Overproduction of IL-2 by Cbl-b deficient CD4⁺ T cells provides resistance against regulatory T cells

References

• Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133(5):775–15. doi:10.1016/j.cell.2008.05.009.
   PubMed Web of Science ®Google Scholar
• Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol. 2010;10(7):490–500. doi:10.1038/nri2785.
   PubMed Web of Science ®Google Scholar
• Lyon MF, Peters J, Glenister PH, Ball S, Wright E. The scurfy mouse mutant has previously unrecognized hematological abnormalities and resembles Wiskott-Aldrich syndrome. Proc Natl Acad Sci U S A. 1990;87:2433–2437.
   PubMed Web of Science ®Google Scholar
• Clark LB, Appleby MW, Brunkow ME, Wilkinson JE, Ziegler SF, Ramsdell F. Cellular and molecular characterization of the scurfy mouse mutant. J Immunol. 1999;162:2546–2554.
   PubMed Web of Science ®Google Scholar
• Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001;27(1):20–21. doi:10.1038/83713.
   PubMed Web of Science ®Google Scholar
• Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko S-A, Wilkinson JE, Galas D, Ziegler SF, Ramsdell F. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet. 2001;27(1):68–73. doi:10.1038/83784.
   PubMed Web of Science ®Google Scholar
• Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova J-L, Buist N, Levy-Lahad E, Mazzella M, Goulet O, Perroni L, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet. 2001;27(1):18–20. doi:10.1038/83707.
   PubMed Web of Science ®Google Scholar
• Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E. Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res. 1999;59:3128–3133.
   PubMed Web of Science ®Google Scholar
• Shimizu J, Yamazaki S, Sakaguchi S. Induction of Tumor Immunity by Removing CD25+CD4+ T Cells: A Common Basis Between Tumor Immunity and Autoimmunity. J Immunol. 1999;163:5211–5218.
   PubMed Web of Science ®Google Scholar
• Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10(9):942–949. doi:10.1038/nm1093.
   PubMed Web of Science ®Google Scholar
• Klages K, Mayer CT, Lahl K, Loddenkemper C, Teng MWL, Ngiow SF, Smyth MJ, Hamann A, Huehn J, Sparwasser T. Selective Depletion of Foxp3+ Regulatory T Cells Improves Effective Therapeutic Vaccination against Established Melanoma. Cancer Res. 2010;70(20):7788–7799. doi:10.1158/0008-5472.CAN-10-1736.
   PubMed Web of Science ®Google Scholar
• Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int J Cancer. 2010;127(4):759–767. doi:10.1002/ijc.25429.
   PubMed Web of Science ®Google Scholar
• Arce Vargas F, Furness AJS, Solomon I, Joshi K, Mekkaoui L, Lesko MH, Miranda Rota E, Dahan R, Georgiou A, Sledzinska A, et al. Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors. Immunity. 2017;46(4):577–586. doi:10.1016/j.immuni.2017.03.013.
   PubMed Web of Science ®Google Scholar
• Josefowicz SZ, Lu L-F, Rudensky AY. Regulatory T Cells: mechanisms of Differentiation and Function. Annu Rev Immunol. 2012;30(1):531–564. doi:10.1146/annurev.immunol.25.022106.141623.
   PubMed Web of Science ®Google Scholar
• Han S, Toker A, Liu ZQ, Ohashi PS. Turning the Tide Against Regulatory T Cells. Front Oncol. 2019;9:279. doi:10.3389/fonc.2019.00279.
   PubMed Web of Science ®Google Scholar
• Pasare C. Toll Pathway-Dependent Blockade of CD4+CD25+ T Cell-Mediated Suppression by Dendritic Cells. Science. 2003;299(5609):1033–1036. doi:10.1126/science.1078231.
   PubMed Web of Science ®Google Scholar
• Ji H, Liao G, Faubion WA, Abadía-Molina AC, Cozzo C, Laroux FS, Caton A, Terhorst C. Cutting edge: the natural ligand for glucocorticoid-induced TNF receptor-related protein abrogates regulatory T cell suppression. J Immunol. 2004;172(10):5823–5827. doi:10.4049/JIMMUNOL.172.10.5823.
