Review
. 2020 Mar; 20(1):e4.
doi: 10.4110/in.2020.20.e4.

Regulatory T Cells in Tumor Microenvironment and Approach for Anticancer Immunotherapy

Jung-Ho Kim 1 Beom Seok Kim 1 Sang-Kyou Lee 1 
Affiliations
  • PMID: 32158592
  •     118 References
  •     15 citations

Abstract

Tregs have a role in immunological tolerance and immune homeostasis by suppressing immune reactions, and its therapeutic potential is critical in autoimmune diseases and cancers. There have been multiple studies conducted on Tregs because of their roles in immune suppression and therapeutic potential. In tumor immunity, Tregs can promote the development and progression of tumors by preventing effective anti-tumor immune responses in tumor-bearing hosts. High infiltration of Tregs into tumor tissue results in poor survival in various types of cancer patients. Identifying factors specifically expressed in Tregs that affect the maintenance of stability and function of Tregs is important for understanding cancer pathogenesis and identifying therapeutic targets. Thus, manipulation of Tregs is a promising anticancer strategy, but finding markers for Treg-specific depletion and controlling these cells require fine-tuning and further research. Here, we discuss the role of Tregs in cancer and the development of Treg-targeted therapies to promote cancer immunotherapy.

Keywords: Immunotherapy; T-lymphocytes, regulatory (Treg cells); Tumor microenvironment.

Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers.
Cécile Badoual, Stéphane Hans, +9 authors, Eric Tartour.
Clin Cancer Res, 2006 Jan 24; 12(2). PMID: 16428488
Highly Cited.
A role for the transcription factor Helios in human CD4(+)CD25(+) regulatory T cells.
Derese Getnet, Joseph F Grosso, +10 authors, Charles G Drake.
Mol Immunol, 2010 Mar 17; 47(7-8). PMID: 20226531    Free PMC article.
Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state.
T Takahashi, Y Kuniyasu, +5 authors, S Sakaguchi.
Int Immunol, 1999 Jan 14; 10(12). PMID: 9885918
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.
Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome.
Michael Gobert, Isabelle Treilleux, +15 authors, Christine Ménétrier-Caux.
Cancer Res, 2009 Feb 27; 69(5). PMID: 19244125
Highly Cited.
The A2B adenosine receptor impairs the maturation and immunogenicity of dendritic cells.
Jeffrey M Wilson, William G Ross, +5 authors, Peter B Ernst.
J Immunol, 2009 Apr 04; 182(8). PMID: 19342636    Free PMC article.
CCR4 as a novel molecular target for immunotherapy of cancer.
Takashi Ishida, Ryuzo Ueda.
Cancer Sci, 2006 Sep 06; 97(11). PMID: 16952304
Review.
The EGR2 targets LAG-3 and 4-1BB describe and regulate dysfunctional antigen-specific CD8+ T cells in the tumor microenvironment.
Jason B Williams, Brendan L Horton, +3 authors, Thomas F Gajewski.
J Exp Med, 2017 Jan 25; 214(2). PMID: 28115575    Free PMC article.
Highly Cited.
BACH transcription factors in innate and adaptive immunity.
Kazuhiko Igarashi, Tomohiro Kurosaki, Rahul Roychoudhuri.
Nat Rev Immunol, 2017 May 04; 17(7). PMID: 28461702
Review.
Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression.
Silvia Deaglio, Karen M Dwyer, +10 authors, Simon C Robson.
J Exp Med, 2007 May 16; 204(6). PMID: 17502665    Free PMC article.
Highly Cited.
Control of regulatory T cell development by the transcription factor Foxp3.
Shohei Hori, Takashi Nomura, Shimon Sakaguchi.
Science, 2003 Jan 11; 299(5609). PMID: 12522256
Highly Cited.
Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer.
Paul Salama, Michael Phillips, +5 authors, Barry Iacopetta.
J Clin Oncol, 2008 Dec 10; 27(2). PMID: 19064967
Highly Cited.
The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3.
C L Bennett, J Christie, +7 authors, H D Ochs.
Nat Genet, 2001 Jan 04; 27(1). PMID: 11137993
Highly Cited.
Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.
Julie R Brahmer, Scott S Tykodi, +23 authors, Jon M Wigginton.
N Engl J Med, 2012 Jun 05; 366(26). PMID: 22658128    Free PMC article.
Highly Cited.
VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer.
Magali Terme, Simon Pernot, +7 authors, Julien Taieb.
Cancer Res, 2012 Oct 31; 73(2). PMID: 23108136
Highly Cited.
Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity.
J Shimizu, S Yamazaki, S Sakaguchi.
J Immunol, 1999 Nov 24; 163(10). PMID: 10553041
Highly Cited.
CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production.
A M Thornton, E M Shevach.
J Exp Med, 1998 Jul 22; 188(2). PMID: 9670041    Free PMC article.
Highly Cited.
Suppression of antitumor immunity by IL-10 and TGF-beta-producing T cells infiltrating the growing tumor: influence of tumor environment on the induction of CD4+ and CD8+ regulatory T cells.
Andrew G Jarnicki, Joanne Lysaght, Stephen Todryk, Kingston H G Mills.
J Immunol, 2006 Jul 05; 177(2). PMID: 16818744
[Anti-CCR4 mAb and regulatory T cells].
Koji Kurose, Yoshihiro Ohue, Mikio Oka.
Gan To Kagaku Ryoho, 2013 Sep 21; 40(9). PMID: 24047773
Human lung tumor FOXP3+ Tregs upregulate four "Treg-locking" transcription factors.
Tatiana Akimova, Tianyi Zhang, +11 authors, Wayne W Hancock.
JCI Insight, 2017 Aug 18; 2(16). PMID: 28814673    Free PMC article.
Improved survival with ipilimumab in patients with metastatic melanoma.
F Stephen Hodi, Steven J O'Day, +26 authors, Walter J Urba.
N Engl J Med, 2010 Jun 08; 363(8). PMID: 20525992    Free PMC article.
Highly Cited.
CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients.
Andrew J Rech, Rosemarie Mick, +13 authors, Robert H Vonderheide.
Sci Transl Med, 2012 May 18; 4(134). PMID: 22593175    Free PMC article.
Highly Cited.
Emerging roles of T helper 17 and regulatory T cells in lung cancer progression and metastasis.
Erin A Marshall, Kevin W Ng, +15 authors, Wan L Lam.
Mol Cancer, 2016 Oct 28; 15(1). PMID: 27784305    Free PMC article.
Review.
Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells.
Nabila Seddiki, Brigitte Santner-Nanan, +9 authors, Barbara Fazekas de St Groth.
