characterized in T cells. The infiltration and degranulation screens converged on an RNA helicase Dhx37. Dhx37 knockout enhanced the efficacy of antigen-specific CD8 T cells against triple-negative breast cancer in vivo. Immunological characterization in mouse and human CD8 T cells revealed that DHX37 suppresses effector functions, cytokine production, and T cell activation. Transcriptomic profiling and biochemical interrogation revealed a role for DHX37 in modulating NF-κB. These data demonstrate high-throughput in vivo genetic screens for immunotherapy target discovery and establishes DHX37 as a functional regulator of CD8 T cells.
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Genome-scale pooled CRISPR loss-of-function screens allow forward genetic studies in many mammalian cell types, including primary T cells, where they have identified genes that may be targeted in future immunotherapies.
“Genome-scale pooled CRISPR loss-of-function screens now allow forward genetic studies in many mammalian cell types (Wang et al., 2014; Shalem et al., 2014) including primary T cells where they have identified genes that may be targeted in future immunotherapies (Dong et al., 2019; Shifrut et al., 2018; Wei et al., 2019).”
From Pooled Knockin Targeting for Genome Engineering of Cellular Immunotherapies (2020) · cites this paper as Dong et al., 2019
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“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript upregulated in sgDhx37 TILs (adjusted p 0.05), including lymphocyte activation, positive regulation of cytokine production, regulation of cell-cell adhesion, regulation of immune effector process, and positive regulation of interferon-gamm…”
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InfluentialNR4A transcription factors limit CAR T cell function in solid tumours
Chen, J., López-Moyado, I. F., Seo, H., Lio, C.-W. J., Hempleman, L. J., Sekiya, T., Yoshimura, A., Scott-Browne, J. P., & Rao, A. (2019) · Nature · doi:10.1038/s41586-019-0985-x · Cited by 874 · cited 1× · see citing works
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Impact of Genetic Polymorphisms on Human Immune Cell Gene Expression
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“Other CRISPR technologies, such as CRISPR activation, CRISPR repression, and orthogonal genetic manipulation will further empower the study of cancer immunotherapy with available and evolving toolkits (Dominguez et al., 2016; Esvelt et al., 2013; Gilbert et al., 2013; Thakore et al., 2016).”
Orthogonal Cas9 proteins for RNA-guided gene regulation and editing
Esvelt, K. M., Mali, P., Braff, J. L., Moosburner, M., Yaung, S. J., & Church, G. M. (2013) · Nature Methods · doi:10.1038/nmeth.2681 · Cited by 786 · cited 1× · see citing works
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Combined Immunodeficiency Associated with DOCK8 Mutations
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“Defects in T cells can lead to recurrent infections (Dumontet et al., 2015; Hersperger et al., 2011; Kurktschiev et al., 2014; Zhang et al., 2009) or cancer (Chia et al.”
Tumor Immunotherapy Directed at PD-1
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“Harnessing T cell inhibitory targets led to the revolution of immune checkpoint blockade therapies (Fesnak et al., 2016; Maude et al., 2014; Maus and June, 2016; Mellman et al., 2011; Ribas, 2012), suggesting that better understanding of the genetic landscape governing T cell function will facilitate the development o…”
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InfluentialJackson, H. J., Rafiq, S., & Brentjens, R. J. (2016) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.36 · Cited by 613 · cited 1× · see citing works
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Genome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function
Shifrut, E., Carnevale, J., Tobin, V., Roth, T. L., Woo, J. M., Bui, C. T., Li, P. J., Diolaiti, M. E., Ashworth, A., & Marson, A. (2018) · Cell · doi:10.1016/j.cell.2018.10.024 · Cited by 573 · see citing works
Highly parallel identification of essential genes in cancer cells
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“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript REAGENT or RESOURCE SOURCE IDENTIFIER Rtsne R package Maaten, 2014; Maaten and Hinton, 2008 https://www.rproject.org Edge R package Robinson et al., 2010 https://www.rproject.org RIGER Luo et al. 2008 https:// software.broadinstitu te.org/…”
InfluentialSelf-citationNoncoding regions are the main source of targetable tumor-specific antigens
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Engineering CAR-T cells: Design concepts
Srivastava, S., & Riddell, S. R. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.06.004 · Cited by 489 · cited 1× · see citing works
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Acquired resistance to immunotherapy and future challenges
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“, 2011), as a large fraction of patients still do not respond to, or have undesired side effects to currently approved ones (Kelderman et al., 2014; Restifo et al., 2016).”
