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NF-κB c-Rel Is Crucial for the Regulatory T Cell Immune Checkpoint in Cancer
Open accessAbstract
Regulatory T cells (Tregs) play a pivotal role in the inhibition of anti-tumor immune responses. Understanding the mechanisms governing Treg homeostasis may therefore be important for development of effective tumor immunotherapy. We have recently demonstrated a key role for the canonical nuclear factor κB (NF-κB) subunits, p65 and c-Rel, in Treg identity and function. In this report, we show that NF-κB c-Rel ablation specifically impairs the generation and maintenance of the activated Treg (aTreg) subset, which is known to be enriched at sites of tumors. Using mouse models, we demonstrate that melanoma growth is drastically reduced in mice lacking c-Rel, but not p65, in Tregs. Moreover, chemical inhibition of c-Rel function delayed melanoma growth by impairing aTreg-mediated immunosuppression and potentiated the effects of anti-PD-1 immunotherapy. Our studies therefore establish inhibition of NF-κB c-Rel as a viable therapeutic approach for enhancing checkpoint-targeting immunotherapy protocols.
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“Among the RECs, the aTregs subset displayed elevated activity of the regulons corresponding to Foxp3, nuclear factor κB (NF-κB) TF family (Nfkb1, Nfkb2, Rel, and Relb), Irf4, and Maf, which were previously associated with activation phenotype of Tregs [Fig. 5B; (46, 47)].”
From Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes (2019) · cites this paper as [47]
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Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625
Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential
Sharma, P., & Allison, J. P. (2015) · Cell · doi:10.1016/j.cell.2015.03.030 · Cited by 2,345
The PD‐1 pathway in tolerance and autoimmunity
Francisco, L. M., Sage, P. T., & Sharpe, A. H. (2010) · Immunological Reviews · doi:10.1111/j.1600-065x.2010.00923.x · Cited by 2,300
Miyara, M., Yoshioka, Y., Kitoh, A., Shima, T., Wing, K., Niwa, A., Parizot, C., Taflin, C., Heike, T., Valeyre, D., et al. (2009) · Immunity · doi:10.1016/j.immuni.2009.03.019 · Cited by 2,291
Crosstalk in NF-κB Signaling Pathways
Oeckinghaus, A., Hayden, M. S., & Ghosh, S. (2011) · Nature Immunology · doi:10.1038/ni.2065 · Cited by 1,942
Self-citationCurran, M. A., Montalvo, W., Yagita, H., & Allison, J. P. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0915174107 · Cited by 1,874
Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-κB
Beg, A. A., Sha, W. C., Bronson, R. T., Ghosh, S., & Baltimore, D. (1995) · Nature · doi:10.1038/376167a0 · Cited by 1,828
Self-citationNF‐κB and the link between inflammation and cancer
DiDonato, J. A., Mercurio, F., & Karin, M. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01099.x · Cited by 1,513
The Foxp3+ regulatory T cell: a jack of all trades, master of regulation
Tang, Q., & Bluestone, J. A. (2008) · Nature Immunology · doi:10.1038/ni1572 · Cited by 1,045
Regulatory T cells in tumor immunity
Nishikawa, H., & Sakaguchi, S. (2010) · International Journal of Cancer · doi:10.1002/ijc.25429 · Cited by 944
Köntgen, F., Grumont, R. J., Strasser, A., Metcalf, D., Li, R., Tarlinton, D. M., & Gerondakis, S. (1995) · Genes & Development · doi:10.1101/gad.9.16.1965 · Cited by 727
Bertrand, A., Kostine, M., Barnetche, T., Truchetet, M.-E., & Schaeverbeke, T. (2015) · BMC Medicine · doi:10.1186/s12916-015-0455-8 · Cited by 704
