. 2019 May; 9:279.
doi: 10.3389/fonc.2019.00279.

Turning the Tide Against Regulatory T Cells

SeongJun Han 1 Aras Toker 1 Zhe Qi Liu 1 Pamela S Ohashi 1 
  • PMID: 31058083
  •     226 References
  •     29 citations


Regulatory T (Treg) cells play crucial roles in health and disease through their immunosuppressive properties against various immune cells. In this review we will focus on the inhibitory role of Treg cells in anti-tumor immunity. We outline how Treg cells restrict T cell function based on our understanding of T cell biology, and how we can shift the equilibrium against regulatory T cells. To date, numerous strategies have been proposed to limit the suppressive effects of Treg cells, including Treg cell neutralization, destabilizing Treg cells and rendering T cells resistant to Treg cells. Here, we focus on key mechanisms which render T cells resistant to the suppressive effects of Treg cells. Lastly, we also examine current limitations and caveats of overcoming the inhibitory activity of Treg cells, and briefly discuss the potential to target Treg cell resistance in the context of anti-tumor immunity.

Keywords: T cells; Treg cells; immune regulation; immune therapy; tumor immunity.

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Regulatory (FoxP3+) T-cell tumor infiltration is a favorable prognostic factor in advanced colon cancer patients undergoing chemo or chemoimmunotherapy.
Pierpaolo Correale, Maria Saveria Rotundo, +10 authors, Pierosandro Tagliaferri.
J Immunother, 2010 Apr 14; 33(4). PMID: 20386463    Free PMC article.
Cbl-b in T-cell activation.
Magdalena Paolino, Josef M Penninger.
Semin Immunopathol, 2010 May 12; 32(2). PMID: 20458601
Depletion of regulatory T cells by anti-GITR mAb as a novel mechanism for cancer immunotherapy.
David Coe, Shaima Begom, +3 authors, Jian-Guo Chai.
Cancer Immunol Immunother, 2010 May 19; 59(9). PMID: 20480365
X-linked lymphoreticular disease in the scurfy (sf) mutant mouse.
V L Godfrey, J E Wilkinson, L B Russell.
Am J Pathol, 1991 Jun 01; 138(6). PMID: 2053595    Free PMC article.
Highly Cited.
FOXP3+ regulatory T cells in the human immune system.
Shimon Sakaguchi, Makoto Miyara, Cristina M Costantino, David A Hafler.
Nat Rev Immunol, 2010 Jun 19; 10(7). PMID: 20559327
Highly Cited. Review.
Cbl-b(-/-) T cells demonstrate in vivo resistance to regulatory T cells but a context-dependent resistance to TGF-beta.
Catherine O Adams, William J Housley, +4 authors, Robert B Clark.
J Immunol, 2010 Jul 14; 185(4). PMID: 20624942
The PD-1 pathway in tolerance and autoimmunity.
Loise M Francisco, Peter T Sage, Arlene H Sharpe.
Immunol Rev, 2010 Jul 20; 236. PMID: 20636820    Free PMC article.
Highly Cited. Review.
Sorafenib reduces the percentage of tumour infiltrating regulatory T cells in renal cell carcinoma patients.
Ingrid M E Desar, J Hans F M Jacobs, +6 authors, I Jolanda J M de Vries.
Int J Cancer, 2010 Sep 15; 129(2). PMID: 20839259
Abrogating Cbl-b in effector CD8(+) T cells improves the efficacy of adoptive therapy of leukemia in mice.
Ingunn M Stromnes, Joseph N Blattman, +3 authors, Philip D Greenberg.
J Clin Invest, 2010 Oct 05; 120(10). PMID: 20890046    Free PMC article.
Selective depletion of Foxp3+ regulatory T cells improves effective therapeutic vaccination against established melanoma.
Katjana Klages, Christian T Mayer, +7 authors, Tim Sparwasser.
Cancer Res, 2010 Oct 07; 70(20). PMID: 20924102
Highly Cited.
IL-35-mediated induction of a potent regulatory T cell population.
Lauren W Collison, Vandana Chaturvedi, +13 authors, Dario A A Vignali.
Nat Immunol, 2010 Oct 19; 11(12). PMID: 20953201    Free PMC article.
Highly Cited.
Essential role of E3 ubiquitin ligase activity in Cbl-b-regulated T cell functions.
