Journal Article
. 2021 Jun; 184(15):3998-4015.e19.
doi: 10.1016/j.cell.2021.05.027.

Expansion of tumor-associated Treg cells upon disruption of a CTLA-4-dependent feedback loop

Francesco Marangoni 1 Ademi Zhakyp 2 Michela Corsini 3 Shannon N Geels 4 Esteban Carrizosa 2 Martin Thelen 3 Vinidhra Mani 2 Jasper N Prüßmann 2 Ross D Warner 3 Aleksandra J Ozga 2 Mauro Di Pilato 2 Shivashankar Othy 4 Thorsten R Mempel 5 
Affiliations
  • PMID: 34157302
  •     100 References
  •     9 citations

Abstract

Foxp3+ T regulatory (Treg) cells promote immunological tumor tolerance, but how their immune-suppressive function is regulated in the tumor microenvironment (TME) remains unknown. Here, we used intravital microscopy to characterize the cellular interactions that provide tumor-infiltrating Treg cells with critical activation signals. We found that the polyclonal Treg cell repertoire is pre-enriched to recognize antigens presented by tumor-associated conventional dendritic cells (cDCs). Unstable cDC contacts sufficed to sustain Treg cell function, whereas T helper cells were activated during stable interactions. Contact instability resulted from CTLA-4-dependent downregulation of co-stimulatory B7-family proteins on cDCs, mediated by Treg cells themselves. CTLA-4-blockade triggered CD28-dependent Treg cell hyper-proliferation in the TME, and concomitant Treg cell inactivation was required to achieve tumor rejection. Therefore, Treg cells self-regulate through a CTLA-4- and CD28-dependent feedback loop that adjusts their population size to the amount of local co-stimulation. Its disruption through CTLA-4-blockade may off-set therapeutic benefits in cancer patients.

Keywords: CD28; CTLA-4; MP-IVM; NFAT; T regulatory cell; Treg cell; cytotoxic T lymphocyte-associated protein 4; multiphoton intravital microscopy; nuclear factor of activated T cells; tumor tolerance.

Feedback control of regulatory T cell homeostasis by dendritic cells in vivo.
Guillaume Darrasse-Jèze, Stephanie Deroubaix, +8 authors, Michel C Nussenzweig.
J Exp Med, 2009 Aug 12; 206(9). PMID: 19667061    Free PMC article.
Highly Cited.
Immunomic, genomic and transcriptomic characterization of CT26 colorectal carcinoma.
John C Castle, Martin Loewer, +11 authors, Ugur Sahin.
BMC Genomics, 2014 Mar 14; 15. PMID: 24621249    Free PMC article.
Highly Cited.
Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer.
Hossein Borghaei, Luis Paz-Ares, +25 authors, Julie R Brahmer.
N Engl J Med, 2015 Sep 29; 373(17). PMID: 26412456    Free PMC article.
Highly Cited.
Immune homeostasis enforced by co-localized effector and regulatory T cells.
Zhiduo Liu, Michael Y Gerner, +3 authors, Ronald N Germain.
Nature, 2015 Nov 26; 528(7581). PMID: 26605524    Free PMC article.
Highly Cited.
The cellular and molecular origin of tumor-associated macrophages.
Ruth A Franklin, Will Liao, +5 authors, Ming O Li.
Science, 2014 May 09; 344(6186). PMID: 24812208    Free PMC article.
Highly Cited.
Tumor-Residing Batf3 Dendritic Cells Are Required for Effector T Cell Trafficking and Adoptive T Cell Therapy.
Stefani Spranger, Daisy Dai, Brendan Horton, Thomas F Gajewski.
Cancer Cell, 2017 May 10; 31(5). PMID: 28486109    Free PMC article.
Highly Cited.
Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength.
Jackson G Egen, James P Allison.
Immunity, 2002 Feb 05; 16(1). PMID: 11825563
Highly Cited.
How regulatory T cells work.