De Simone, M., Arrigoni, A., Rossetti, G., Gruarin, P., Ranzani, V., Politano, C., Bonnal, R. J. P., Provasi, E., Sarnicola, M. L., Panzeri, I., et al. (2016) · Immunity · doi:10.1016/j.immuni.2016.10.021 · Cited by 687
Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth
Kleffel, S., Posch, C., Barthel, S. R., Mueller, H., Schlapbach, C., Guenova, E., Elco, C. P., Lee, N., Juneja, V. R., Zhan, Q., et al. (2015) · Cell · doi:10.1016/j.cell.2015.08.052 · Cited by 672
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 638
Huehn, J., Siegmund, K., Lehmann, J., Siewert, C., Haubold, U., Feuerer, M., Debes, G. F., Lauber, J., Frey, O., Przybylski, G. K., et al. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20031562 · Cited by 624
Greten, F. R., Arkan, M. C., Bollrath, J., Hsu, L.-C., Goode, J., Miething, C., Göktuna, S. I., Neuenhahn, M., Fierer, J., Paxian, S., et al. (2007) · Cell · doi:10.1016/j.cell.2007.07.009 · Cited by 616
Self-citationContinuous requirement for the TCR in regulatory T cell function
Levine, A. G., Arvey, A. J., Jin, W., & Rudensky, A. Y. (2014) · Nature Immunology · doi:10.1038/ni.3004 · Cited by 536
Foxp3 Exploits a Pre-Existent Enhancer Landscape for Regulatory T Cell Lineage Specification
Samstein, R. M., Arvey, A., Josefowicz, S. Z., Peng, X., Reynolds, A., Sandstrom, R., Neph, S., Sabo, P., Kim, J. M., Liao, W., et al. (2012) · Cell · doi:10.1016/j.cell.2012.06.053 · Cited by 472
Novel Foxo1-dependent transcriptional programs control Treg cell function
Ouyang, W., Liao, W., Luo, C. T., Yin, N., Huse, M., Kim, M. V., Peng, M., Chan, P., Ma, Q., Mo, Y., et al. (2012) · Nature · doi:10.1038/nature11581 · Cited by 430
Mulligan, G., Mitsiades, C. S., Bryant, B. M., Zhan, F., Chng, W. J., Roels, S. M., Koenig, E. M., Fergus, A., Huang, Y., Richardson, P. G. G., et al. (2006) · Blood · doi:10.1182/blood-2006-09-044974 · Cited by 418
Development of Foxp3+ Regulatory T Cells Is Driven by the c-Rel Enhanceosome
Ruan, Q., Kameswaran, V., Tone, Y., Li, L., Liou, H., Greene, M. I., Tone, M., & Chen, Y. H. (2009) · Immunity · doi:10.1016/j.immuni.2009.10.006 · Cited by 397
Long, M., Park, S., Strickland, I., Hayden, M. S., & Ghosh, S. (2009) · Immunity · doi:10.1016/j.immuni.2009.09.022 · Cited by 392
Self-citationNF-κB and IKK as therapeutic targets in cancer
Kim, H. J., Hawke, N. A., & Baldwin, A. S. (2006) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401877 · Cited by 390
Continuous T Cell Receptor Signals Maintain a Functional Regulatory T Cell Pool
Vahl, J. C., Drees, C., Heger, K., Heink, S., Fischer, J. C., Nedjic, J., Ohkura, N., Morikawa, H., Poeck, H., Schallenberg, S., et al. (2014) · Immunity · doi:10.1016/j.immuni.2014.10.012 · Cited by 330
Godec, J., Tan, Y. Q., Liberzon, A., Tamayo, P., Bhattacharya, S., Butte, A. J., Mesirov, J. P., & Haining, W. N. (2016) · Immunity · doi:10.1016/j.immuni.2015.12.006 · Cited by 295
Chen, S., Lee, L., Fisher, T. S., Jessen, B. A., Elliott, M., Evering, W., Logronio, K. A., Tu, G. H., Tsaparikos, K. E., Li, X., et al. (2014) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-14-0118 · Cited by 287
Response to self antigen imprints regulatory memory in tissues
Rosenblum, M. D., Gratz, I. K., Paw, J. S., Lee, K., Marshak‐Rothstein, A., & Abbas, A. K. (2011) · Nature · doi:10.1038/nature10664 · Cited by 281
c-Rel is required for the development of thymic Foxp3+ CD4 regulatory T cells