Magdalena Paolino, Christine B F Thien, +4 authors, Josef M Penninger.
J Immunol, 2011 Jan 21; 186(4). PMID: 21248250
Plasticity of human regulatory T cells in healthy subjects and patients with type 1 diabetes.
Stephanie A McClymont, Amy L Putnam, +8 authors, Todd M Brusko.
J Immunol, 2011 Mar 04; 186(7). PMID: 21368230    Free PMC article.
Highly Cited.
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.
Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy.
Steven A Rosenberg, James C Yang, +12 authors, Mark E Dudley.
Clin Cancer Res, 2011 Apr 19; 17(13). PMID: 21498393    Free PMC article.
Highly Cited.
Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation.
Ashutosh Chaudhry, Robert M Samstein, +8 authors, Alexander Y Rudensky.
Immunity, 2011 Apr 23; 34(4). PMID: 21511185    Free PMC article.
Highly Cited.
Identification of T helper type 1-like, Foxp3+ regulatory T cells in human autoimmune disease.
Margarita Dominguez-Villar, Clare M Baecher-Allan, David A Hafler.
Nat Med, 2011 May 05; 17(6). PMID: 21540856    Free PMC article.
Highly Cited.
Cutting edge: Human regulatory T cells require IL-35 to mediate suppression and infectious tolerance.
Vandana Chaturvedi, Lauren W Collison, +2 authors, Dario A A Vignali.
J Immunol, 2011 May 18; 186(12). PMID: 21576509    Free PMC article.
Regulatory T cell plasticity: beyond the controversies.
Shohei Hori.
Trends Immunol, 2011 Jun 04; 32(7). PMID: 21636323
Anti-PD-1 synergizes with cyclophosphamide to induce potent anti-tumor vaccine effects through novel mechanisms.
Mikayel Mkrtichyan, Yana G Najjar, +5 authors, Samir N Khleif.
Eur J Immunol, 2011 Jun 29; 41(10). PMID: 21710477    Free PMC article.
Cell-autonomous and -non-autonomous roles of CTLA-4 in immune regulation.
Kajsa Wing, Tomoyuki Yamaguchi, Shimon Sakaguchi.
Trends Immunol, 2011 Jul 05; 32(9). PMID: 21723783
IL-21 inhibits T cell IL-2 production and impairs Treg homeostasis.
Kesley Attridge, Chun Jing Wang, +5 authors, Lucy S K Walker.
Blood, 2012 Mar 24; 119(20). PMID: 22442347
Exploiting a natural conformational switch to engineer an interleukin-2 'superkine'.
Aron M Levin, Darren L Bates, +11 authors, K Christopher Garcia.
Nature, 2012 Mar 27; 484(7395). PMID: 22446627    Free PMC article.
Highly Cited.
JAK and STAT signaling molecules in immunoregulation and immune-mediated disease.
John J O'Shea, Robert Plenge.
Immunity, 2012 Apr 24; 36(4). PMID: 22520847    Free PMC article.
Highly Cited. Review.
Levels of peripheral CD4(+)FoxP3(+) regulatory T cells are negatively associated with clinical response to adoptive immunotherapy of human cancer.
Xin Yao, Mojgan Ahmadzadeh, +7 authors, Paul F Robbins.
Blood, 2012 May 05; 119(24). PMID: 22555974    Free PMC article.
E3 ubiquitin ligase Cbl-b regulates Pten via Nedd4 in T cells independently of its ubiquitin ligase activity.
Hui Guo, Guilin Qiao, +8 authors, Jian Zhang.
Cell Rep, 2012 Jul 06; 1(5). PMID: 22763434    Free PMC article.
Depletion of radio-resistant regulatory T cells enhances antitumor immunity during recovery from lymphopenia.
Junko Baba, Satoshi Watanabe, +15 authors, Ichiei Narita.
Blood, 2012 Jul 19; 120(12). PMID: 22806892
Efficacy of adoptive cell transfer of tumor-infiltrating lymphocytes after lymphopenia induction for metastatic melanoma.
Shari Pilon-Thomas, Lisa Kuhn, +10 authors, Amod A Sarnaik.
J Immunother, 2012 Sep 22; 35(8). PMID: 22996367    Free PMC article.
Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients.