Editing the epigenome: technologies for programmable transcription and epigenetic modulation
Thakore, P. I., Black, J. B., Hilton, I. B., & Gersbach, C. A. (2016) · Nature Methods · doi:10.1038/nmeth.3733 · Cited by 451 · cited 1× · see citing works
“Other CRISPR technologies, such as CRISPR activation, CRISPR repression, and orthogonal genetic manipulation will further empower the study of cancer immunotherapy with available and evolving toolkits (Dominguez et al., 2016; Esvelt et al., 2013; Gilbert et al., 2013; Thakore et al., 2016).”
The determinants of tumour immunogenicity
Blankenstein, T. J. F., Coulie, P. G., Gilboa, E., & Jaffee, E. M. (2012) · Nature reviews. Cancer · doi:10.1038/nrc3246 · Cited by 437 · cited 1× · see citing works
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CD8 T Cell Responses to Infectious Pathogens
Wong, P., & Pamer, E. G. (2003) · Annual Review of Immunology · doi:10.1146/annurev.immunol.21.120601.141114 · Cited by 424 · see citing works
A Distinct Gene Module for Dysfunction Uncoupled from Activation in Tumor-Infiltrating T Cells
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“Application of CRISPR enables manipulation of the T cell genome (Beil-Wagner et al., 2016; Singer et al., 2016; Su et al., 2016).”
Self-citationZambelli, F., Pesole, G., & Pavesi, G. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkp464 · Cited by 402 · cited 1× · see citing works
“Motif enrichment analysis in the promoters of differentially expressed genes was performed using (Zambelli et al., 2009), using a −450 to +50 bp interval and the TRANSFAC database.”
Anti–CTLA-4 therapy broadens the melanoma-reactive CD8 + T cell response
Kvistborg, P., Philips, D., Kelderman, S., Hageman, L., Ottensmeier, C. H. H., Joseph‐Pietras, D., Welters, M. J. P., van der Burg, S., Kapiteijn, E., Michielin, O. A., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3008918 · Cited by 378 · cited 1× · see citing works
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Autoimmune Lymphoproliferative Syndrome with SomaticFasMutations
Hölzelova, E., Vonarbourg, C., Stolzenberg, M., Arkwright, P. D., Selz, F., Prieur, A., Blanche, S., Bartůňková, J., VILMER, E., Fischer, A., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa040036 · Cited by 332 · cited 1× · see citing works
“, 2016), while dysregulated activation of CD8+ T cells can result in immunopathology and autoimmunity (Gravano and Hoyer, 2013; Holzelova et al., 2004; Valori et al., 2016; Walter and Santamaria, 2005).”
Karaca, E., Harel, T., Pehli̇van, D., Jhangiani, S. N., Gambin, T., Coban‐Akdemir, Z., Gonzaga-Jauregui, C. G., Erdin, S., Bayram, Y., Campbell, I. M., et al. (2015) · Neuron · doi:10.1016/j.neuron.2015.09.048 · Cited by 315 · cited 1× · see citing works
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Efficient generation of Rosa26 knock-in mice using CRISPR/Cas9 in C57BL/6 zygotes
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CRISPR-Cas9 mediated efficient PD-1 disruption on human primary T cells from cancer patients
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Self-citationPhosphotyrosine-Dependent Coupling of Tim-3 to T-Cell Receptor Signaling Pathways
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“In line with the TIL scRNA-seq result, Dhx37 mutant have higher levels of surface PD-1, Lag3 and Tim-3 (Figure 5D–F), which are known immune checkpoints and also linked to intrinsic T cell activation (Lee et al., 2011).”