   PubMed Web of Science ®Google Scholar
• Stephens GL, McHugh RS, Whitters MJ, Young DA, Luxenberg D, Carreno BM, Collins M, Shevach EM. Engagement of glucocorticoid-induced TNFR family-related receptor on effector T cells by its ligand mediates resistance to suppression by CD4+CD25+ T cells. J Immunol. 2004;173(8):5008–5020. doi:10.4049/jimmunol.173.8.5008.
   PubMed Web of Science ®Google Scholar
• Ruprecht CR, Gattorno M, Ferlito F, Gregorio A, Martini A, Lanzavecchia A, Sallusto F. Coexpression of CD25 and CD27 identifies FoxP3+ regulatory T cells in inflamed synovia. J Exp. 2005;201(11):1793–1803. doi:10.1084/jem.20050085.
   PubMed Web of Science ®Google Scholar
• O’Sullivan BJ, Thomas HE, Pai S, Santamaria P, Iwakura Y, Steptoe RJ, Kay TWH, Thomas R. IL-1β Breaks Tolerance through Expansion of CD25 + Effector T Cells. J Immunol. 2006;176(12):7278–7287. doi:10.4049/JIMMUNOL.176.12.7278.
   PubMed Web of Science ®Google Scholar
• Pace L, Rizzo S, Palombi C, Brombacher F, Doria G. Cutting Edge: IL-4-Induced Protection of CD4+CD25 Th Cells from CD4+CD25+Regulatory T Cell-Mediated Suppression. J Immunol. 2006;176(7):3900–3904. doi:10.4049/JIMMUNOL.176.7.3900.
   PubMed Web of Science ®Google Scholar
• Peluso I, Fantini MC, Fina D, Caruso R, Boirivant M, MacDonald TT, Pallone F, Monteleone G. IL-21 counteracts the regulatory T cell-mediated suppression of human CD4+ T lymphocytes. J Immunol. 2007;178(2):732–739. doi:10.4049/JIMMUNOL.178.2.732.
   PubMed Web of Science ®Google Scholar
• Wan S, Xia C, Morel L. IL-6 produced by dendritic cells from lupus-prone mice inhibits CD4+CD25+ T cell regulatory functions. J Immunol. 2007;178(1):271–279. doi:10.4049/jimmunol.178.1.271.
   PubMed Web of Science ®Google Scholar
• Ben Ahmed M, Belhadj Hmida N, Moes N, Buyse S, Abdeladhim M, Louzir H, Cerf-Bensussan N. IL-15 renders conventional lymphocytes resistant to suppressive functions of regulatory T cells through activation of the phosphatidylinositol 3-kinase pathway. J Immunol. 2009;182(11):6763–6770. doi:10.4049/jimmunol.0801792.
   PubMed Web of Science ®Google Scholar
• Chen X, Das R, Komorowski R, Beres A, Hessner MJ, Mihara M, Drobyski WR. Blockade of interleukin-6 signaling augments regulatory T-cell reconstitution and attenuates the severity of graft-versus-host disease. Blood. 2009;114(4):891–900. doi:10.1182/blood-2009-01-197178.
   PubMed Web of Science ®Google Scholar
• Wohlfert EA, Clark RB. ‘Vive la Résistance!’ – the PI3K–Akt pathway can determine target sensitivity to regulatory T cell suppression. Trends Immunol. 2007;28(4):154–160. doi:10.1016/j.it.2007.02.003.
   PubMed Web of Science ®Google Scholar
• Mercadante ER, Lorenz UM. Breaking free of control: how conventional T cells overcome regulatory T cell suppression. Front Immunol. 2016;193(7):1–16. doi:10.3389/fimmu.2016.00193.
   PubMed Web of Science ®Google Scholar
• Wohlfert EA, Callahan MK, Clark RB. Resistance to CD4+CD25+ regulatory T cells and TGF-beta in Cbl-b-/- mice. J Immunol. 2004;173(2):1059–1065. doi:10.4049/jimmunol.173.2.1059.
