Identification of essential genes for cancer immunotherapy
Open accessAbstract
Somatic gene mutations can alter the vulnerability of cancer cells to T-cell-based immunotherapies. Here we perturbed genes in human melanoma cells to mimic loss-of-function mutations involved in resistance to these therapies, by using a genome-scale CRISPR-Cas9 library that consisted of around 123,000 single-guide RNAs, and profiled genes whose loss in tumour cells impaired the effector function of CD8+ T cells. The genes that were most enriched in the screen have key roles in antigen presentation and interferon-γ signalling, and correlate with cytolytic activity in patient tumours from The Cancer Genome Atlas. Among the genes validated using different cancer cell lines and antigens, we identified multiple loss-of-function mutations in APLNR, encoding the apelin receptor, in patient tumours that were refractory to immunotherapy. We show that APLNR interacts with JAK1, modulating interferon-γ responses in tumours, and that its functional loss reduces the efficacy of adoptive cell transfer and checkpoint blockade immunotherapies in mouse models. Our results link the loss of essential genes for the effector function of CD8+ T cells with the resistance or non-responsiveness of cancer to immunotherapies.
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There is no known mouse homolog of CD58.
“Notably, there is no known mouse homolog of CD58, emphasizing the value of performing such screens in human models10.”
From Multimodal pooled Perturb-CITE-seq screens in patient models define mechanisms of cancer immune evasion (2021) · cites this paper as [10]
CRISPR/Cas9 KO screens in murine models or engineered human cell lines identified putative novel immune evasion mechanisms involving chromatin regulators, TNFα signaling, SOX4, PTPN2, and APLNR, but their clinical relevance is unclear.
“CRISPR/Cas9 KO screens in murine models or engineered human cell lines testing tumor-T cell interactions identified putative novel mechanisms of immune evasion involving chromatin regulators10, TNFα signaling11, SOX412, PTPN213, and APLNR10, yet their clinical relevance is unclear.”
From Multimodal pooled Perturb-CITE-seq screens in patient models define mechanisms of cancer immune evasion (2021) · cites this paper as [10]
sgRNAs have a structure suitable for direct capture: the variable targeting region is at the 5' end and the 3' end is an invariant scaffold.
“sgRNAs have a structure that lends themselves to direct capture: the variable region that guides Cas9 to its target site is at the 5’ end while the 3’ end is an invariant scaffold25,26.”
From Multiplexed detection of proteins, transcriptomes, clonotypes and CRISPR perturbations in single cells (2019) · cites this paper as [25]
Previous screens used antigen-specific T cells targeting model tumor-associated antigens such as OVA, gp100, and NY-ESO-1.
“In previous screens, antigen-specific T cells targeting model tumor associated antigen (TAA), such as OVA, gp100, and NY-ESO-1, were used (Manguso et al., 2017; Pan et al., 2018; Patel et al., 2017).”
From Protein Barcodes Enable High-Dimensional Single-Cell CRISPR Screens (2018) · cites this paper as Patel et al., 2017
These findings are consistent with clinical data correlating resistance to checkpoint inhibitors with mutations in B2m and IFNγ pathways and with recent genome-wide CRISPR screening data.
“These findings are consistent with emerging clinical data correlating resistance to checkpoint inhibitors with mutations in the B2m and IFNγ pathways (Gao et al., 2016; Zaretsky et al., 2016), and with recent genome-wide CRISPR screening data (Patel et al., 2017).”
From Protein Barcodes Enable High-Dimensional Single-Cell CRISPR Screens (2018) · cites this paper as Patel et al., 2017
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References 51 · Cited by 870
- Authors
- Patel, S. J., Sanjana, N. E., Kishton, R. J., Eidizadeh, A., Vodnala, S. K., Cam, M., Gartner, J. J., Jia, L., Steinberg, S. M., Yamamoto, T. N., Merchant, A. S., Mehta, G. U., Chichura, A., Shalem, O., Tran, E., Eil, R., Sukumar, M., Guijarro, E. P., Day, C.-P., Robbins, P., Feldman, S., Merlino, G., Zhang, F., & Restifo, N. P.
- Affiliations
- National Institutes of Health (US)
- New York Genome Center (US)
- Children's Hospital of Philadelphia (US)
- Broad Institute (US)
- Corresponding author
- Patel, Shashank J.
- Sanjana, Neville E.
- Restifo, Nicholas P.
- ORCID
- Patel, Shashank J.
- Sanjana, Neville E.
- Kishton, Rigel J.
- Vodnala, Suman K.
- Cam, Maggie
- Gartner, Jared J.
- Steinberg, Seth M.
- Yamamoto, Tori N.
- Merchant, Anand S.
- Mehta, Gautam U.
- Chichura, Anna
- Shalem, Ophir
- Tran, Eric
- Eil, Robert
- Sukumar, Madhusudhanan
- Day, Chi-Ping
- Robbins, Paul
- Merlino, Glenn
- Zhang, Feng
- Restifo, Nicholas P.
- Venue
- Nature
- Published
- 2017-08
- Volume
- 548
- Issue
- 7669
- Pages
- 537-542
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5870757
- OpenAlex
- W2744743363
- Cited by
- 870
- References
- 51
- Citations by year
- 2026: 40 · 2025: 78 · 2024: 81 · 2023: 93 · 2022: 115 · 2021: 119 · 2020: 117 · 2019: 102 · 2018: 103 · 2017: 21
- FWCI
- 42.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- National Institutes of Health
- National Human Genome Research Institute (R00HG008171)
- National Cancer Institute
- Moonshot Research and Development Program
- Cancer Moonshot
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- cancer immunotherapy resistance, melanoma, CD8+ T cell effector function, CRISPR-Cas9 loss-of-function screen, apelin receptor, JAK1, interferon-gamma signaling, MHC class I antigen presentation, adoptive cell transfer, immune checkpoint blockade, T cell cytotoxicity
- MeSH terms
- Apelin, Apelin Receptors, Animals, Female, Humans, Immunotherapy, Interferon-gamma, Melanoma, Mutation, Neoplasms, T-Lymphocytes, Cytotoxic, Reproducibility of Results, Histocompatibility Antigens Class I, Genome, Antigen Presentation, Adoptive Transfer, Genes, Essential, Cell Line, Tumor, Knowledge Bases, Mice, Janus Kinase 1, CRISPR-Cas Systems
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