Dario A A Vignali, Lauren W Collison, Creg J Workman.
Nat Rev Immunol, 2008 Jun 21; 8(7). PMID: 18566595    Free PMC article.
Highly Cited. Review.
FOXP3 controls regulatory T cell function through cooperation with NFAT.
Yongqing Wu, Madhuri Borde, +11 authors, Anjana Rao.
Cell, 2006 Jul 29; 126(2). PMID: 16873067
Highly Cited.
T cell and APC dynamics in situ control the outcome of vaccination.
Kamal M Khanna, David A Blair, +3 authors, Leo Lefrançois.
J Immunol, 2010 Jun 10; 185(1). PMID: 20530268    Free PMC article.
Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces.
Yuri P Rubtsov, Jeffrey P Rasmussen, +9 authors, Alexander Y Rudensky.
Immunity, 2008 Apr 05; 28(4). PMID: 18387831
Highly Cited.
Regulatory T cells: mechanisms of differentiation and function.
Steven Z Josefowicz, Li-Fan Lu, Alexander Y Rudensky.
Annu Rev Immunol, 2012 Jan 10; 30. PMID: 22224781    Free PMC article.
Highly Cited. Review.
Adoptive therapy with redirected primary regulatory T cells results in antigen-specific suppression of arthritis.
Graham P Wright, Clare A Notley, +5 authors, Hans J Stauss.
Proc Natl Acad Sci U S A, 2009 Nov 04; 106(45). PMID: 19884493    Free PMC article.
Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck.
Robert L Ferris, George Blumenschein, +20 authors, Maura L Gillison.
N Engl J Med, 2016 Oct 11; 375(19). PMID: 27718784    Free PMC article.
Highly Cited.
Dual Roles for Regulatory T-cell Depletion and Costimulatory Signaling in Agonistic GITR Targeting for Tumor Immunotherapy.
Ashley E Mahne, Smita Mauze, +5 authors, Renu Jain.
Cancer Res, 2017 Jan 26; 77(5). PMID: 28122327
CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets.
Kate S Smigiel, Elizabeth Richards, +4 authors, Daniel J Campbell.
J Exp Med, 2014 Jan 01; 211(1). PMID: 24378538    Free PMC article.
Highly Cited.
Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells.
Mark J Selby, John J Engelhardt, +4 authors, Alan J Korman.
Cancer Immunol Res, 2014 Apr 30; 1(1). PMID: 24777248
Highly Cited.
Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations.
Desirée Schubert, Claudia Bode, +37 authors, Bodo Grimbacher.
Nat Med, 2014 Oct 21; 20(12). PMID: 25329329    Free PMC article.
Highly Cited.
In vivo dynamics of antigen-specific regulatory T cells not predicted from behavior in vitro.
Ludger Klein, Khashayarsha Khazaie, Harald von Boehmer.
Proc Natl Acad Sci U S A, 2003 Jul 15; 100(15). PMID: 12857946    Free PMC article.
Highly Cited.
Regulatory T Cells and Human Disease.
Shimon Sakaguchi, Norihisa Mikami, +3 authors, Naganari Ohkura.
Annu Rev Immunol, 2020 Feb 06; 38. PMID: 32017635
Review.
In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes.
Qizhi Tang, Kammi J Henriksen, +7 authors, Jeffrey A Bluestone.
J Exp Med, 2004 Jun 09; 199(11). PMID: 15184499    Free PMC article.
Highly Cited.
Critical Role for CD103(+)/CD141(+) Dendritic Cells Bearing CCR7 for Tumor Antigen Trafficking and Priming of T Cell Immunity in Melanoma.
Edward W Roberts, Miranda L Broz, +7 authors, Matthew F Krummel.
Cancer Cell, 2016 Jul 19; 30(2). PMID: 27424807    Free PMC article.
Highly Cited.
Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs.
Bertrand Allard, Sandra Pommey, Mark J Smyth, John Stagg.