   PubMed Web of Science ®Google Scholar
• King CG, Kobayashi T, Cejas PJ, Kim T, Yoon K, Kim GK, Chiffoleau E, Hickman SP, Walsh PT, Turka LA, et al. TRAF6 is a T cell–intrinsic negative regulator required for the maintenance of immune homeostasis. Nat Med. 2006;12(9):1088–1092. doi:10.1038/nm1449.
   PubMed Web of Science ®Google Scholar
• Wohlfert EA, Gorelik L, Mittler R, Flavell RA, Clark RB. Cutting edge: deficiency in the E3 Ubiquitin Ligase Cbl-b results in a multifunctional defect in T cell TGF-beta sensitivity In Vitro and In Vivo. J Immunol. 2006;176(3):1316–1320. doi:10.4049/jimmunol.176.3.1316.
   PubMed Web of Science ®Google Scholar
• Chang M, Lee AJ, Fitzpatrick L, Zhang M, Sun S-C. NF- B1 p105 regulates T cell homeostasis and prevents chronic inflammation. J Immunol. 2009;182(5):3131–3138. doi:10.4049/jimmunol.0803637.
   PubMed Web of Science ®Google Scholar
• Stahl HF, Fauti T, Ullrich N, Bopp T, Kubach J, Rust W, Labhart P, Alexiadis V, Becker C, Hafner M, et al. miR-155 inhibition sensitizes CD4+ Th cells for TREG mediated suppression Unutmaz D, editor. PLoS One. 2009;4(9):e7158. doi:10.1371/journal.pone.0007158.
   PubMed Web of Science ®Google Scholar
• Adams CO, Housley WJ, Bhowmick S, Cone RE, Rajan TV, Forouhar F, Clark RB. Cbl-b(-/-) T cells demonstrate in vivo resistance to regulatory T cells but a context-dependent resistance to TGF-beta. J Immunol. 2010;185(4):2051–2058. doi:10.4049/jimmunol.1001171.
   PubMed Web of Science ®Google Scholar
• Schenten D, Nish SA, Yu S, Yan X, Lee HK, Brodsky I, Pasman L, Yordy B, Wunderlich FT, Brüning JC, et al. Signaling through the adaptor molecule MyD88 in CD4+ T cells is required to overcome suppression by regulatory T cells. Immunity. 2014;40(1):78–90. doi:10.1016/j.immuni.2013.10.023.
   PubMed Web of Science ®Google Scholar
• Mercadante ER, Lorenz UM. T cells deficient in the tyrosine phosphatase SHP-1 resist suppression by regulatory T cells. J Immunol. 2017;199(1):129–137. doi:10.4049/jimmunol.1602171.
   PubMed Web of Science ®Google Scholar
• Liu Y-C. Ubiquitin ligases and the immune response. Annu Rev Immunol. 2004;22(1):81–127. doi:10.1146/annurev.immunol.22.012703.104813.
   PubMedGoogle Scholar
• Paolino M, Penninger JM. Cbl-b in T-cell activation. Semin Immunopathol. 2010;32(2):137–148. doi:10.1007/s00281-010-0197-9.
   PubMed Web of Science ®Google Scholar
• Bachmaier K, Krawczyk C, Kozieradzki I, Kong -Y-Y, Sasaki T, Oliveira-dos-santos A, Mariathasan S, Bouchard D, Wakeham A, Itie A, et al. Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature. 2000;403(6766):211–216. doi:10.1038/35003228.
   PubMed Web of Science ®Google Scholar
• Nakao A, Afrakhte M, Morn A, Nakayama T, Christian JL, Heuchel R, Itoh S, Kawabata M, Heldin N-E, Heldin C-H, et al. Identification of Smad7, a TGFβ-inducible antagonist of TGF-β signalling. Nature. 1997;389(6651):631–635. doi:10.1038/39369.
   PubMed Web of Science ®Google Scholar
• Gruber T, Hinterleitner R, Hermann-Kleiter N, Meisel M, Kleiter I, Wang CM, Viola A, Pfeifhofer-Obermair C, Baier G. Cbl-b mediates TGFβ sensitivity by downregulating inhibitory SMAD7 in primary T cells. J Mol Cell Biol. 2013;5(6):358–368. doi:10.1093/jmcb/mjt017.