Isomura, I., Palmer, S. E., Grumont, R. J., Bunting, K., Hoyne, G. F., Wilkinson, N., Banerjee, A., Proietto, A. I., Gugasyan, R., Wu, L., et al. (2009) · The Journal of Experimental Medicine · doi:10.1084/jem.20091411 · Cited by 269
Oh, H.-J., Grinberg‐Bleyer, Y., Liao, W., Maloney, D., Wang, P., Wu, Z., Wang, J., Bhatt, D. M., Heise, N., Schmid, R. M., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.08.010 · Cited by 233
Self-citationHeise, N., Silva, N. S. D., Silva, K., Carette, A., Simonetti, G., Pasparakis, M., & Klein, U. (2014) · The Journal of Experimental Medicine · doi:10.1084/jem.20132613 · Cited by 220
Self-citationAlgül, H., Treiber, M., Lesina, M., Nakhai, H., Saur, D., Geisler, F., Pfeifer, A., Paxian, S. A., & Schmid, R. (2007) · Journal of Clinical Investigation · doi:10.1172/jci29882 · Cited by 194
Self-citationGraded Foxo1 activity in Treg cells differentiates tumour immunity from spontaneous autoimmunity
Luo, C. T., Liao, W., Dadi, S., Toure, A., & Li, M. O. (2016) · Nature · doi:10.1038/nature16486 · Cited by 193
Foxp3+ T Cells Induce Perforin-Dependent Dendritic Cell Death in Tumor-Draining Lymph Nodes
Boissonnas, A., Scholer‐Dahirel, A., Simon-Blancal, V., Pace, L., Valet, F., Kissenpfennig, A., Sparwasser, T. D., MALISSEN, B., Fetler, L., & Amigorena, S. (2010) · Immunity · doi:10.1016/j.immuni.2009.11.015 · Cited by 184
Nakagawa, H., Sido, J. M., Reyes, E. E., Kiers, V., Cantor, H., & Kim, H.-J. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1604765113 · Cited by 176
Darrasse-Jèze, G., Bergot, A., Durgeau, A., Billiard, F., Salomon, B. L., Cohen, J. L., Bellier, B., Podsypanina, K., & Klatzmann, D. (2009) · Journal of Clinical Investigation · doi:10.1172/jci36628 · Cited by 156
T Cell Surveillance of Oncogene-Induced Prostate Cancer Is Impeded by T Cell-Derived TGF-β1 Cytokine
Donkor, M. K., Sarkar, A., Savage, P. A., Franklin, R. A., Johnson, L. K., Jungbluth, A. A., Allison, J. P., & Li, M. O. (2011) · Immunity · doi:10.1016/j.immuni.2011.04.019 · Cited by 130
Jiménez, J. L., Punzón, C., Navarro, J., Muñoz‐Fernández, M. Á., & Fresno, M. (2001) · PubMed · Cited by 115
Dias, S., D’Amico, A., Cretney, E., Liao, Y., Tellier, J., Bruggeman, C. W., Almeida, F. F., Leahy, J., Belz, G. T., Smyth, G. K., et al. (2017) · Immunity · doi:10.1016/j.immuni.2016.12.017 · Cited by 109
c-Rel Is a Target of Pentoxifylline-Mediated Inhibition of T Lymphocyte Activation
Wang, W., Tam, W. F., Hughes, C. C. W., Rath, S., & Sen, R. (1997) · Immunity · doi:10.1016/s1074-7613(00)80423-9 · Cited by 84
Jandus, C., Bioley, G., Speiser, D. E., & Romero, P. J. (2008) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-008-0507-4 · Cited by 75
Fingert, H. J., Pu, A. T., Chen, Z. Y., Googe, P. B., Alley, M. C., & Pardee, A. B. (1988) · PubMed · Cited by 70
Jiménez, J. L., Punzón, C., Navarro, J., Muñoz‐Fernández, M. Á., & Fresno, M. (2001) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)29287-9 · Cited by 68
Shono, Y., Tuckett, A. Z., Ouk, S., Liou, H., Altan-Bonnet, G. Y., Tsai, J. J.-Y., Oyler, J. E., Smith, O. M., West, M. L., Singer, N. V., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0585 · Cited by 59
Pinzani, M., Marra, F., Caligiuri, A., DeFranco, R., Gentilini, A., Failli, P., & Geñtilini, P. (1996) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.1996.tb16012.x · Cited by 55