Clin Cancer Res, 2013 Aug 29; 19(20). PMID: 23983257
Highly Cited.
Cell-extrinsic CTLA4-mediated regulation of dendritic cell maturation depends on STAT3.
Aleksandra Kowalczyk, Cheryl A D'Souza, Li Zhang.
Eur J Immunol, 2013 Dec 18; 44(4). PMID: 24338929
Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.
Frederick Arce Vargas, Andrew J S Furness, +32 authors, Sergio A Quezada.
Cancer Cell, 2018 Mar 27; 33(4). PMID: 29576375    Free PMC article.
Highly Cited.
Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling.
Louise M D'Cruz, Ludger Klein.
Nat Immunol, 2005 Oct 18; 6(11). PMID: 16227983
Highly Cited.
Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice.
Qizhi Tang, Jason Y Adams, +7 authors, Jeffrey A Bluestone.
Nat Immunol, 2005 Nov 29; 7(1). PMID: 16311599    Free PMC article.
Highly Cited.
CTLA-4 can function as a negative regulator of T cell activation.
T L Walunas, D J Lenschow, +5 authors, J A Bluestone.
Immunity, 1994 Aug 01; 1(5). PMID: 7882171
Highly Cited.
Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins.
Vigo Heissmeyer, Fernando Macián, +7 authors, Anjana Rao.
Nat Immunol, 2004 Feb 20; 5(3). PMID: 14973438
Highly Cited.
Depletion of CD4+CD25+ regulatory T cells enhances interleukin-2-induced antitumor immunity in a mouse model of colon adenocarcinoma.
Hisashi Imai, Masanao Saio, +9 authors, Tsuyoshi Takami.
Cancer Sci, 2007 Feb 03; 98(3). PMID: 17270031
The initial phase of an immune response functions to activate regulatory T cells.
William E O'Gorman, Hans Dooms, +5 authors, Abul K Abbas.
J Immunol, 2009 Jun 23; 183(1). PMID: 19542444    Free PMC article.
Activating Fc γ receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies.
Yannick Bulliard, Rose Jolicoeur, +6 authors, Jennifer L Brogdon.
J Exp Med, 2013 Jul 31; 210(9). PMID: 23897982    Free PMC article.
Highly Cited.
Selective inhibition of NFAT activation by a peptide spanning the calcineurin targeting site of NFAT.
J Aramburu, F Garcia-Cózar, +3 authors, P G Hogan.
Mol Cell, 1998 Jul 14; 1(5). PMID: 9660947
Highly Cited.
Aire-dependent thymic development of tumor-associated regulatory T cells.
Sven Malchow, Daniel S Leventhal, +9 authors, Peter A Savage.
Science, 2013 Mar 09; 339(6124). PMID: 23471412    Free PMC article.
Highly Cited.
Optimal population of FoxP3+ T cells in tumors requires an antigen priming-dependent trafficking receptor switch.
Chuanwu Wang, Jee H Lee, Chang H Kim.
PLoS One, 2012 Feb 01; 7(1). PMID: 22292042    Free PMC article.
Calcineurin B1 is essential for positive but not negative selection during thymocyte development.
Joel R Neilson, Monte M Winslow, Eun Mi Hur, Gerald R Crabtree.
Immunity, 2004 Mar 20; 20(3). PMID: 15030770
The transcription factor NFAT promotes exhaustion of activated CD8⁺ T cells.
Gustavo J Martinez, Renata M Pereira, +13 authors, Anjana Rao.
Immunity, 2015 Feb 15; 42(2). PMID: 25680272    Free PMC article.
Highly Cited.
Regulatory T Cells Exhibit Distinct Features in Human Breast Cancer.
George Plitas, Catherine Konopacki, +5 authors, Alexander Y Rudensky.
Immunity, 2016 Nov 17; 45(5). PMID: 27851913    Free PMC article.
Highly Cited.
Expression of the zinc finger transcription factor zDC (Zbtb46, Btbd4) defines the classical dendritic cell lineage.