   PubMed Web of Science ®Google Scholar
• Fantini MC, Rizzo A, Fina D, Caruso R, Sarra M, Stolfi C, Becker C, MacDonald TT, Pallone F, Neurath MF, et al. Smad7 controls resistance of colitogenic T cells to regulatory T cell-mediated suppression. Gastroenterology. 2009;136(4):1308–1316.e3. doi:10.1053/j.gastro.2008.12.053.
   PubMed Web of Science ®Google Scholar
• Oderup C, Cederbom L, Makowska A, Cilio CM, Ivars F. Cytotoxic T lymphocyte antigen-4-dependent down-modulation of costimulatory molecules on dendritic cells in CD4+ CD25+ regulatory T-cell-mediated suppression. Immunology. 2006;118(2):240–249. doi:10.1111/j.1365-2567.2006.02362.x.
   PubMed Web of Science ®Google Scholar
• Onishi Y, Fehervari Z, Yamaguchi T, Sakaguchi S. Foxp3+ natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation. Proc Natl Acad Sci U S A. 2008;105(29):10113–10118. doi:10.1073/pnas.0711106105.
   PubMed Web of Science ®Google Scholar
• Chiang YJ, Kole HK, Brown K, Naramura M, Fukuhara S, Hu R-J, Jang IK, Gutkind JS, Shevach E, Gu H. Cbl-b regulates the CD28 dependence of T-cell activation. Nature. 2000;403(6766):216–220. doi:10.1038/35003235.
   PubMed Web of Science ®Google Scholar
• Jeon M-S, Atfield A, Venuprasad K, Krawczyk C, Sarao R, Elly C, Yang C, Arya S, Bachmaier K, Su L, et al. Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction. Immunity. 2004;21(2):167–177. doi:10.1016/j.immuni.2004.07.013.
   PubMed Web of Science ®Google Scholar
• Chiang JY, Jang IK, Hodes R, Gu H, Boon T, Houghton AN, Gold JS, Blachere NE, Rosenberg SA, Rosenberg SA, et al. Ablation of Cbl-b provides protection against transplanted and spontaneous tumors. J Clin Invest. 2007;117(4):1029–1036. doi:10.1172/JCI29472.
   PubMed Web of Science ®Google Scholar
• Loeser S, Loser K, Bijker MS, Rangachari M, van der Burg SH, Wada T, Beissert S, Melief CJM, Penninger JM. Spontaneous tumor rejection by cbl-b–deficient CD8+ T cells. J Exp Med. 2007;204(4):879–891. doi:10.1084/jem.20061699.
   PubMed Web of Science ®Google Scholar
• McMurchy AN, Levings MK. Suppression assays with human T regulatory cells: A technical guide. Eur J Immunol. 2012;42(1):27–34. doi:10.1002/eji.201141651.
   PubMed Web of Science ®Google Scholar
• Stromnes IM, Blattman JN, Tan X, Jeevanjee S, Gu H, Greenberg PD. Abrogating Cbl-b in effector CD8(+) T cells improves the efficacy of adoptive therapy of leukemia in mice. J Clin Invest. 2010;120(10):3722–3734. doi:10.1172/JCI41991.
   PubMed Web of Science ®Google Scholar
• Pandiyan P, Zheng L, Ishihara S, Reed J, Lenardo MJ. CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation–mediated apoptosis of effector CD4+ T cells. Nat Immunol. 2007;8(12):1353–1362. doi:10.1038/ni1536.
   PubMed Web of Science ®Google Scholar
• McNally A, Hill GR, Sparwasser T, Thomas R, Steptoe RJ. CD4+CD25+ regulatory T cells control CD8+ T-cell effector differentiation by modulating IL-2 homeostasis. Proc Natl Acad Sci U S A. 2011;108(18):7529–7534. doi:10.1073/pnas.1103782108.
   PubMed Web of Science ®Google Scholar
• Chinen T, Kannan AK, Levine AG, Fan X, Klein U, Zheng Y, Gasteiger G, Feng Y, Fontenot JD, Rudensky AY. An essential role for the IL-2 receptor in Treg cell function. Nat Immunol. 2016;17(11):1322–1333. doi:10.1038/ni.3540.