Making Better Chimeric Antigen Receptors for Adoptive T-cell Therapy
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Driving gene-engineered T cell immunotherapy of cancer
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In vivo discovery of immunotherapy targets in the tumour microenvironment
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Acquired and intrinsic resistance in cancer immunotherapy
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“, 2011), as a large fraction of patients still do not respond to, or have undesired side effects to currently approved ones (Kelderman et al., 2014; Restifo et al., 2016).”
Henriksson, J., Chen, X. X., Gomes, T., Ullah, U., Meyer, K. B., Miragaia, R. J., Duddy, G., Pramanik, J., Yusa, K., Lahesmaa, R., et al. (2019) · Cell · doi:10.1016/j.cell.2018.11.044 · Cited by 195 · see citing works
Cancers Related to Immunodeficiencies: Update and Perspectives
Mortaz, E., Tabarsi, P., Mansouri, D., Khosravi, A., Garssen, J., Velayati, A. A., & Adcock, I. M. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00365 · Cited by 190 · cited 1× · see citing works
“, 2009) or cancer (Chia et al., 2009; Clementi et al., 2005; Mortaz et al., 2016), while dysregulated activation of CD8+ T cells can result in immunopathology and autoimmunity (Gravano and Hoyer, 2013; Holzelova et al.”
A proportion of patients with lymphoma may harbor mutations of the perforin gene
Clementi, R. (2005) · Blood · doi:10.1182/blood-2004-04-1477 · Cited by 188 · cited 1× · see citing works
“, 2009) or cancer (Chia et al., 2009; Clementi et al., 2005; Mortaz et al., 2016), while dysregulated activation of CD8+ T cells can result in immunopathology and autoimmunity (Gravano and Hoyer, 2013; Holzelova et al.”
Hersperger, A. R., Martin, J. N., Shin, L. Y., Sheth, P. M., Kovacs, C. M., Cosma, G. L., Makedonas, G., Pereyra, F., Walker, B. D., Kaul, R., et al. (2011) · Blood · doi:10.1182/blood-2010-12-322727 · Cited by 180 · cited 1× · see citing works
“Defects in T cells can lead to recurrent infections (Dumontet et al., 2015; Hersperger et al., 2011; Kurktschiev et al., 2014; Zhang et al., 2009) or cancer (Chia et al.”
Promotion and prevention of autoimmune disease by CD8+ T cells
Gravano, D. M., & Hoyer, K. K. (2013) · Journal of Autoimmunity · doi:10.1016/j.jaut.2013.06.004 · Cited by 166 · see citing works
One-step generation of modular CAR-T cells with AAV–Cpf1
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Self-citationSizing up the key determinants of the CD8+ T cell response
Tscharke, D. C., Croft, N. P., Doherty, P. C., & Gruta, N. L. L. (2015) · Nature reviews. Immunology · doi:10.1038/nri3905 · Cited by 148 · see citing works
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“We did not pursue Lyn because it is not normally expressed in T cells (Tsantikos et al., 2009; Yamanashi et al., 1989).”
Cytokines and the inception of CD8 T cell responses
Cox, M. A., Harrington, L. E., & Zajac, A. J. (2011) · Trends in Immunology · doi:10.1016/j.it.2011.01.004 · Cited by 138 · see citing works
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Combination Approaches with Immune-Checkpoint Blockade in Cancer Therapy
Swart, M., Verbrugge, I., & Beltman, J. B. (2016) · Frontiers in Oncology · doi:10.3389/fonc.2016.00233 · Cited by 137 · cited 1× · see citing works
“Approved immune checkpoint inhibitors enhance anti-tumor response of CD8 T cells by neutralizing CTLA-4 or PD-1/PD-L1 (Brahmer et al., 2010; Kvistborg et al., 2014; Pardoll, 2012; Ribas, 2012; Swart et al., 2016; Tumeh et al., 2014).”
Walter, U., & Santamaría, P. (2005) · Current Opinion in Immunology · doi:10.1016/j.coi.2005.09.014 · Cited by 124 · see citing works
Immune checkpoints in cancer clinical trials
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“These drugs are effective in multiple indications (Mellman et al., 2011; Sharon et al., 2014), either as monotherapies or in combination with other therapies (Larkin et al.”
RNA helicases: regulators of differentiation
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“The putative ATP-Dependent RNA Helicase domain and conservation implies that it might affect gene expression (Abdelhaleem, 2005).”