Laszlo G Radvanyi, Chantale Bernatchez, +32 authors, Patrick Hwu.
Clin Cancer Res, 2012 Oct 04; 18(24). PMID: 23032743    Free PMC article.
Highly Cited.
Tumour-infiltrating FOXP3(+) lymphocytes are associated with cytotoxic immune responses and good clinical outcome in oestrogen receptor-negative breast cancer.
N R West, S E Kost, +4 authors, P H Watson.
Br J Cancer, 2012 Nov 22; 108(1). PMID: 23169287    Free PMC article.
The scurfy mouse mutant has previously unrecognized hematological abnormalities and resembles Wiskott-Aldrich syndrome.
M F Lyon, J Peters, +2 authors, E Wright.
Proc Natl Acad Sci U S A, 1990 Apr 01; 87(7). PMID: 2320565    Free PMC article.
Cyclophosphamide promotes chronic inflammation-dependent immunosuppression and prevents antitumor response in melanoma.
Alexandra Sevko, Moshe Sade-Feldman, +8 authors, Viktor Umansky.
J Invest Dermatol, 2012 Dec 12; 133(6). PMID: 23223128
TLR agonists: our best frenemy in cancer immunotherapy.
Sabina Kaczanowska, Ann Mary Joseph, Eduardo Davila.
J Leukoc Biol, 2013 Mar 12; 93(6). PMID: 23475577    Free PMC article.
Highly Cited. Review.
The plasticity and stability of regulatory T cells.
Shimon Sakaguchi, Dario A A Vignali, +2 authors, Herman Waldmann.
Nat Rev Immunol, 2013 May 18; 13(6). PMID: 23681097
Highly Cited.
IL-21 restricts virus-driven Treg cell expansion in chronic LCMV infection.
Iwana Schmitz, Christoph Schneider, +7 authors, Manfred Kopf.
PLoS Pathog, 2013 May 23; 9(5). PMID: 23696736    Free PMC article.
Cbl-b mediates TGFβ sensitivity by downregulating inhibitory SMAD7 in primary T cells.
Thomas Gruber, Reinhard Hinterleitner, +6 authors, Gottfried Baier.
J Mol Cell Biol, 2013 May 28; 5(6). PMID: 23709694
Modulation of Treg cells/T effector function by GITR signaling is context-dependent.
Amal Ephrem, Alan L Epstein, +3 authors, Ethan M Shevach.
Eur J Immunol, 2013 Jun 01; 43(9). PMID: 23722868
Natural and induced T regulatory cells in cancer.
Dennis O Adeegbe, Hiroyoshi Nishikawa.
Front Immunol, 2013 Jul 23; 4. PMID: 23874336    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.
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.
Inhibition of p300 impairs Foxp3⁺ T regulatory cell function and promotes antitumor immunity.
Yujie Liu, Liqing Wang, +11 authors, Wayne W Hancock.
Nat Med, 2013 Aug 21; 19(9). PMID: 23955711    Free PMC article.
Antibodies targeting human OX40 expand effector T cells and block inducible and natural regulatory T cell function.
Kui S Voo, Laura Bover, +5 authors, Yong J Liu.
J Immunol, 2013 Sep 10; 191(7). PMID: 24014877    Free PMC article.
Current status of interleukin-10 and regulatory T-cells in cancer.
Kristen L Dennis, Nichole R Blatner, Fotini Gounari, Khashayarsha Khazaie.
Curr Opin Oncol, 2013 Oct 01; 25(6). PMID: 24076584    Free PMC article.
Highly Cited. Review.
Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans.
Daisuke Sugiyama, Hiroyoshi Nishikawa, +10 authors, Shimon Sakaguchi.
Proc Natl Acad Sci U S A, 2013 Oct 16; 110(44). PMID: 24127572    Free PMC article.
Highly Cited.
Intratumoral regulatory T cells upregulate immunosuppressive molecules in head and neck cancer patients.
H-B Jie, N Gildener-Leapman, +4 authors, R L Ferris.
Br J Cancer, 2013 Oct 31; 109(10). PMID: 24169351    Free PMC article.
Highly Cited.
Microenvironmental regulation of tumor progression and metastasis.
Daniela F Quail, Johanna A Joyce.
Nat Med, 2013 Nov 10; 19(11). PMID: 24202395    Free PMC article.
Highly Cited. Review.