   PubMed Web of Science ®Google Scholar
• Gronski MA, Boulter JM, Moskophidis D, Nguyen LT, Holmberg K, Elford AR, Deenick EK, Kim HO, Penninger JM, Odermatt B, et al. TCR affinity and negative regulation limit autoimmunity. Nat Med. 2004;10(11):1234–1239. doi:10.1038/nm1114.
   PubMed Web of Science ®Google Scholar
• Hémar A, Subtil A, Lieb M, Morelon E, Hellio R, Dautry-Varsat A. Endocytosis of interleukin 2 receptors in human T lymphocytes: distinct intracellular localization and fate of the receptor alpha, beta, and gamma chains. J Cell Biol. 1995;129(1):55–64. doi:10.1083/JCB.129.1.55.
   PubMed Web of Science ®Google Scholar
• Yu A, Malek TR. The proteasome regulates receptor-mediated endocytosis of interleukin-2. J Biol Chem. 2001;276(1):381–385. doi:10.1074/jbc.M007991200.
   PubMed Web of Science ®Google Scholar
• Su EW, Moore CJ, Suriano S, Johnson CB, Songalia N, Patterson A, Neitzke DJ, Andrijauskaite K, Garrett-Mayer E, Mehrotra S, et al. IL-2Rα mediates temporal regulation of IL-2 signaling and enhances immunotherapy. Sci Transl Med. 2015;7(311):1–19. doi:10.1126/scitranslmed.aac8155.
   Web of Science ®Google Scholar
• Goodman WA, Levine AD, Massari JV, Sugiyama H, McCormick TS, Cooper KD. IL-6 signaling in psoriasis prevents immune suppression by regulatory T cells. J Immunol. 2009;183(5):3170–3176. doi:10.4049/jimmunol.0803721.
   PubMed Web of Science ®Google Scholar
• Goodman WA, Young AB, McCormick TS, Cooper KD, Levine AD. Stat3 phosphorylation mediates resistance of primary human T cells to regulatory T cell suppression. J Immunol. 2011;186(6):3336–3345. doi:10.4049/jimmunol.1001455.
   PubMed Web of Science ®Google Scholar
• Schneider A, Long SA, Cerosaletti K, Ni CT, Samuels P, Kita M, Buckner JH. In active relapsing-remitting multiple sclerosis, effector T cell resistance to adaptive T(regs) involves IL-6-mediated signaling. Sci Transl Med. 2013;5(170):1–15. doi:10.1126/scitranslmed.3004970.
   Web of Science ®Google Scholar
• Shifrut E, Carnevale J, Tobin V, Diolaiti ME, Ashworth A, Marson Correspondence A. Genome-wide CRISPR screens in primary human T cells reveal key regulators of immune function. Cell. 2018;175(1958–1971.e15). doi:10.1016/j.cell.2018.10.024.
   PubMedGoogle Scholar
• Thornton AM, Donovan EE, Piccirillo CA, Shevach EM. Cutting edge: IL-2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function. J Immunol. 2004;172(11):6519–6523. doi:10.4049/JIMMUNOL.172.11.6519.
   PubMed Web of Science ®Google Scholar
• Zhang H, Chua KS, Guimond M, Kapoor V, Brown MV, Fleisher TA, Long LM, Bernstein D, Hill BJ, Douek DC, et al. Lymphopenia and interleukin-2 therapy alter homeostasis of CD4+CD25+ regulatory T cells. Nat Med. 2005;11(11):1238–1243. doi:10.1038/nm1312.
   PubMed Web of Science ®Google Scholar
• Zorn E, Nelson EA, Mohseni M, Porcheray F, Kim H, Litsa D, Bellucci R, Raderschall E, Canning C, Soiffer RJ, et al. IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood. 2006;108(5):1571–1579. doi:10.1182/blood-2006-02-004747.
   PubMed Web of Science ®Google Scholar
• Lemoine FM, Cherai M, Giverne C, Dimitri D, Rosenzwajg M, Trebeden-Negre H, Chaput N, Barrou B, Thioun N, Gattegnio B, et al. Massive expansion of regulatory T-cells following interleukin 2 treatment during a phase I-II dendritic cell-based immunotherapy of metastatic renal cancer. Int J Oncol. 2009;35(3):569–581.