Matthew M Meredith, Kang Liu, +8 authors, Michel C Nussenzweig.
J Exp Med, 2012 May 23; 209(6). PMID: 22615130    Free PMC article.
Highly Cited.
Depleting tumor-specific Tregs at a single site eradicates disseminated tumors.
Aurélien Marabelle, Holbrook Kohrt, +13 authors, Ronald Levy.
J Clin Invest, 2013 Jun 04; 123(6). PMID: 23728179    Free PMC article.
Highly Cited.
Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification.
Robert M Samstein, Aaron Arvey, +11 authors, Alexander Y Rudensky.
Cell, 2012 Oct 02; 151(1). PMID: 23021222    Free PMC article.
Highly Cited.
A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization.
Miguel F Sanmamed, Lieping Chen.
Cell, 2018 Oct 06; 175(2). PMID: 30290139    Free PMC article.
Highly Cited. Review.
CTLA-4 control over Foxp3+ regulatory T cell function.
Kajsa Wing, Yasushi Onishi, +5 authors, Shimon Sakaguchi.
Science, 2008 Oct 11; 322(5899). PMID: 18845758
Highly Cited.
Thymic selection of CD8+ single positive cells with a class II major histocompatibility complex-restricted receptor.
J Kirberg, A Baron, +3 authors, H von Boehmer.
J Exp Med, 1994 Jul 01; 180(1). PMID: 8006585    Free PMC article.
Highly Cited.
Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma.
Robert J Motzer, Nizar M Tannir, +30 authors, CheckMate 214 Investigators.
N Engl J Med, 2018 Mar 22; 378(14). PMID: 29562145    Free PMC article.
Highly Cited.
Stability of the regulatory T cell lineage in vivo.
Yuri P Rubtsov, Rachel E Niec, +5 authors, Alexander Y Rudensky.
Science, 2010 Oct 12; 329(5999). PMID: 20929851    Free PMC article.
Highly Cited.
Critical roles of a dendritic cell subset expressing a chemokine receptor, XCR1.
Chihiro Yamazaki, Masanaka Sugiyama, +12 authors, Tsuneyasu Kaisho.
J Immunol, 2013 May 15; 190(12). PMID: 23670193
Understanding the tumor immune microenvironment (TIME) for effective therapy.
Mikhail Binnewies, Edward W Roberts, +15 authors, Matthew F Krummel.
Nat Med, 2018 Apr 25; 24(5). PMID: 29686425    Free PMC article.
Highly Cited. Review.
CD28-CD80 interactions control regulatory T cell motility and immunological synapse formation.
Timothy J Thauland, Yoshinobu Koguchi, Michael L Dustin, David C Parker.
J Immunol, 2014 Oct 31; 193(12). PMID: 25355918    Free PMC article.
Combination therapy with anti-CTL antigen-4 and anti-4-1BB antibodies enhances cancer immunity and reduces autoimmunity.
Ergun Kocak, Kenneth Lute, +8 authors, Yang Liu.
Cancer Res, 2006 Jul 20; 66(14). PMID: 16849577
Differential IL-2 expression defines developmental fates of follicular versus nonfollicular helper T cells.
Daniel DiToro, Colleen J Winstead, +16 authors, Casey T Weaver.
Science, 2018 Sep 15; 361(6407). PMID: 30213884    Free PMC article.
Highly Cited.
Homeostasis and anergy of CD4(+)CD25(+) suppressor T cells in vivo.
Marc A Gavin, Sally R Clarke, +2 authors, Alexander Rudensky.
Nat Immunol, 2001 Dec 12; 3(1). PMID: 11740498
Highly Cited.
Imbalanced signal transduction in regulatory T cells expressing the transcription factor FoxP3.
Dapeng Yan, Julia Farache, +2 authors, Christophe Benoist.
Proc Natl Acad Sci U S A, 2015 Dec 03; 112(48). PMID: 26627244    Free PMC article.
Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors.
