Instability of Helios-deficient Tregs is associated with conversion to a T-effector phenotype and enhanced antitumor immunity
Open accessAbstract
Significance: Depletion or inhibition of regulatory T cells (Tregs) has been associated with increased effector T-cell activation that may enhance antitumor responses. A potentially more effective strategy depends on induction of lineage instability that allows conversion of intratumoral but not systemic Tregs into effector T cells (Teffs). We show that targeted deletion of the Helios transcription factor within CD4 Tregs promotes instability and effector cell conversion of Tregs in tumors and increased antitumor immunity. Ab-dependent ligation of Treg surface receptors that diminishes Helios expression can also induce intratumoral Treg conversion. These findings indicate that targeting of signaling pathways that reduce Helios expression by intratumoral Tregs may represent a potentially robust approach to cancer immunotherapy.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Loss of IKZF2 can shift TRegs toward a pro-inflammatory state such that they secrete IL-2 and IFN-γ and behave like tumor-fighting Teff-like cells.
“However, its loss can shift tRegs toward a pro-inflammatory state such they secrete il-2 and iFN-γ and behave like tumor-fighting teff-like cells (Kim et al. 2015;Nakagawa et al. 2016).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Nakagawa et al. 2016
The Results report that Helios-deficient intratumoral Tregs produce IFN-γ, convert toward a Teff phenotype, and are associated with enhanced antitumor immunity. They do not report that these Tregs secrete IL-2; the Discussion instead describes defective IL-2 responses. The observed conversion is principally within tumors, not systemic Tregs. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHelios is critical for maintaining identity and suppressive activity of Tregs, and mouse models with Helios-deficient Treg cells show enhanced antitumor immunity.
“Helios is critical for maintaining the identity and suppressive activity of Tregs, and mouse models with Helios-deficient Treg cells have shown enhanced antitumor immunity.168”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [168]
Helios is critical for maintaining the identity, anergic phenotype, and suppressive activity of regulatory T cells.
“The zinc finger transcription factor Helios is critical for maintaining the identity, anergic phenotype, and suppressive activity of regulatory T cells.”
From Acute pharmacological degradation of Helios destabilizes regulatory T cells (2021) · cites this paper as [5]
Acute pharmacological degradation of Helios recapitulates the phenotype of genetic loss of Ikzf2 in Tregs.
“Notably, the preferential Helios degrader ALV2 destabilized the anergic phenotype of regulatory Tregs, consistent with previously reported phenotypes of Ikzf2−/− Tregs5,6,29, demonstrating that acute pharmacological degradation of Helios recapitulates the phenotype of genetic loss of Ikzf2 in Tregs.”
From Acute pharmacological degradation of Helios destabilizes regulatory T cells (2021) · cites this paper as [5]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
1 retracted
TIGIT predominantly regulates the immune response via regulatory T cells
Kurtuluş, S., Sakuishi, K., Ngiow, S. F., Joller, N., Tan, D. J., Teng, M. W. L., Smyth, M. J., Kuchroo, V. K., & Anderson, A. C. (2015) · Journal of Clinical Investigation · doi:10.1172/jci81187 · Cited by 544 · see citing works
RetractedCoussens, L. M., & Werb, Z. (2002) · Nature · doi:10.1038/nature01322 · Cited by 15,111 · see citing works
PD-L1 regulates the development, maintenance, and function of induced regulatory T cells
Francisco, L. M., Salinas, V. H., Brown, K. E., Vanguri, V. K., Freeman, G. J., Kuchroo, V. K., & Sharpe, A. H. (2009) · The Journal of Experimental Medicine · doi:10.1084/jem.20090847 · Cited by 2,072 · see citing works
Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance
Shimizu, J., Yamazaki, S., Takahashi, T., Ishida, Y., & Sakaguchi, S. (2002) · Nature Immunology · doi:10.1038/ni759 · Cited by 1,729 · see citing works
Simpson, T. R., Li, F., Montalvo-Ortiz, W., Sepulveda, M. A., Bergerhoff, K., Arce, F., Roddie, C., Henry, J. Y., Yagita, H., Wolchok, J. D., et al. (2013) · Journal of Experimental Medicine · doi:10.1084/jem.20130579 · Cited by 1,472 · see citing works
Thornton, A. M., Korty, P. E., Tran, D. Q., Wohlfert, E. A., Murray, P. E., Belkaid, Y., & Shevach, E. M. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0904028 · Cited by 1,382 · see citing works