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“Similar to previous studies (Chen et al., 2014; Zhou et al., 2014), for each infection replicate, a total of > 1 × 108 Cas9 or naive OT-I; Cas9 CD8+ T cells were transduced with concentrated lentivirus containing the MKO library described above, to achieve an initial library coverage of > 700x.…”
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Functional genomics to uncover drug mechanism of action
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“RNAi operate by degrading mRNA or suppressing their translation, but have substantial off-target effects (Nijman, 2015).”
Cell-Intrinsic Barriers of T Cell-Based Immunotherapy
Ghoneim, H. E., Zamora, A. E., Thomas, P. G., & Youngblood, B. (2016) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2016.10.002 · Cited by 70 · cited 1× · see citing works
“Systematic approaches to identify new regulators of T cell functions in vivo can provide potentially orthogonal or complementary opportunities (Ghoneim et al., 2016).”
Engineering Therapeutic T Cells: From Synthetic Biology to Clinical Trials
Esensten, J. H., Bluestone, J. A., & Lim, W. A. (2017) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-052016-100304 · Cited by 62 · cited 1× · see citing works
“, 2016; Srivastava and Riddell, 2015) showed success in hematopoietic malignancies (Esensten et al., 2016; Jackson et al., 2016; Johnson and June, 2017) and were recently approved.”
A novel class of somatic mutations in blood detected preferentially in CD8 + cells
Valori, M., Jansson, L., Kiviharju, A., Ellonen, P., Rajala, H. L. M., Awad, S. A., Mustjoki, S. M., & Tienari, P. J. (2016) · Clinical Immunology · doi:10.1016/j.clim.2016.11.018 · Cited by 42 · cited 1× · see citing works
“, 2016), while dysregulated activation of CD8+ T cells can result in immunopathology and autoimmunity (Gravano and Hoyer, 2013; Holzelova et al., 2004; Valori et al., 2016; Walter and Santamaria, 2005).”
Hirata, H., Ogino, K., Yamada, K., Leacock, S., & Harvey, R. J. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.1157-13.2013 · Cited by 36 · cited 1× · see citing works
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Roychowdhury, A., Joret, C., Bourgeois, G., Heurgué‐Hamard, V., Lafontaine, D. L. J., & Graille, M. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz529 · Cited by 25 · cited 1× · see citing works
“Dhx37 is a highly conserved DEAH box RNA helicase that has been reported to be involved with biogenesis of the small ribosomal subunit through its release of U3 small nucleolar RNA (snoRNA) (Roychowdhury et al., 2019).”
Tsantikos, E., Quilici, C., Harder, K. W., Wang, B., Zhu, H., Anderson, G. P., Tarlinton, D. M., & Hibbs, M. L. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0804346 · Cited by 24 · cited 1× · see citing works
“We did not pursue Lyn because it is not normally expressed in T cells (Tsantikos et al., 2009; Yamanashi et al., 1989).”
Recurrent Respiratory Infections Revealing CD8α Deficiency
Dumontet, E., Osman, J., Guillemont-Lambert, N., Cros, G., Moshous, D., & Pïcard, C. (2015) · Journal of Clinical Immunology · doi:10.1007/s10875-015-0213-x · Cited by 20 · cited 2× · see citing works
“Defects in T cells can lead to recurrent infections (Dumontet et al., 2015; Hersperger et al., 2011; Kurktschiev et al., 2014; Zhang et al., 2009) or cancer (Chia et al., 2009; Clementi et al., 2005; Mortaz et al., 2016), while dysregulated activation of CD8+ T cells can result in immunopathology…”
T cell-specific inactivation of mouse CD2 by CRISPR/Cas9
Beil-Wagner, J., Dössinger, G., Schober, K., Berg, J. V., Tresch, A., Grandl, M., Palle, P., Mair, F., Gerhard, M., Becher, B., et al. (2016) · Scientific Reports · doi:10.1038/srep21377 · Cited by 13 · cited 1× · see citing works
“Application of CRISPR enables manipulation of the T cell genome (Beil-Wagner et al., 2016; Singer et al., 2016; Su et al., 2016).”