Frederick Arce Vargas, Andrew J S Furness, +29 authors, Sergio A Quezada.
Immunity, 2017 Apr 16; 46(4). PMID: 28410988    Free PMC article.
Highly Cited.
Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity.
Miranda L Broz, Mikhail Binnewies, +12 authors, Matthew F Krummel.
Cancer Cell, 2014 Dec 03; 26(5). PMID: 25446897    Free PMC article.
Highly Cited.
Transcriptional Landscape of Human Tissue Lymphocytes Unveils Uniqueness of Tumor-Infiltrating T Regulatory Cells.
Marco De Simone, Alberto Arrigoni, +28 authors, Massimiliano Pagani.
Immunity, 2016 Nov 17; 45(5). PMID: 27851914    Free PMC article.
Highly Cited.
Anti-CTLA-4 Immunotherapy Does Not Deplete FOXP3+ Regulatory T Cells (Tregs) in Human Cancers-Letter.
Roberto Ferrara, Sandrine Susini, Aurelien Marabelle.
Clin Cancer Res, 2018 Dec 06; 25(11). PMID: 30514779
Continuous requirement for the TCR in regulatory T cell function.
Andrew G Levine, Aaron Arvey, Wei Jin, Alexander Y Rudensky.
Nat Immunol, 2014 Sep 30; 15(11). PMID: 25263123    Free PMC article.
Highly Cited.
Unleashing Type-2 Dendritic Cells to Drive Protective Antitumor CD4+ T Cell Immunity.
Mikhail Binnewies, Adriana M Mujal, +15 authors, Matthew F Krummel.
Cell, 2019 Apr 09; 177(3). PMID: 30955881    Free PMC article.
Highly Cited.
Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice.
Jeong M Kim, Jeffrey P Rasmussen, Alexander Y Rudensky.
Nat Immunol, 2006 Dec 01; 8(2). PMID: 17136045
Highly Cited.
An obligate cell-intrinsic function for CD28 in Tregs.
Ruan Zhang, Alexandria Huynh, +3 authors, Laurence A Turka.
J Clin Invest, 2013 Jan 03; 123(2). PMID: 23281398    Free PMC article.
Highly Cited.
Continuous T cell receptor signals maintain a functional regulatory T cell pool.
J Christoph Vahl, Christoph Drees, +19 authors, Marc Schmidt-Supprian.
Immunity, 2014 Dec 04; 41(5). PMID: 25464853
Highly Cited.
Regulatory T cell development in the absence of functional Foxp3.
Wen Lin, Dipica Haribhai, +4 authors, Talal A Chatila.
Nat Immunol, 2007 Feb 03; 8(4). PMID: 17273171
Highly Cited.
Selective stimulation of T cell subsets with antibody-cytokine immune complexes.
Onur Boyman, Marek Kovar, +2 authors, Jonathan Sprent.
Science, 2006 Feb 18; 311(5769). PMID: 16484453
Highly Cited.
B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes.
B Salomon, D J Lenschow, +4 authors, J A Bluestone.
Immunity, 2000 May 05; 12(4). PMID: 10795741
Highly Cited.
Control of T helper 2 responses by transcription factor IRF4-dependent dendritic cells.
Yan Gao, Simone A Nish, +5 authors, Ruslan Medzhitov.
Immunity, 2013 Oct 01; 39(4). PMID: 24076050    Free PMC article.
Highly Cited.
Targeting CCR8 Induces Protective Antitumor Immunity and Enhances Vaccine-Induced Responses in Colon Cancer.
Daniel O Villarreal, Andrew L'Huillier, +5 authors, Michael F Princiotta.
Cancer Res, 2018 Jul 22; 78(18). PMID: 30026324
Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma.
Jedd D Wolchok, Vanna Chiarion-Sileni, +30 authors, James Larkin.
N Engl J Med, 2017 Sep 12; 377(14). PMID: 28889792    Free PMC article.
Highly Cited.