IL-2 therapy promotes suppressive ICOS+ Treg expansion in melanoma patients.
Geok Choo Sim, Natalia Martin-Orozco, +9 authors, Laszlo Radvanyi.
J Clin Invest, 2013 Dec 03; 124(1). PMID: 24292706    Free PMC article.
Highly Cited.
Regulatory T cells in cancer immunotherapy.
Hiroyoshi Nishikawa, Shimon Sakaguchi.
Curr Opin Immunol, 2014 Jan 15; 27. PMID: 24413387
Highly Cited. Review.
GITR pathway activation abrogates tumor immune suppression through loss of regulatory T cell lineage stability.
David A Schaer, Sadna Budhu, +8 authors, Jedd D Wolchok.
Cancer Immunol Res, 2014 Jan 15; 1(5). PMID: 24416730    Free PMC article.
Highly Cited.
Preactivation with IL-12, IL-15, and IL-18 induces CD25 and a functional high-affinity IL-2 receptor on human cytokine-induced memory-like natural killer cells.
Jeffrey W Leong, Julie M Chase, +4 authors, Todd A Fehniger.
Biol Blood Marrow Transplant, 2014 Jan 18; 20(4). PMID: 24434782    Free PMC article.
Highly Cited.
Immunological and biological changes during ipilimumab treatment and their potential correlation with clinical response and survival in patients with advanced melanoma.
Ester Simeone, Giusy Gentilcore, +20 authors, Paolo A Ascierto.
Cancer Immunol Immunother, 2014 Apr 04; 63(7). PMID: 24695951
Highly Cited.
Once a Treg, always a Treg?
Deepali V Sawant, Dario A A Vignali.
Immunol Rev, 2014 Apr 10; 259(1). PMID: 24712466    Free PMC article.
Highly Cited. Review.
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.
In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates.
Changyu Wang, Kent B Thudium, +15 authors, Alan J Korman.
Cancer Immunol Res, 2014 May 30; 2(9). PMID: 24872026
Highly Cited.
PD-1 regulates extrathymic regulatory T-cell differentiation.
Xiufen Chen, Dominick Fosco, +4 authors, Justin Kline.
Eur J Immunol, 2014 Jul 01; 44(9). PMID: 24975127    Free PMC article.
Rapid rebound of the Treg compartment in DEREG mice limits the impact of Treg depletion on mycobacterial burden, but prevents autoimmunity.
Luciana Berod, Philipp Stüve, +8 authors, Tim Sparwasser.
PLoS One, 2014 Jul 23; 9(7). PMID: 25050936    Free PMC article.
Toll-like receptor signaling pathways.
Takumi Kawasaki, Taro Kawai.
Front Immunol, 2014 Oct 14; 5. PMID: 25309543    Free PMC article.
Highly Cited. Review.
Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability.
Alexandria Huynh, Michel DuPage, +9 authors, Laurence A Turka.
Nat Immunol, 2015 Jan 07; 16(2). PMID: 25559257    Free PMC article.
Highly Cited.
Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses.
Sharad Shrestha, Kai Yang, +3 authors, Hongbo Chi.
Nat Immunol, 2015 Jan 07; 16(2). PMID: 25559258    Free PMC article.
Highly Cited.
Regulatory T cell reprogramming toward a Th2-cell-like lineage impairs oral tolerance and promotes food allergy.
Magali Noval Rivas, Oliver T Burton, +5 authors, Talal A Chatila.
Immunity, 2015 Mar 15; 42(3). PMID: 25769611    Free PMC article.
Highly Cited.
Modulation of Immune Cell Functions by the E3 Ligase Cbl-b.
Christina Lutz-Nicoladoni, Dominik Wolf, Sieghart Sopper.
Front Oncol, 2015 Mar 31; 5. PMID: 25815272    Free PMC article.
Adoptive cell transfer as personalized immunotherapy for human cancer.
Steven A Rosenberg, Nicholas P Restifo.
Science, 2015 Apr 04; 348(6230). PMID: 25838374    Free PMC article.
Highly Cited. Review.
Immune checkpoint blockade: a common denominator approach to cancer therapy.
Suzanne L Topalian, Charles G Drake, Drew M Pardoll.
Cancer Cell, 2015 Apr 11; 27(4). PMID: 25858804    Free PMC article.
