In vivo discovery of immunotherapy targets in the tumour microenvironment
Open accessAbstract
Recent clinical trials showed that targeting of inhibitory receptors on T cells induces durable responses in a subset of cancer patients, despite advanced disease. However, the regulatory switches controlling T-cell function in immunosuppressive tumours are not well understood. Here we show that such inhibitory mechanisms can be systematically discovered in the tumour microenvironment. We devised an in vivo pooled short hairpin RNA (shRNA) screen in which shRNAs targeting negative regulators became highly enriched in murine tumours by releasing a block on T-cell proliferation upon tumour antigen recognition. Such shRNAs were identified by deep sequencing of the shRNA cassette from T cells infiltrating tumour or control tissues. One of the target genes was Ppp2r2d, a regulatory subunit of the PP2A phosphatase family. In tumours, Ppp2r2d knockdown inhibited T-cell apoptosis and enhanced T-cell proliferation as well as cytokine production. Key regulators of immune function can therefore be discovered in relevant tissue microenvironments.
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Many negative regulators in the screen were enriched among hits from a published shRNA screen (Zhou et al., 2014) designed to find targets that boost T cell proliferation in tumor tissue in vivo (FDR < 0.01).
“Many of the negative regulators in our screen were enriched in the list of hits from a published shRNA screen (Zhou et al., 2014) that was designed to discover gene targets that boost T cell proliferation in tumor tissue in vivo (FDR < 0.01).”
From Genome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function (2018) · cites this paper as Zhou et al., 2014
The gene set used as external reference for the in vivo immunotherapy hits in Figure 2E comprises 43 genes identified by Zhou et al. as having at least three shRNA guides enriched more than fourfold in tumor-tissue T cells relative to spleen.
“For the external gene set for in vivo immunotherapy hits shown in Figure 2E, we used the 43 genes as determined by Zhou et al. (Zhou et al., 2014), having 3 or more shRNA guides with over 4-fold enrichment in T cells from tumor tissue compared to spleen.”
From Genome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function (2018) · cites this paper as Zhou et al., 2014
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References 59 · Cited by 237
- Authors
- Zhou, P., Shaffer, D. R., Alvarez Arias, D. A., Nakazaki, Y., Pos, W., Torres, A. J., Cremasco, V., Dougan, S. K., Cowley, G. S., Elpek, K., Brogdon, J., Lamb, J., Turley, S. J., Ploegh, H. L., Root, D. E., Love, J. C., Dranoff, G., Hacohen, N., Cantor, H., & Wucherpfennig, K. W.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Koch Institute for Integrative Cancer Research At MIT (US)
- Massachusetts Institute of Technology (US)
- Broad Institute (US)
- Genomics Institute of the Novartis Research Foundation (US)
- Corresponding author
- Wucherpfennig, Kai W.
- ORCID
- Venue
- Nature
- Published
- 2014-01-29
- Volume
- 506
- Issue
- 7486
- Pages
- 52-57
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4052214
- OpenAlex
- W2065897880
- Cited by
- 237
- References
- 59
- Citations by year
- 2026: 8 · 2025: 18 · 2024: 18 · 2023: 17 · 2022: 17 · 2021: 18 · 2020: 21 · 2019: 21 · 2018: 24 · 2017: 12 · 2016: 20 · 2015: 27 · 2014: 16
- FWCI
- 12.08
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Melanoma Research Alliance
- Dana-Farber/Harvard Cancer Center
- Terri Brodeur Breast Cancer Foundation
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (P30-CA14051)
- National Institutes of Health (T32 grant)
- National Cancer Institute (CA14051, R01CA173750, P30CA014051, P30-CA-14051)
- National Institute of Allergy and Infectious Diseases (T32AI007386, P01AI045757, T32 AI 07386)
- National Institute of Diabetes and Digestive and Kidney Diseases (DP3DK097681)
- 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
- tumor microenvironment, T cell suppression, protein phosphatase 2A, T cell proliferation, T cell apoptosis, cancer immunotherapy
- MeSH terms
- Animals, Antigens, Neoplasm, Female, Immunotherapy, Melanoma, Experimental, Mice, Inbred C57BL, Reproducibility of Results, CD4-Positive T-Lymphocytes, Cytokines, Lymphocytes, Tumor-Infiltrating, Apoptosis, CD8-Positive T-Lymphocytes, RNA, Small Interfering, Cell Proliferation, Mice, Protein Phosphatase 2, Gene Knockdown Techniques, Molecular Targeted Therapy, High-Throughput Nucleotide Sequencing, Tumor Microenvironment
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