Lentiviral transduction of mammary stem cells for analysis of gene function during development and cancer.
Bryan E Welm, Gerrit J P Dijkgraaf, +2 authors, Zena Werb.
Cell Stem Cell, 2008 Mar 29; 2(1). PMID: 18371425    Free PMC article.
Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients.
Emanuela Romano, Monika Kusio-Kobialka, +7 authors, Daniel E Speiser.
Proc Natl Acad Sci U S A, 2015 Apr 29; 112(19). PMID: 25918390    Free PMC article.
Highly Cited.
Deletion of CTLA-4 on regulatory T cells during adulthood leads to resistance to autoimmunity.
Alison M Paterson, Scott B Lovitch, +9 authors, Arlene H Sharpe.
J Exp Med, 2015 Sep 16; 212(10). PMID: 26371185    Free PMC article.
Highly Cited.
Targeting the CBM complex causes Treg cells to prime tumours for immune checkpoint therapy.
Mauro Di Pilato, Edward Y Kim, +14 authors, Thorsten R Mempel.
Nature, 2019 May 17; 570(7759). PMID: 31092922    Free PMC article.
Highly Cited.
Tumor induction relationships in development of transplantable cancers of the colon in mice for chemotherapy assays, with a note on carcinogen structure.
T H Corbett, D P Griswold, +2 authors, F M Schabel.
Cancer Res, 1975 Sep 11; 35(9). PMID: 1149045
Highly Cited.
Migratory CD11b+ conventional dendritic cells induce T follicular helper cell-dependent antibody responses.
Jayendra Kumar Krishnaswamy, Uthaman Gowthaman, +17 authors, Stephanie C Eisenbarth.
Sci Immunol, 2017 Dec 03; 2(18). PMID: 29196450    Free PMC article.
Highly Cited.
Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal.
Brian T Fife, Kristen E Pauken, +6 authors, Jeffrey A Bluestone.
Nat Immunol, 2009 Sep 29; 10(11). PMID: 19783989    Free PMC article.
Highly Cited.
A soluble form of CTLA-4 generated by alternative splicing is expressed by nonstimulated human T cells.
G Magistrelli, P Jeannin, +4 authors, Y Delneste.
Eur J Immunol, 1999 Nov 11; 29(11). PMID: 10556814
Anti-CTLA-4 Immunotherapy Does Not Deplete FOXP3+ Regulatory T Cells (Tregs) in Human Cancers.
Anu Sharma, Sumit K Subudhi, +6 authors, Padmanee Sharma.
Clin Cancer Res, 2018 Jul 29; 25(4). PMID: 30054281    Free PMC article.
Highly Cited.
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma.
Tyler R Simpson, Fubin Li, +11 authors, Sergio A Quezada.
J Exp Med, 2013 Jul 31; 210(9). PMID: 23897981    Free PMC article.
Highly Cited.
Tumor Tolerance-Promoting Function of Regulatory T Cells Is Optimized by CD28, but Strictly Dependent on Calcineurin.
Francesco Marangoni, Ruan Zhang, +8 authors, Thorsten R Mempel.
J Immunol, 2018 Apr 18; 200(10). PMID: 29661826    Free PMC article.
Differential control of human Treg and effector T cells in tumor immunity by Fc-engineered anti-CTLA-4 antibody.
Danbee Ha, Atsushi Tanaka, +10 authors, Shimon Sakaguchi.
Proc Natl Acad Sci U S A, 2018 Dec 28; 116(2). PMID: 30587582    Free PMC article.
PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer.
Takahiro Kamada, Yosuke Togashi, +13 authors, Hiroyoshi Nishikawa.
Proc Natl Acad Sci U S A, 2019 Apr 28; 116(20). PMID: 31028147    Free PMC article.
Highly Cited.
Identification of Natural Regulatory T Cell Epitopes Reveals Convergence on a Dominant Autoantigen.
John D Leonard, Dana C Gilmore, +6 authors, Peter A Savage.