Highly Cited. Review.
The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases.
David Klatzmann, Abul K Abbas.
Nat Rev Immunol, 2015 Apr 18; 15(5). PMID: 25882245
Highly Cited. Review.
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.
A TLR9 agonist enhances the anti-tumor immunity of peptide and lipopeptide vaccines via different mechanisms.
Ying-Chyi Song, Shih-Jen Liu.
Sci Rep, 2015 Jul 29; 5. PMID: 26215533    Free PMC article.
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.
Protein Tyrosine Phosphatase SHP-1 Modulates T Cell Responses by Controlling Cbl-b Degradation.
Yun Xiao, Guilin Qiao, +6 authors, Jian Zhang.
J Immunol, 2015 Sep 30; 195(9). PMID: 26416283    Free PMC article.
Phase Ia Study of FoxP3+ CD4 Treg Depletion by Infusion of a Humanized Anti-CCR4 Antibody, KW-0761, in Cancer Patients.
Koji Kurose, Yoshihiro Ohue, +13 authors, Eiichi Nakayama.
Clin Cancer Res, 2015 Oct 03; 21(19). PMID: 26429981
Highly Cited.
PD-1 Blockade Expands Intratumoral Memory T Cells.
Antoni Ribas, Daniel Sanghoon Shin, +14 authors, Begoña Comin-Anduix.
Cancer Immunol Res, 2016 Jan 21; 4(3). PMID: 26787823    Free PMC article.
Highly Cited.
NKTR-214, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models.
Deborah H Charych, Ute Hoch, +19 authors, Stephen K Doberstein.
Clin Cancer Res, 2016 Feb 03; 22(3). PMID: 26832745
Highly Cited.
T regulatory cell chemokine production mediates pathogenic T cell attraction and suppression.
Scott J Patterson, Anne M Pesenacker, +8 authors, Megan K Levings.
J Clin Invest, 2016 Feb 09; 126(3). PMID: 26854929    Free PMC article.
The future of cancer treatment: immunomodulation, CARs and combination immunotherapy.
Danny N Khalil, Eric L Smith, Renier J Brentjens, Jedd D Wolchok.
Nat Rev Clin Oncol, 2016 Mar 16; 13(5). PMID: 26977780    Free PMC article.
Highly Cited. Review.
Two FOXP3(+)CD4(+) T cell subpopulations distinctly control the prognosis of colorectal cancers.
Takuro Saito, Hiroyoshi Nishikawa, +19 authors, Shimon Sakaguchi.
Nat Med, 2016 Apr 26; 22(6). PMID: 27111280
Highly Cited.
Instability of Helios-deficient Tregs is associated with conversion to a T-effector phenotype and enhanced antitumor immunity.
Hidetoshi Nakagawa, Jessica M Sido, +3 authors, Hye-Jung Kim.
Proc Natl Acad Sci U S A, 2016 May 18; 113(22). PMID: 27185917    Free PMC article.
OX40, PD-1 and CTLA-4 are selectively expressed on tumor-infiltrating T cells in head and neck cancer.
Ryan Montler, R Bryan Bell, +8 authors, Andrew Weinberg.
Clin Transl Immunology, 2016 May 20; 5(4). PMID: 27195113    Free PMC article.
CD19-targeted CAR T-cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date.
Jae H Park, Mark B Geyer, Renier J Brentjens.
Blood, 2016 May 22; 127(26). PMID: 27207800    Free PMC article.
Highly Cited. Review.
Dephosphorylation of the adaptor LAT and phospholipase C-γ by SHP-1 inhibits natural killer cell cytotoxicity.
Omri Matalon, Sophia Fried, +5 authors, Mira Barda-Saad.
Sci Signal, 2016 May 26; 9(429). PMID: 27221712
Breaking Free of Control: How Conventional T Cells Overcome Regulatory T Cell Suppression.
Emily R Mercadante, Ulrike M Lorenz.
Front Immunol, 2016 Jun 01; 7. PMID: 27242798    Free PMC article.
Co-stimulate or Co-inhibit Regulatory T Cells, Which Side to Go?
Weifeng Liu, Steven C Almo, Xingxing Zang.
Immunol Invest, 2016 Oct 25; 45(8). PMID: 27419268
Spatially selective depletion of tumor-associated regulatory T cells with near-infrared photoimmunotherapy.