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Exploring treatment options in cancer: tumor treatment strategies
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Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation
Dhatchinamoorthy, K., Colbert, J. D., & Rock, K. L. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.636568 · Cited by 1,077 · see citing works
“Inhibiting or silencing of MAPKs increased levels of IRF1 and STAT1 (215) as well as MHC I expression (214).”
BackgroundInfluentialCD8+ T cell differentiation and dysfunction in cancer
Philip, M., & Schietinger, A. (2022) · Nature Reviews Immunology · doi:10.1038/s41577-021-00574-3 · Cited by 1,052 · see citing works
CAR immune cells: design principles, resistance and the next generation
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Ferroptosis in cancer and cancer immunotherapy
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“However, due to the complexity of the tumormicroenvironment and insufficient activation of the host immune system, the systemic antitumor response rate of immune checkpoint blocking therapy for many cancers is still limited (Figure 5) [185, 186].”
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“This approach has been used in screens of T cell tumour engagement 130 , cancer signalling pathways 131 , immune cell activation 132 and cell differentiation 133–135 .”
BackgroundMethodInfluentialSelf-citationCRISPR in cancer biology and therapy
Katti, A., Diaz, B. J., Caragine, C. M., Sanjana, N. E., & Dow, L. E. (2022) · Nature reviews. Cancer · doi:10.1038/s41568-022-00441-w · Cited by 440 · see citing works
An NK-like CAR T cell transition in CAR T cell dysfunction
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CAR-T and CAR-NK as cellular cancer immunotherapy for solid tumors
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“For example, many of the solutions to overcome the limitations of CAR-T and NK cells summarized in this review have been achieved through the application of high-throughput CRISPR technology [123, 124, 126, 128, 129, 251].”
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“For example, prior CRISPR-Cas9 screens in T cells have been used to identify transcription factors andmetabolic regulators of T cell fate in vivo, as well as therapeutic targets (Chen et al., 2021; Dong et al., 2019; Huang et al., 2021; LaFleur et al., 2019; Wei et al., 2019).”
BackgroundPrinciples and therapeutic applications of adaptive immunity
Chi, H., Pepper, M., & Thomas, P. G. (2024) · Cell · doi:10.1016/j.cell.2024.03.037 · Cited by 363 · see citing works
Epigenetic regulation of T cell exhaustion
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CRISPR activation and interference screens decode stimulation responses in primary human T cells
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A new era in functional genomics screens
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Self-citationRASA2 ablation in T cells boosts antigen sensitivity and long-term function
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Self-citationThe future of engineered immune cell therapies
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Synthetic Lethality in Cancer Therapeutics: The Next Generation
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“High-throughput in vivo CRISPR screens in primary CD8+ T-cells have been shown to allow for the discovery of negative regulators of anti-tumor T-cell immunity, as evidenced by their ability to recover known immunotherapy targets such as PD-1 and Tim-3 (42).”
BackgroundAn expanded universe of cancer targets
Hahn, W. C., Bader, J. S., Braun, T. P., Califano, A., Clemons, P. A., Druker, B. J., Ewald, A. J., Fu, H., Jagu, S., Kemp, C. J., et al. (2021) · Cell · doi:10.1016/j.cell.2021.02.020 · Cited by 213 · see citing works
Self-citationIn vivo CD8+ T cell CRISPR screening reveals control by Fli1 in infection and cancer
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A genome-scale screen for synthetic drivers of T cell proliferation
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Next-Generation CAR T-cell Therapies
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Genetic engineering of T cells for immunotherapy
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Role of CD8+ T lymphocyte cells: Interplay with stromal cells in tumor microenvironment
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Recent advances and applications of CRISPR-Cas9 in cancer immunotherapy
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Efficient engineering of human and mouse primary cells using peptide-assisted genome editing
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Improving the ability of CAR-T cells to hit solid tumors: Challenges and strategies
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Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy
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Base-editing mutagenesis maps alleles to tune human T cell functions
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CAR-T cells in solid tumors: Challenges and breakthroughs
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Engineering Strategies to Enhance TCR-Based Adoptive T Cell Therapy
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In vitro modeling of CD8 + T cell exhaustion enables CRISPR screening to reveal a role for BHLHE40
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CRISPR screens for functional interrogation of immunity
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Tumor Microenvironment: Key Players in Triple Negative Breast Cancer Immunomodulation
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Strategies to enhance CAR-T persistence
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Base editing screens map mutations affecting interferon-γ signaling in cancer
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CRISPR/Cas9 revitalizes adoptive T-cell therapy for cancer immunotherapy
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NF-κB in Cancer Immunity: Friend or Foe?