Immunity, 2017 Jul 16; 47(1). PMID: 28709804    Free PMC article.
Expansion and Activation of CD103(+) Dendritic Cell Progenitors at the Tumor Site Enhances Tumor Responses to Therapeutic PD-L1 and BRAF Inhibition.
Hélène Salmon, Juliana Idoyaga, +19 authors, Miriam Merad.
Immunity, 2016 Apr 21; 44(4). PMID: 27096321    Free PMC article.
Highly Cited.
Dynamic Treg interactions with intratumoral APCs promote local CTL dysfunction.
Christian A Bauer, Edward Y Kim, +3 authors, Thorsten R Mempel.
J Clin Invest, 2014 May 09; 124(6). PMID: 24812664    Free PMC article.
Highly Cited.
Landscape of Infiltrating T Cells in Liver Cancer Revealed by Single-Cell Sequencing.
Chunhong Zheng, Liangtao Zheng, +13 authors, Zemin Zhang.
Cell, 2017 Jun 18; 169(7). PMID: 28622514
Highly Cited.
Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo.
Carlos E Tadokoro, Guy Shakhar, +5 authors, Michael L Dustin.
J Exp Med, 2006 Mar 15; 203(3). PMID: 16533880    Free PMC article.
Highly Cited.
Depletion of CD25+ regulatory cells uncovers immune responses to shared murine tumor rejection antigens.
Denise Golgher, Emma Jones, +2 authors, Awen Gallimore.
Eur J Immunol, 2003 Jan 31; 32(11). PMID: 12555672
Human FOXP3+ Regulatory T Cell Heterogeneity and Function in Autoimmunity and Cancer.
James B Wing, Atsushi Tanaka, Shimon Sakaguchi.
Immunity, 2019 Feb 21; 50(2). PMID: 30784578
Highly Cited. Review.
A function for interleukin 2 in Foxp3-expressing regulatory T cells.
Jason D Fontenot, Jeffrey P Rasmussen, Marc A Gavin, Alexander Y Rudensky.
Nat Immunol, 2005 Oct 18; 6(11). PMID: 16227984
Highly Cited.
Confusing signals: recent progress in CTLA-4 biology.
Lucy S K Walker, David M Sansom.
Trends Immunol, 2015 Jan 15; 36(2). PMID: 25582039    Free PMC article.
Highly Cited. Review.
CTLA-4-mediated transendocytosis of costimulatory molecules primarily targets migratory dendritic cells.
Vitalijs Ovcinnikovs, Ellen M Ross, +9 authors, Lucy S K Walker.
Sci Immunol, 2019 Jun 04; 4(35). PMID: 31152091    Free PMC article.
Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4.
Omar S Qureshi, Yong Zheng, +12 authors, David M Sansom.
Science, 2011 Apr 09; 332(6029). PMID: 21474713    Free PMC article.
Highly Cited.
Tumor-infiltrating human CD4+ regulatory T cells display a distinct TCR repertoire and exhibit tumor and neoantigen reactivity.
Mojgan Ahmadzadeh, Anna Pasetto, +4 authors, Steven A Rosenberg.
Sci Immunol, 2019 Jan 13; 4(31). PMID: 30635355    Free PMC article.
Highly Cited.
Transcriptional mechanisms underlying lymphocyte tolerance.
Fernando Macián, Francisco García-Cózar, +3 authors, Anjana Rao.
Cell, 2002 Jun 28; 109(6). PMID: 12086671
Highly Cited.
Defective activation of protein kinase C and Ras-ERK pathways limits IL-2 production and proliferation by CD4+CD25+ regulatory T cells.
Somia P Hickman, Jaeseok Yang, +2 authors, Laurence A Turka.
J Immunol, 2006 Aug 05; 177(4). PMID: 16887978
The transcription factor NFAT exhibits signal memory during serial T cell interactions with antigen-presenting cells.
Francesco Marangoni, Thomas T Murooka, +4 authors, Thorsten R Mempel.