   PubMed Web of Science ®Google Scholar
• Antov A, Yang L, Vig M, Baltimore D, Van Parijs L. Essential role for STAT5 signaling in CD25+CD4+ regulatory T cell homeostasis and the maintenance of self-tolerance. J Immunol. 2003;171:3435–3441.
   PubMed Web of Science ®Google Scholar
• Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. J Immunol. 2014;192(12):5451–5458. doi:10.4049/jimmunol.1490019.
   PubMed Web of Science ®Google Scholar
• Rosenberg SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, Seipp CA, Einhorn JH, White DE. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994;271:907–913.
   PubMed Web of Science ®Google Scholar
• Lotze MT, Chang AE, Seipp CA, Simpson C, Vetto JT, Rosenberg SA. High-dose recombinant interleukin 2 in the treatment of patients with disseminated cancer. JAMA. 1986;256(22):3117. doi:10.1001/jama.1986.03380220083027.
   PubMed Web of Science ®Google Scholar
• Spolski R, Li P, Leonard WJ. Biology and regulation of IL-2: from molecular mechanisms to human therapy. Nat Rev Immunol. 2018;18(10):648–659. doi:10.1038/s41577-018-0046-y.
   PubMed Web of Science ®Google Scholar
• Abbas AK, Trotta E, Simeonov DR, Marson A, Bluestone JA. Revisiting IL-2: biology and therapeutic prospects. Sci Immunol. 2018;3(25). doi:10.1126/sciimmunol.aat1482.
   PubMed Web of Science ®Google Scholar
• Klatzmann D, Abbas AK. The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases. Nat Rev Immunol. 2015;15(5):283–294. doi:10.1038/nri3823.
   PubMed Web of Science ®Google Scholar
• Hirakawa M, Matos TR, Liu H, Koreth J, Kim HT, Paul NE, Murase K, Whangbo J, Alho AC, Nikiforow S, et al. Low-dose IL-2 selectively activates subsets of CD4+ Tregs and NK cells. JCI Insight. 2016;1(18):e89278. doi:10.1172/jci.insight.89278.
   PubMed Web of Science ®Google Scholar
• Ahmadzadeh M, Rosenberg SA. IL-2 administration increases CD4+ CD25(hi) Foxp3+ regulatory T cells in cancer patients. Blood. 2006;107(6):2409–2414. doi:10.1182/blood-2005-06-2399.
   PubMed Web of Science ®Google Scholar
• Cesana GC, DeRaffele G, Cohen S, Moroziewicz D, Mitcham J, Stoutenburg J, Cheung K, Hesdorffer C, Kim-Schulze S, Kaufman HL. Characterization of CD4+CD25+ regulatory T cells in patients treated with high-dose interleukin-2 for metastatic melanoma or renal cell carcinoma. J Clin Oncol. 2006;24(7):1169–1177. doi:10.1200/JCO.2005.03.6830.
   PubMed Web of Science ®Google Scholar
• Sim GC, Martin-Orozco N, Jin L, Yang Y, Wu S, Washington E, Sanders D, Lacey C, Wang Y, Vence L, et al. IL-2 therapy promotes suppressive ICOS+ Treg expansion in melanoma patients. J Clin Invest. 2014;124(1):99–110. doi:10.1172/JCI46266.
   PubMed Web of Science ®Google Scholar
• Yao X, Ahmadzadeh M, Lu Y-C, Liewehr DJ, Dudley ME, Liu F, Schrump DS, Steinberg SM, Rosenberg SA, Robbins PF, et al. Levels of peripheral CD4(+)FoxP3(+) regulatory T cells are negatively associated with clinical response to adoptive immunotherapy of human cancer. Blood. 2012;119(24):5688–5696. doi:10.1182/blood-2011-10-386482.
   PubMed Web of Science ®Google Scholar
• Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, Robbins PF, Huang J, Citrin DE, Leitman SF, et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol. 2008;26(32):5233–5239. doi:10.1200/JCO.2008.16.5449.
   PubMed Web of Science ®Google Scholar
• Besser MJ, Shapira-Frommer R, Treves AJ, Zippel D, Itzhaki O, Hershkovitz L, Levy D, Kubi A, Hovav E, Chermoshniuk N, et al. Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients. Clin Cancer Res. 2010;16(9):2646–2655. doi:10.1158/1078-0432.CCR-10-0041.