Kazuhide Sato, Noriko Sato, +5 authors, Hisataka Kobayashi.
Sci Transl Med, 2016 Aug 19; 8(352). PMID: 27535621    Free PMC article.
Engineered T cells: the promise and challenges of cancer immunotherapy.
Andrew D Fesnak, Carl H June, Bruce L Levine.
Nat Rev Cancer, 2016 Aug 24; 16(9). PMID: 27550819    Free PMC article.
Highly Cited. Review.
Worse outcome in breast cancer with higher tumor-infiltrating FOXP3+ Tregs : a systematic review and meta-analysis.
Jiafeng Shou, Zhigang Zhang, +2 authors, Jian Huang.
BMC Cancer, 2016 Aug 28; 16. PMID: 27566250    Free PMC article.
Systematic Review.
An essential role for the IL-2 receptor in Treg cell function.
Takatoshi Chinen, Arun K Kannan, +7 authors, Alexander Y Rudensky.
Nat Immunol, 2016 Oct 21; 17(11). PMID: 27595233    Free PMC article.
Highly Cited.
Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression.
Valerie A Gerriets, Rigel J Kishton, +10 authors, Jeffrey C Rathmell.
Nat Immunol, 2016 Nov 01; 17(12). PMID: 27695003    Free PMC article.
Highly Cited.
Low-dose IL-2 selectively activates subsets of CD4+ Tregs and NK cells.
Masahiro Hirakawa, Tiago R Matos, +16 authors, Jerome Ritz.
JCI Insight, 2016 Nov 05; 1(18). PMID: 27812545    Free PMC article.
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.
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.
Improved cancer immunotherapy by a CD25-mimobody conferring selectivity to human interleukin-2.
Natalia Arenas-Ramirez, Chao Zou, +11 authors, Onur Boyman.
Sci Transl Med, 2016 Dec 03; 8(367). PMID: 27903862
Regulatory T cells in cancer immunotherapy.
Atsushi Tanaka, Shimon Sakaguchi.
Cell Res, 2016 Dec 21; 27(1). PMID: 27995907    Free PMC article.
Highly Cited. Review.
Strong adhesion by regulatory T cells induces dendritic cell cytoskeletal polarization and contact-dependent lethargy.
Jiahuan Chen, Anutosh Ganguly, +14 authors, Yan Shi.
J Exp Med, 2017 Jan 14; 214(2). PMID: 28082358    Free PMC article.
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
Cbl-b Deficiency Mediates Resistance to Programmed Death-Ligand 1/Programmed Death-1 Regulation.
Mai Fujiwara, Emily J Anstadt, Robert B Clark.
Front Immunol, 2017 Feb 12; 8. PMID: 28184224    Free PMC article.
Higher densities of Foxp3+ regulatory T cells are associated with better prognosis in triple-negative breast cancer.
Joe Yeong, Aye Aye Thike, +6 authors, Jabed Iqbal.
Breast Cancer Res Treat, 2017 Feb 25; 163(1). PMID: 28233108
Phase I Escalating-Dose Trial of CAR-T Therapy Targeting CEA+ Metastatic Colorectal Cancers.
Chengcheng Zhang, Zhe Wang, +20 authors, Cheng Qian.
Mol Ther, 2017 Apr 04; 25(5). PMID: 28366766    Free PMC article.
Highly Cited.
Synergistic Immunostimulatory Effects and Therapeutic Benefit of Combined Histone Deacetylase and Bromodomain Inhibition in Non-Small Cell Lung Cancer.
Dennis O Adeegbe, Yan Liu, +22 authors, Kwok-Kin Wong.
Cancer Discov, 2017 Apr 15; 7(8). PMID: 28408401    Free PMC article.
Highly Cited.
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.
T Cells Deficient in the Tyrosine Phosphatase SHP-1 Resist Suppression by Regulatory T Cells.
Emily R Mercadante, Ulrike M Lorenz.
J Immunol, 2017 May 28; 199(1). PMID: 28550200    Free PMC article.
Interferon-γ Drives Treg Fragility to Promote Anti-tumor Immunity.
Abigail E Overacre-Delgoffe, Maria Chikina, +15 authors, Dario A A Vignali.
Cell, 2017 May 30; 169(6). PMID: 28552348    Free PMC article.
Highly Cited.