Immunity, 2013 Jan 15; 38(2). PMID: 23313588    Free PMC article.
Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-beta signals in vivo.
Mei-Ling Chen, Mikaël J Pittet, +4 authors, Khashayarsha Khazaie.
Proc Natl Acad Sci U S A, 2004 Dec 30; 102(2). PMID: 15623559    Free PMC article.
Highly Cited.
Dendritic Cells Coordinate the Development and Homeostasis of Organ-Specific Regulatory T Cells.
Daniel S Leventhal, Dana C Gilmore, +9 authors, Peter A Savage.
Immunity, 2016 Apr 03; 44(4). PMID: 27037189    Free PMC article.
B7-1 and B7-2 selectively recruit CTLA-4 and CD28 to the immunological synapse.
Tsvetelina Pentcheva-Hoang, Jackson G Egen, Kathleen Wojnoonski, James P Allison.
Immunity, 2004 Sep 11; 21(3). PMID: 15357951
Highly Cited.
Regulatory T cells reversibly suppress cytotoxic T cell function independent of effector differentiation.
Thorsten R Mempel, Mikael J Pittet, +4 authors, Ulrich H von Andrian.
Immunity, 2006 Jul 25; 25(1). PMID: 16860762
Highly Cited.
Role of reactive oxygen species in tumors based on the 'seed and soil' theory: A complex interaction (Review).
Wei Liang, Xinying He, +2 authors, Yunchuan Sun.
Oncol Rep, 2021 Jul 31; 46(3). PMID: 34328200    Free PMC article.
Review.
Fibroblast Growth Factor Inhibitors for Treating Locally Advanced/Metastatic Bladder Urothelial Carcinomas via Dual Targeting of Tumor-Specific Oncogenic Signaling and the Tumor Immune Microenvironment.
Hye Won Lee, Ho Kyung Seo.
Int J Mol Sci, 2021 Sep 11; 22(17). PMID: 34502435    Free PMC article.
Review.
Regulatory T Cells in Autoimmunity and Cancer: A Duplicitous Lifestyle.
Aikaterini Hatzioannou, Athina Boumpas, +4 authors, Panayotis Verginis.
Front Immunol, 2021 Sep 21; 12. PMID: 34539668    Free PMC article.
Review.
Exposure to Tobacco Smoking Induces a subset of Activated Tumor-resident Tregs in Non-Small Cell Lung Cancer.
Yudi Hu, Chaoqun Xu, +6 authors, Qiyuan Li.
Transl Oncol, 2021 Nov 13; 15(1). PMID: 34768099    Free PMC article.
Addressing the Elephant in the Immunotherapy Room: Effector T-Cell Priming versus Depletion of Regulatory T-Cells by Anti-CTLA-4 Therapy.
Megan M Y Hong, Saman Maleki Vareki.
Cancers (Basel), 2022 Mar 26; 14(6). PMID: 35326731    Free PMC article.
Review.
Intravital and high-content multiplex imaging of the immune system.
Jyh Liang Hor, Ronald N Germain.
Trends Cell Biol, 2021 Dec 19; 32(5). PMID: 34920936    Free PMC article.
Review.
Biomimetic and Materials-Potentiated Cell Engineering for Cancer Immunotherapy.
Tingting Zhang, Yushan Yang, +6 authors, Yongyong Li.
Pharmaceutics, 2022 Apr 24; 14(4). PMID: 35456568    Free PMC article.
Review.
Landscape of helper and regulatory antitumour CD4+ T cells in melanoma.
Giacomo Oliveira, Kari Stromhaug, +24 authors, Catherine J Wu.
Nature, 2022 May 05; 605(7910). PMID: 35508657
Immunosuppressive cells in cancer: mechanisms and potential therapeutic targets.
Yan Tie, Fan Tang, Yu-Quan Wei, Xia-Wei Wei.
J Hematol Oncol, 2022 May 19; 15(1). PMID: 35585567    Free PMC article.
Review.