   PubMed Web of Science ®Google Scholar
• Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, Citrin DE, Restifo NP, Robbins PF, Wunderlich JR, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011;17(13):4550–4557. doi:10.1158/1078-0432.CCR-11-0116.
   PubMed Web of Science ®Google Scholar
• Pilon-Thomas S, Kuhn L, Ellwanger S, Janssen W, Royster E, Marzban S, Kudchadkar R, Zager J, Gibney G, Sondak VK, et al. Efficacy of adoptive cell transfer of tumor-infiltrating lymphocytes after lymphopenia induction for metastatic melanoma. J Immunother. 2012;35(8):615–620. doi:10.1097/CJI.0b013e31826e8f5f.
   PubMed Web of Science ®Google Scholar
• Radvanyi LG, Bernatchez C, Zhang M, Fox PS, Miller P, Chacon J, Wu R, Lizee G, Mahoney S, Alvarado G, et al. Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients. Clin Cancer Res. 2012;18(24):6758–6770. doi:10.1158/1078-0432.CCR-12-1177.
   PubMed Web of Science ®Google Scholar
• Andersen R, Donia M, Ellebaek E, Borch TH, Kongsted P, Iversen TZ, Hölmich LR, Hendel HW, Met Ö, Andersen MH, et al. Long-lasting complete responses in patients with metastatic melanoma after adoptive cell therapy with tumor-infiltrating lymphocytes and an attenuated IL2 regimen. Clin Cancer Res. 2016;22(15):3734–3745. doi:10.1158/1078-0432.CCR-15-1879.
   PubMed Web of Science ®Google Scholar
• Nguyen LT, Saibil SD, Sotov V, Le MX, Khoja L, Ghazarian D, Bonilla L, Majeed H, Hogg D, Joshua AM, et al. Phase II clinical trial of adoptive cell therapy for patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and low-dose interleukin-2. Cancer Immunol Immunother. 2019 Feb;11:1–13. doi:10.1007/s00262-019-02307-x.
   Google Scholar
• Levin AM, Bates DL, Ring AM, Krieg C, Lin JT, Su L, Moraga I, Raeber ME, Bowman GR, Novick P, et al. Exploiting a natural conformational switch to engineer an interleukin-2 “superkine”. Nature. 2012;484(7395):529–533. doi:10.1038/nature10975.
   PubMed Web of Science ®Google Scholar
• Colbeck EJ, Hindley JP, Smart K, Jones E, Bloom A, Bridgeman H, McPherson RC, Turner DG, Ladell K, Price DA, et al. Eliminating roles for T-bet and IL-2 but revealing superior activation and proliferation as mechanisms underpinning dominance of regulatory T cells in tumors. Oncotarget. 2015;6(28):24649–24659. doi:10.18632/oncotarget.5584.
   PubMedGoogle Scholar
• Klevorn LE, Berrien-Elliott MM, Yuan J, Kuehm LM, Felock GD, Crowe SA, Teague RM. Rescue of tolerant CD8+ T cells during cancer immunotherapy with IL2: antibodyComplexes. Cancer Immunol Res. 2016;4(12):1016–1026. doi:10.1158/2326-6066.CIR-16-0159.
   PubMed Web of Science ®Google Scholar
• Charych DH, Hoch U, Langowski JL, Lee SR, Addepalli MK, Kirk PB, Sheng D, Liu X, Sims PW, VanderVeen LA, et al. NKTR-214, an engineered cytokine with biased IL2 receptor binding, increased tumor exposure, and marked efficacy in mouse tumor models. Clin Cancer Res. 2016;22(3):680–690. doi:10.1158/1078-0432.CCR-15-1631.
   PubMed Web of Science ®Google Scholar
• Sockolosky JT, Trotta E, Parisi G, Picton L, Su LL, Le AC, Chhabra A, Silveria SL, George BM, King IC, et al. Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes. Science. 2018;359(6379):1037–1042. doi:10.1126/science.aar3246.
   PubMed Web of Science ®Google Scholar