Combination cancer immunotherapy and new immunomodulatory targets
Mahoney, K. M., Rennert, P. D., & Freeman, G. J. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4591 · Cited by 1,294 · see citing works
Quezada, S. A., Simpson, T. R., Peggs, K. S., Merghoub, T., Vider, J., Fan, X., Blasberg, R., Yagita, H., Muranski, P., Antony, P. A., et al. (2010) · Journal of Experimental Medicine · doi:10.1084/jem.20091918 · Cited by 898 · see citing works
Cancer/testis antigens: an expanding family of targets for cancer immunotherapy
Scanlan, M. J., Gure, A. O., Jungbluth, A. A., Old, L. J., & Chen., Y. (2002) · Immunological Reviews · doi:10.1034/j.1600-065x.2002.18803.x · Cited by 875 · see citing works
Regulatory T cells in cancer immunotherapy
Nishikawa, H., & Sakaguchi, S. (2014) · Current Opinion in Immunology · doi:10.1016/j.coi.2013.12.005 · Cited by 702 · see citing works
Sugiyama, D., Nishikawa, H., Maeda, Y., Nishioka, M., Tanemura, A., Katayama, I., Ezoe, S., Kanakura, Y., Sato, E., Fukumori, Y., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1316796110 · Cited by 629 · see citing works
Immune Modulation in Cancer with Antibodies
Page, D. B., Postow, M. A., Callahan, M. K., Allison, J. P., & Wolchok, J. D. (2013) · Annual Review of Medicine · doi:10.1146/annurev-med-092012-112807 · Cited by 516 · see citing works
Stable inhibitory activity of regulatory T cells requires the transcription factor Helios
Kim, H.-J., Barnitz, R. A., Kreslavsky, T., Brown, F. D., Moffett, H., Lemieux, M. E., Kaygusuz, Y., Meissner, T., Holderried, T. A. W., Chan, S., et al. (2015) · Science · doi:10.1126/science.aad0616 · Cited by 441 · see citing works
Self-citationHomeostatic control of regulatory T cell diversity
Liston, A., & Gray, D. H. D. (2014) · Nature reviews. Immunology · doi:10.1038/nri3605 · Cited by 428 · see citing works
Control of the Inheritance of Regulatory T Cell Identity by a cis Element in the Foxp3 Locus
Feng, Y., Arvey, A., Chinen, T., van der Veeken, J., Gasteiger, G., & Rudensky, A. Y. (2014) · Cell · doi:10.1016/j.cell.2014.07.031 · Cited by 422 · see citing works
Control of Immune Responses by Antigen-Specific Regulatory T Cells Expressing the Folate Receptor
Yamaguchi, T., Hirota, K., Nagahama, K., Ohkawa, K., Takahashi, T., Nomura, T., & Sakaguchi, S. (2007) · Immunity · doi:10.1016/j.immuni.2007.04.017 · Cited by 359 · see citing works
Aire-Dependent Thymic Development of Tumor-Associated Regulatory T Cells
Malchow, S., Leventhal, D. S., Nishi, S., Fischer, B. I., Shen, L., Paner, G. P., Amit, A. S., Kang, C., Geddes, J., Allison, J. P., et al. (2013) · Science · doi:10.1126/science.1233913 · Cited by 329 · see citing works
TIM3+FOXP3+regulatory T cells are tissue-specific promoters of T-cell dysfunction in cancer
Sakuishi, K., Ngiow, S. F., Sullivan, J. M., Teng, M. W. L., Kuchroo, V. K., Smyth, M. J., & Anderson, A. C. (2013) · OncoImmunology · doi:10.4161/onci.23849 · Cited by 329 · see citing works
Helios Controls a Limited Subset of Regulatory T Cell Functions
Sebastian, M., Lopez-Ocasio, M., Metidji, A., Rieder, S. A., Shevach, E. M., & Thornton, A. M. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1501704 · Cited by 172 · see citing works
Schaer, D., Budhu, S., Liu, C., Bryson, C. F., Malandro, N., Cohen, A. D., Zhong, H., Yang, X., Houghton, A. N., Merghoub, T., et al. (2013) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-13-0086 · Cited by 160 · see citing works
Hirschhorn-Cymerman, D., Budhu, S., Kitano, S., Liu, C., Zhao, F., Zhong, H., Lesokhin, A. M., Avogadri-Connors, F., Yuan, J. D., Li, Y., et al. (2012) · The Journal of Experimental Medicine · doi:10.1084/jem.20120532 · Cited by 157 · see citing works
GITR subverts Foxp3+ Tregs to boost Th9 immunity through regulation of histone acetylation
Xiao, X., Shi, X., Fan, Y., Zhang, X., Wu, M., Lan, P., Minze, L. J., Fu, Y., Ghobrial, R. M., Liu, W., et al. (2015) · Nature Communications · doi:10.1038/ncomms9266 · Cited by 113 · see citing works
Helios Deficiency Has Minimal Impact on T Cell Development and function
Cai, Q., Dierich, A., Oulad‐Abdelghani, M., Chan, S. H., & Kastner, P. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0901407 · Cited by 79 · see citing works
Malandro, N., Budhu, S., Kuhn, N. F., Liu, C., Murphy, J. T., Cortez, C. A., Zhong, H., Yang, X., Rizzuto, G. A., Altan-Bonnet, G. Y., et al. (2016) · Immunity · doi:10.1016/j.immuni.2015.12.018 · Cited by 55 · see citing works