Cblb-deficient T cells are less susceptible to PD-L1-mediated inhibition.
Sebastian Peer, Gottfried Baier, Thomas Gruber.
Oncotarget, 2017 Jun 15; 8(26). PMID: 28611299    Free PMC article.
A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma.
Donald M O'Rourke, MacLean P Nasrallah, +18 authors, Marcela V Maus.
Sci Transl Med, 2017 Jul 21; 9(399). PMID: 28724573    Free PMC article.
Highly Cited.
Low-Dose Cyclophosphamide Induces Antitumor T-Cell Responses, which Associate with Survival in Metastatic Colorectal Cancer.
Martin Scurr, Tom Pembroke, +13 authors, Andrew Godkin.
Clin Cancer Res, 2017 Sep 01; 23(22). PMID: 28855352    Free PMC article.
PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome.
Hashem O Alsaab, Samaresh Sau, +4 authors, Arun K Iyer.
Front Pharmacol, 2017 Sep 08; 8. PMID: 28878676    Free PMC article.
Highly Cited. Review.
In-vitro effect of pembrolizumab on different T regulatory cell subsets.
S M Toor, A S Syed Khaja, I Alkurd, E Elkord.
Clin Exp Immunol, 2017 Oct 01; 191(2). PMID: 28963773    Free PMC article.
Glycogen Synthase Kinase-3 Modulates Cbl-b and Constrains T Cell Activation.
Charles W Tran, Samuel D Saibil, +14 authors, Pamela S Ohashi.
J Immunol, 2017 Nov 08; 199(12). PMID: 29109121
Comparative transcriptome analysis reveals distinct genetic modules associated with Helios expression in intratumoral regulatory T cells.
Kathleen Yates, Kevin Bi, +2 authors, Hye-Jung Kim.
Proc Natl Acad Sci U S A, 2018 Feb 15; 115(9). PMID: 29440380    Free PMC article.
A reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy.
Xuexiang Du, Fei Tang, +14 authors, Yang Liu.
Cell Res, 2018 Feb 24; 28(4). PMID: 29472691    Free PMC article.
Highly Cited.
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.
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.
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Foxp3+ T Regulatory Cells: Still Many Unanswered Questions-A Perspective After 20 Years of Study.
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Front Immunol, 2018 Jun 06; 9. PMID: 29868011    Free PMC article.
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Targeting EZH2 Reprograms Intratumoral Regulatory T Cells to Enhance Cancer Immunity.
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Cell Rep, 2018 Jun 14; 23(11). PMID: 29898397    Free PMC article.
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Resistance to Radiotherapy and PD-L1 Blockade Is Mediated by TIM-3 Upregulation and Regulatory T-Cell Infiltration.
Ayman Oweida, Mohammad K Hararah, +14 authors, Sana D Karam.
Clin Cancer Res, 2018 Jul 26; 24(21). PMID: 30042205    Free PMC article.
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Clin Cancer Res, 2018 Aug 02; 24(22). PMID: 30065096
A Phase I/IIa Trial Using CD19-Targeted Third-Generation CAR T Cells for Lymphoma and Leukemia.
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Clin Cancer Res, 2018 Aug 12; 24(24). PMID: 30097433
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Decreased Suppression and Increased Phosphorylated STAT3 in Regulatory T Cells are Associated with Benefit from Adjuvant PD-1 Blockade in Resected Metastatic Melanoma.
David M Woods, Rupal Ramakrishnan, +4 authors, Jeffrey S Weber.
Clin Cancer Res, 2018 Aug 23; 24(24). PMID: 30131384    Free PMC article.
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Clin Exp Immunol, 2019 Jan 30; 196(3). PMID: 30693485    Free PMC article.
α-PD-1 therapy elevates Treg/Th balance and increases tumor cell pSmad3 that are both targeted by α-TGFβ antibody to promote durable rejection and immunity in squamous cell carcinomas.
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J Immunother Cancer, 2019 Mar 06; 7(1). PMID: 30832732    Free PMC article.
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CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production.
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Balancing STAT Activity as a Therapeutic Strategy.
Kelsey L Polak, Noah M Chernosky, +2 authors, Mark W Jackson.
Cancers (Basel), 2019 Nov 07; 11(11). PMID: 31684144    Free PMC article.
The Binary Classification Of Chronic Diseases.