Messina, N. L., Fulford, T. S., O’Reilly, L. A., Loh, W. X., Motyer, J. M., Ellis, D., McLean, C., Naeem, H., Lin, A. E.-J., Gugasyan, R., et al. (2016) · Journal of Autoimmunity · doi:10.1016/j.jaut.2016.03.017 · Cited by 53
Pentoxifylline inhibits melanoma tumor growth and angiogenesis by targeting STAT3 signaling pathway
Kamran, M. Z., & Gude, R. P. (2013) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2013.03.020 · Cited by 50
c-Rel Regulates Ezh2 Expression in Activated Lymphocytes and Malignant Lymphoid Cells
Neo, W. H., Lim, J. F., Grumont, R. J., Gerondakis, S., & Su, I.-H. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.574517 · Cited by 42
Bravo‐Cuéllar, A., Hernández‐Flores, G., Lerma-Díaz, J. M., Domínguez-Rodríguez, J. R., Jave‐Suárez, L. F., Célis, R. D., Aguilar‐Lemarroy, A., Gómez-Lomelí, P., & Ortiz‐Lazareno, P. C. (2013) · Journal of Biomedical Science · doi:10.1186/1423-0127-20-13 · Cited by 37
Increased Survival From Stage IV Melanoma Associated With Fewer Regulatory T Cells
Baumgartner, J. M., Gonzalez, R. C., Lewis, K. D., Robinson, W. A., Richter, D. A., Palmer, B. E., Wilson, C. C., & McCarter, M. D. (2008) · Journal of Surgical Research · doi:10.1016/j.jss.2008.04.043 · Cited by 32
Ratheesh, A., Ingle, A., & Gude, R. P. (2007) · Cancer Biology & Therapy · doi:10.4161/cbt.6.11.4833 · Cited by 26
Suramin augments the antitumor and antimetastatic activity of pentoxifylline in B16F10 melanoma
Dua, P., Ingle, A., & Gude, R. P. (2007) · International Journal of Cancer · doi:10.1002/ijc.22843 · Cited by 26
Radhakrishnan, S., Vig, M., Bhatia, S., Goodspeed, E. P. B., John, B., Kandpal, U., Srivastava, S., George, A., Sen, R., Bal, V., et al. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.8.4262 · Cited by 24
Regulatory T cells in the immunotherapy of melanoma
Ouyang, Z., Wu, H., Li, L., Luo, Y., Li, X., & Huang, G. (2015) · Tumor Biology · doi:10.1007/s13277-015-4315-0 · Cited by 22
Deree, J., Melbostad, H. S., Loomis, W. H., Putnam, J. G., & Coimbra, R. S. M. (2007) · Surgery · doi:10.1016/j.surg.2007.04.008 · Cited by 14
Edward, M., & MacKie, R. M. (1991) · International Journal of Cancer · doi:10.1002/ijc.2910490514 · Cited by 5
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Metadata
- Authors
- 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.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Columbia University (US)
- TUM Klinikum (DE)
- Herbert Irving Comprehensive Cancer Center (US)
- Dartmouth–Hitchcock Medical Center (US)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Ghosh, Sankar
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 170
- Issue
- 6
- Pages
- 1096-1108.e13
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5633372
- OpenAlex
- W2739636520
- Cited by
- 297
- References
- 56
- Citations by year
- 2026: 13 · 2025: 25 · 2024: 35 · 2023: 29 · 2022: 34 · 2021: 35 · 2020: 49 · 2019: 41 · 2018: 30 · 2017: 6
- FWCI
- 15.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Funders
- Cancer Research Institute
- NIH (R01-AI068977)
- Herbert Irving Cancer Center at Columbia University
- Columbia University
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- c-Rel, NF-κB, regulatory T cells, tumor immune checkpoint, melanoma, anti-PD-1 therapy, immunosuppression, cancer immunotherapy, NF-κB p65
- MeSH terms
- Animals, Disease Models, Animal, Female, Immunotherapy, Male, Melanoma, Mice, Inbred C57BL, NF-kappa B, Mice, Knockout, Proto-Oncogene Proteins c-rel, T-Lymphocytes, Regulatory, Mice
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