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Targeting monoamine oxidase A for T cell–based cancer immunotherapy
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“Hence, previous CRISPR-Cas9 screens were conducted on cancer cells or T cells to identify potential immuno-therapy targets or genes sensitizing tumors to immunotherapy ( 10 , 27 – 29 ).”
Wang, Z., Ahmed, S. U., Labib, M., Wang, H., Hu, X., Wei, J., Yao, Y., Moffat, J., Sargent, E. H., & Kelley, S. O. (2022) · Nature Biomedical Engineering · doi:10.1038/s41551-021-00820-y · Cited by 75 · see citing works
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Polyamine Immunometabolism: Central Regulators of Inflammation, Cancer and Autoimmunity
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Targeted Anti‐Tumor Immunotherapy Using Tumor Infiltrating Cells
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Self-citationGene editing and its applications in biomedicine
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“In transplantationbased screens, sgRNA-containing tumor cells or activated immune cells are transferred to recipient animals and subjected to selection conditions (Chen et al., 2015a; Chen et al., 2021; Dong et al., 2019).”
BackgroundThe Art of Finding the Right Drug Target: Emerging Methods and Strategies
Jia, Z.-C., Yang, X., Wu, Y., Li, M., Das, D., Chen, M., & Wu, J. (2024) · Pharmacological Reviews · doi:10.1124/pharmrev.123.001028 · Cited by 67 · see citing works
A T cell resilience model associated with response to immunotherapy in multiple tumor types
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In vivo functional screening for systems-level integrative cancer genomics
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Effect of CRISPR/Cas9-Edited PD-1/PD-L1 on Tumor Immunity and Immunotherapy
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“They reidentified typical immunotherapy targets such as PD-1 and TIM-3, as well as other novel sites, and verified the region of CRISPR in vivo screening of CD8 T cells for tumour infiltration (83).”
BackgroundEngineering chimeric antigen receptor T cells for solid tumour therapy
Liu, L., Qu, Y., Cheng, L., Yoon, C. W., He, P., Monther, A., Guo, T., Chittle, S. J., & Wang, Y. (2022) · Clinical and Translational Medicine · doi:10.1002/ctm2.1141 · Cited by 59 · see citing works
Future perspectives on engineered T cells for cancer
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The outstanding antitumor capacity of CD4+ T helper lymphocytes
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Loss of Rnf31 and Vps4b sensitizes pancreatic cancer to T cell-mediated killing
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CRISPR-based screens uncover determinants of immunotherapy response in multiple myeloma
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CRISPR–Cas9 applications in T cells and adoptive T cell therapies
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“This can work as a candidate target for immunotherapy [58].”
BackgroundMassively parallel knock-in engineering of human T cells
Dai, X., Park, J. J.-Y., Du, Y., Na, Z., Lam, S. Z., Chow, R. D.-W., Renauer, P. A., Gu, J., Shan, X., Chu, Z., et al. (2023) · Nature Biotechnology · doi:10.1038/s41587-022-01639-x · Cited by 54 · see citing works
“Sample size Sample size needed for experiments were estimated based on our prior work or similar experiments in the field (Dai et al. 2019; Dong et al. 2019; Eqyuem et al. 2017).”