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T-Regulatory Cells In Tumor Progression And Therapy.
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Cancer Manag Res, 2020 Jan 11; 11. PMID: 31920383    Free PMC article.
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Modulation of tumor microenvironment for immunotherapy: focus on nanomaterial-based strategies.
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The Proportion and Prognostic Significance of T-Regulatory Cells in Patients with Gynecological Cancers: A Systematic Review and Meta-Analysis.
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Overproduction of IL-2 by Cbl-b deficient CD4+ T cells provides resistance against regulatory T cells.
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Alternative macrophage polarisation associated with resistance to anti-PD1 blockade is possibly supported by the splicing of FKBP51 immunophilin in melanoma patients.
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Tumor-Infiltrating Lymphocytes and Their Prognostic Value in Cutaneous Melanoma.
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Front Immunol, 2020 Oct 06; 11. PMID: 33013886    Free PMC article.
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Heterologous Prime Boost Vaccination Induces Protective Melanoma-Specific CD8+ T Cell Responses.
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Mol Ther Oncolytics, 2020 Nov 20; 19. PMID: 33209978    Free PMC article.
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Robert A Kazmierczak, Bakul Dhagat-Mehta, +5 authors, Yves C Chabu.
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Machine and deep learning approaches for cancer drug repurposing.
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FOXP3 in Melanoma with Regression: Between Tumoral Expression and Regulatory T Cell Upregulation.
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J Immunol Res, 2020 Dec 05; 2020. PMID: 33274240    Free PMC article.
Revisiting the role of CD4+ T cells in cancer immunotherapy-new insights into old paradigms.
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Tackling Immune Targets for Breast Cancer: Beyond PD-1/PD-L1 Axis.
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Parking CAR T Cells in Tumours: Oncolytic Viruses as Valets or Vandals?
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Clinical Significance of Tumor Microenvironment in Acral Melanoma: A Large Single-Institution Study of Caucasians.
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A Biological Circuit Involving Mef2c, Mef2d, and Hdac9 Controls the Immunosuppressive Functions of CD4+Foxp3+ T-Regulatory Cells.
Eros Di Giorgio, Liqing Wang, +8 authors, Wayne W Hancock.
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Mogamulizumab in Combination with Durvalumab or Tremelimumab in Patients with Advanced Solid Tumors: A Phase I Study.
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Natural Killer Cells and Type 1 Innate Lymphoid Cells in Hepatocellular Carcinoma: Current Knowledge and Future Perspectives.
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Aptamer-mediated transcriptional gene silencing of Fox p 3 inhibits regulatory T cells and potentiates antitumor response.
Andrea J Manrique-Rincón, Luciana P Ruas, +6 authors, Marcio C Bajgelman.
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Activation and expansion of T-follicular helper cells in chronic lymphocytic leukemia nurselike cell co-cultures.
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Leukemia, 2022 Feb 13; 36(5). PMID: 35149845
A Specific CD44lo CD25lo Subpopulation of Regulatory T Cells Inhibits Anti-Leukemic Immune Response and Promotes the Progression in a Mouse Model of Chronic Lymphocytic Leukemia.
Agnieszka Goral, Malgorzata Firczuk, +15 authors, Angelika Muchowicz.
Front Immunol, 2022 Mar 18; 13. PMID: 35296093    Free PMC article.
Revisiting the melanomagenic pathways and current therapeutic approaches.
Pavan Kumar Dhanyamraju, Solomon Rotimi, Priyanjali Bhattacharya, Trupti N Patel.
Mol Biol Rep, 2022 Apr 11;. PMID: 35397763
CD8+ T Cells in SARS-CoV-2 Induced Disease and Cancer-Clinical Perspectives.
Keywan Mortezaee, Jamal Majidpoor.
Front Immunol, 2022 Apr 19; 13. PMID: 35432340    Free PMC article.
Tumors and Cytomegalovirus: An Intimate Interplay.
Georges Herbein.
Viruses, 2022 Apr 24; 14(4). PMID: 35458542    Free PMC article.
Obesity modulates the immune macroenvironment associated with breast cancer development.
Aleida Núñez-Ruiz, Flor Sánchez-Brena, +2 authors, Gloria Soldevila.
PLoS One, 2022 Apr 27; 17(4). PMID: 35472214    Free PMC article.