Anaphylaxis caused by repetitive doses of a GITR agonist monoclonal antibody in mice
Murphy, J. T., Burey, A. P., Beebe, A. M., et al. (2014) · Blood · doi:10.1182/blood-2013-12-544742 · Cited by 32 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Human FOXP3+ Regulatory T Cell Heterogeneity and Function in Autoimmunity and Cancer
Wing, J. B., Tanaka, A., & Sakaguchi, S. (2019) · Immunity · doi:10.1016/j.immuni.2019.01.020 · Cited by 726 · see citing works
T cell‐targeting nanoparticles focus delivery of immunotherapy to improve antitumor immunity
Schmid, D., Park, C. G., Hartl, C. A., Subedi, N., Cartwright, A. N., Puerto, R. B., Zheng, Y., Maiarana, J., Freeman, G. J., Wucherpfennig, K. W., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01830-8 · Cited by 449 · see citing works
Targeting EZH2 Reprograms Intratumoral Regulatory T Cells to Enhance Cancer Immunity
Wang, D., Quiros, J., Mahuron, K., Pai, C.-C., Ranzani, V., Young, A., Silveria, S., Harwin, T., Abnousian, A., Pagani, M., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.05.050 · Cited by 318 · see citing works
NF-κB c-Rel Is Crucial for the Regulatory T Cell Immune Checkpoint in Cancer
Grinberg-Bleyer, Y., Oh, H., Desrichard, A., Bhatt, D. M., Caron, R., Chan, T. A., Schmid, R. M., Klein, U., Hayden, M. S., & Ghosh, S. (2017) · Cell · doi:10.1016/j.cell.2017.08.004 · Cited by 297 · see citing works
Chasing molecular glue degraders: screening approaches
Domostegui, A., Nieto-Barrado, L., Perez-Lopez, C., & Mayor-Ruiz, C. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00197g · Cited by 200 · see citing works
Discovery and characterization of a selective IKZF2 glue degrader for cancer immunotherapy
Bonazzi, S., d’Hennezel, E., Beckwith, R. E. J., Xu, L., Fazal, A., Magracheva, A., Ramesh, R., Cernijenko, A., Antonakos, B., Bhang, H.-E. C., et al. (2023) · Cell Chemical Biology · doi:10.1016/j.chembiol.2023.02.005 · Cited by 167 · see citing works
Acute pharmacological degradation of Helios destabilizes regulatory T cells
Wang, E. S., Verano, A. L., Nowak, R. P., Yuan, J. C., Donovan, K. A., Eleuteri, N. A., Yue, H., Ngo, K. H., Lizotte, P. H., Gokhale, P. C., et al. (2021) · Nature Chemical Biology · doi:10.1038/s41589-021-00802-w · Cited by 124 · see citing works
Treg Fragility: A Prerequisite for Effective Antitumor Immunity?
Overacre-Delgoffe, A. E., & Vignali, D. A. A. (2018) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-18-0066 · Cited by 102 · see citing works
Helios: still behind the clouds
Thornton, A. M., & Shevach, E. M. (2019) · Immunology · doi:10.1111/imm.13115 · Cited by 101 · see citing works
Yates, K., Bi, K., Haining, W. N., Cantor, H., & Kim, H.-J. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1720447115 · Cited by 55 · see citing works
Self-citationFrom serendipity to strategy: molecular glue degraders in cancer therapeutics
Darling, S., Bajrami, I., & West, S. C. (2025) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2025.2564068 · Cited by 10 · see citing works
“…can shift tRegs toward a pro-inflammatory state such they secrete il-2 and iFN-γ and behave like tumor-fighting teff-like cells (Kim et al. 2015; Nakagawa et al. 2016). iKZF2 has therefore been linked to t cell exhaustion, a state marked by reduced proliferation, decreased cytokine production…”
- Authors
- Nakagawa, H., Sido, J. M., Reyes, E. E., Kiers, V., Cantor, H., & Kim, H.-J.
- Affiliations
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2016-05-16
- Volume
- 113
- Issue
- 22
- Pages
- 6248-6253
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4896716
- OpenAlex
- W2401985889
- Cited by
- 176
- References
- 25
- Citations by year
- 2026: 13 · 2025: 18 · 2024: 18 · 2023: 11 · 2022: 18 · 2021: 24 · 2020: 20 · 2019: 21 · 2018: 18 · 2017: 8 · 2016: 7
- FWCI
- 10.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | National Institutes of Health (RO1AI037562)
- The LeRoy Schecter Research Foundation (n/a)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- Helios, regulatory T cells, antitumor immunity, tumor microenvironment, Foxp3, inflammatory cytokines, CD4+ T cells, cancer immunotherapy
- MeSH terms
- Animals, DNA-Binding Proteins, T-Lymphocytes, Helper-Inducer, Melanoma, Experimental, Receptors, Antigen, T-Cell, Transcription Factors, T-Lymphocyte Subsets, Lymphocytes, Tumor-Infiltrating, Mice, Knockout, T-Lymphocytes, Regulatory, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