MethodSelf-citationMoving from in vitro to in vivo CRISPR screens
Kuhn, M., Santinha, A. J., & Platt, R. J. (2021) · Gene and Genome Editing · doi:10.1016/j.ggedit.2021.100008 · Cited by 53 · see citing works
Advances in Genomics for Drug Development
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IKZF3 deficiency potentiates chimeric antigen receptor T cells targeting solid tumors
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Re-education of the Tumor Microenvironment With Targeted Therapies and Immunotherapies
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In vivo CRISPR screens reveal a HIF-1α-mTOR-network regulates T follicular helper versus Th1 cells
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Genome-wide CRISPR screen in human T cells reveals regulators of FOXP3
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Self-citationCAR-T therapy dilemma and innovative design strategies for next generation
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CRISPR Gene Editing of Human Primary NK and T Cells for Cancer Immunotherapy
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Large-scale multiplexed mosaic CRISPR perturbation in the whole organism
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Metabolic rewiring and communication in cancer immunity
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CRISPR screen in mechanism and target discovery for cancer immunotherapy
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CRISPR/Cas9 system: recent applications in immuno-oncology and cancer immunotherapy
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Perturbomics: CRISPR–Cas screening-based functional genomics approach for drug target discovery
Park, B.-S., Lee, M., Kim, J. Y., & Kim, T. (2025) · Experimental & Molecular Medicine · doi:10.1038/s12276-025-01487-0 · Cited by 41 · see citing works
“Chen and colleagues used a genome-wide knockout sgRNA library in primary CD8 + T cells from Cas9-transgenic mice, identifying Dhx37, which modulates CD8 + T cell function via NF-κ B signaling 53 .”
Ferroptosis in Cancer and Inflammatory Diseases: Mechanisms and Therapeutic Implications
Shen, G., Liu, J., Wang, Y., Deng, Z., & Deng, F. (2025) · MedComm · doi:10.1002/mco2.70349 · Cited by 43 · see citing works
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“DHX37 has been reported to be able to interact with the NFkB subunit p65 and PDCD11 to regulate NFkB pathway activity in CD8-positive T cells; this finding was the first to show that DHX37 is related to the progression of cancer (8).”
BackgroundNon-viral siRNA delivery to T cells: Challenges and opportunities in cancer immunotherapy
Hoeck, J. V., Braeckmans, K., Smedt, S. C. D., & Raemdonck, K. (2022) · Biomaterials · doi:10.1016/j.biomaterials.2022.121510 · Cited by 37 · see citing works
Genome-scale CRISPR screening in a single mouse liver
Keys, H. R., & Knouse, K. A. (2022) · Cell Genomics · doi:10.1016/j.xgen.2022.100217 · Cited by 36 · see citing works
“As such, genome-wide CRISPR screening has largely been limited to cell culture systems or cellular transplantation models.(5,6) Bringing genome-scale screening into the organism requires overcoming the barriers to stable, high-coverage sgRNAdelivery into tissues.”
Epigenetic modulation of immunotherapy and implications in head and neck cancer
Zhou, L., Xu, N., Shibata, H., Saloura, V., & Uppaluri, R. (2021) · Cancer and Metastasis Reviews · doi:10.1007/s10555-020-09944-0 · Cited by 35 · see citing works
Finding functional microproteins
Azam, S., Yang, F., & Wu, X. (2025) · Trends in Genetics · doi:10.1016/j.tig.2024.12.001 · Cited by 37 · see citing works
CRISPR screen in cancer: status quo and future perspectives.
He, C., Han, S., Chang, Y., Wu, M., Zhao, Y., Chen, C. Y., & Chu, X. (2021) · PubMed Central · Cited by 32 · see citing works
CAR T cell therapy: newer approaches to counter resistance and cost
Yadav, R. K., Ali, A., Kumar, S., Sharma, A., Baghchi, B., Singh, P., Das, S., Singh, C., & Sharma, S. (2020) · Heliyon · doi:10.1016/j.heliyon.2020.e03779 · Cited by 31 · see citing works
Tumor immunology CRISPR screening: present, past, and future
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Self-citationHigh-throughput methods for genome editing: the more the better
Huang, Y., Shang, M., Liu, T., & Wang, K. (2022) · PLANT PHYSIOLOGY · doi:10.1093/plphys/kiac017 · Cited by 30 · see citing works
Stresses in the metastatic cascade: molecular mechanisms and therapeutic opportunitiesPreprint
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“In contrast, stiffer ECM is required for EMT and metastasis in hepatocellular carcinoma (Dong et al. 2019b).”
BackgroundResultCRISPR-StAR enables high-resolution genetic screening in complex in vivo models
Uijttewaal, E. C. H., Lee, J., Sell, A. C., Botay, N., Vainorius, G., Novatchkova, M., Baar, J. C., Yang, J., Potzler, T., Leij, S., et al. (2024) · Nature Biotechnology · doi:10.1038/s41587-024-02512-9 · Cited by 30 · see citing works
Novel Mouse Models for Cancer Immunology
Connolly, K. A., Fitzgerald, B., Damo, M., & Joshi, N. S. (2022) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-070620-105523 · Cited by 30 · see citing works
Biomaterial-Based CRISPR/Cas9 Delivery Systems for Tumor Treatment
Li, M., Chen, F., Yang, Q., Tang, Q., Xiao, Z., Tong, X., Zhang, Y., Lei, L., & Li, S. (2024) · Biomaterials Research · doi:10.34133/bmr.0023 · Cited by 31 · see citing works
“In CD8-positive T cells, knockdown of DHX37 can improve adoptive immuno-therapy in TNBC [71].”
Functional CRISPR screens in T cells reveal new opportunities for cancer immunotherapies
Xiang, M., Li, H., Zhan, Y., Ma, D., Gao, Q., & Fang, Y. (2024) · Molecular Cancer · doi:10.1186/s12943-024-01987-z · Cited by 28 · see citing works
“It remains challenging to screen for regulators of T cell priming or naive T cell homeostasis as well as conducting in vivo screens using other types of immune cells [117, 122, 124].”
BackgroundUsing CRISPR to enhance T cell effector function for therapeutic applications
Heeren, J. J. F. (2020) · Cytokine X · doi:10.1016/j.cytox.2020.100049 · Cited by 29 · see citing works
“DHX37 expression in TILs from breast cancer patients correlates with poor outcomes [53].”
BackgroundInfluentialMethods and applications of in vivo CRISPR screening
Santinha, A. J., Strano, A., & Platt, R. J. (2025) · Nature Reviews Genetics · doi:10.1038/s41576-025-00873-8 · Cited by 29 · see citing works
“…in the mouse retina identified repressors of retinal ganglion cell survival whose knockout was neuroprotective in a glaucoma model 208 , and transplantation screens in immune cell types can directly inform on perturbations that lead to more effective cancer immunotherapies 20,47,50,154,209,210 .”
Wang, F., Zhu, J., Wang, Y.-T., & Li, J. (2022) · Nanomaterials · doi:10.3390/nano12101656 · Cited by 28 · see citing works
- Authors
- Dong, M. B., Wang, G., Chow, R. D., Ye, L., Zhu, L., Dai, X., Park, J. J., Kim, H. R., Errami, Y., Guzman, C. D., Zhou, X., Chen, K. Y., Renauer, P. A., Du, Y., Shen, J., Lam, S. Z., Zhou, J. J., Lannin, D. R., Herbst, R. S., & Chen, S.
- Affiliations
- Yale University (US)
- Yale Cancer Center (US)
- Corresponding author
- Chen, Sidi
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2019-08
- Volume
- 178
- Issue
- 5
- Pages
- 1189-1204.e23
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6719679
- OpenAlex
- W2969378520
- Cited by
- 330
- References
- 116
- Citations by year
- 2026: 27 · 2025: 63 · 2024: 54 · 2023: 44 · 2022: 60 · 2021: 43 · 2020: 37 · 2019: 2
- FWCI
- 15.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- CD8+ T cells, cancer immunotherapy, in vivo CRISPR screen, tumor infiltration, T cell degranulation, PD-1, TIM-3, DHX37, RNA helicase, NF-κB signaling, triple-negative breast cancer, T cell effector function, cytokine production, T cell activation
- MeSH terms
- RNA, Guide, CRISPR-Cas Systems, Animals, Breast Neoplasms, Female, Humans, Immunologic Memory, Immunotherapy, Male, Cytokines, NF-kappa B, Mice, Knockout, CD8-Positive T-Lymphocytes, RNA Helicases, Cell Line, Tumor, Mice, Transcriptome, Programmed Cell Death 1 Receptor, Clustered Regularly Interspaced Short Palindromic Repeats
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