J Exp Med, 2006 Jul 05; 203(7). PMID: 16818676    Free PMC article.
Highly Cited.
Extracellular adenosine-mediated modulation of regulatory T cells.
Akio Ohta, Michail Sitkovsky.
Front Immunol, 2014 Jul 30; 5. PMID: 25071765    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.
Interleukin-35 Limits Anti-Tumor Immunity.
Meghan E Turnis, Deepali V Sawant, +7 authors, Dario A A Vignali.
Immunity, 2016 Feb 14; 44(2). PMID: 26872697    Free PMC article.
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.
Regulatory T cell-resistant CD8+ T cells induced by glucocorticoid-induced tumor necrosis factor receptor signaling.
Hiroyoshi Nishikawa, Takuma Kato, +6 authors, Hiroshi Shiku.
Cancer Res, 2008 Jul 18; 68(14). PMID: 18632650
Highly prevalent colorectal cancer-infiltrating LAP⁺ Foxp3⁻ T cells exhibit more potent immunosuppressive activity than Foxp3⁺ regulatory T cells.
M Scurr, K Ladell, +10 authors, A Godkin.
Mucosal Immunol, 2013 Sep 26; 7(2). PMID: 24064667    Free PMC article.
An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires.
Chyi-Song Hsieh, Ye Zheng, +2 authors, Alexander Y Rudensky.
Nat Immunol, 2006 Mar 15; 7(4). PMID: 16532000
Highly Cited.
Relationship between B7-H4, regulatory T cells, and patient outcome in human ovarian carcinoma.
Ilona Kryczek, Shuang Wei, +6 authors, Weiping Zou.
Cancer Res, 2007 Sep 19; 67(18). PMID: 17875732
Highly Cited.
Targeting TGF-β Signaling in Cancer.
Selcuk Colak, Peter Ten Dijke.
Trends Cancer, 2017 Jul 19; 3(1). PMID: 28718426
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.
Sialyl Lewis x (CD15s) identifies highly differentiated and most suppressive FOXP3high regulatory T cells in humans.
Makoto Miyara, Driss Chader, +14 authors, Guy Gorochov.
Proc Natl Acad Sci U S A, 2015 May 28; 112(23). PMID: 26015572    Free PMC article.
Highly Cited.
Dendritic cell vaccination in combination with anti-CD25 monoclonal antibody treatment: a phase I/II study in metastatic melanoma patients.
Joannes F M Jacobs, Cornelis J A Punt, +8 authors, Gosse J Adema.
Clin Cancer Res, 2010 Aug 26; 16(20). PMID: 20736326
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.
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
Suzanne L Topalian, F Stephen Hodi, +27 authors, Mario Sznol.
N Engl J Med, 2012 Jun 05; 366(26). PMID: 22658127    Free PMC article.
Highly Cited.
Phenotypical and functional specialization of FOXP3+ regulatory T cells.
Daniel J Campbell, Meghan A Koch.
Nat Rev Immunol, 2011 Jan 27; 11(2). PMID: 21267013    Free PMC article.
Highly Cited. Review.
Phase I Trial of M7824 (MSB0011359C), a Bifunctional Fusion Protein Targeting PD-L1 and TGFβ, in Advanced Solid Tumors.
Julius Strauss, Christopher R Heery, +12 authors, James L Gulley.
Clin Cancer Res, 2018 Jan 05; 24(6). PMID: 29298798    Free PMC article.
Highly Cited.
Differential PI3Kδ Signaling in CD4+ T-cell Subsets Enables Selective Targeting of T Regulatory Cells to Enhance Cancer Immunotherapy.
Shamim Ahmad, Rasha Abu-Eid, +8 authors, Samir N Khleif.
Cancer Res, 2017 Jan 22; 77(8). PMID: 28108509
Detection of self-reactive CD8⁺ T cells with an anergic phenotype in healthy individuals.
Yuka Maeda, Hiroyoshi Nishikawa, +8 authors, Shimon Sakaguchi.
Science, 2014 Dec 20; 346(6216). PMID: 25525252
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.
Foxp3 programs the development and function of CD4+CD25+ regulatory T cells.
Jason D Fontenot, Marc A Gavin, Alexander Y Rudensky.
Nat Immunol, 2003 Mar 04; 4(4). PMID: 12612578
Highly Cited.
Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate.
Ye Zheng, Steven Josefowicz, +3 authors, Alexander Y Rudensky.
Nature, 2010 Jan 15; 463(7282). PMID: 20072126    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.
Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses.
Nicole Joller, Ester Lozano, +13 authors, Vijay K Kuchroo.
Immunity, 2014 Apr 22; 40(4). PMID: 24745333    Free PMC article.
Highly Cited.
Antigen-specific peripheral shaping of the natural regulatory T cell population.
Stephanie K Lathrop, Nicole A Santacruz, +2 authors, Chyi-Song Hsieh.
J Exp Med, 2008 Dec 10; 205(13). PMID: 19064700    Free PMC article.
Highly Cited.
Induction of tolerance by IL-10-treated dendritic cells.
K Steinbrink, M Wölfl, +2 authors, A H Enk.
J Immunol, 1997 Nov 20; 159(10). PMID: 9366401
Highly Cited.
Tumor infiltrating Foxp3+ regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients.
Rebecca P Petersen, Michael J Campa, +4 authors, Edward F Patz.
Cancer, 2006 Nov 14; 107(12). PMID: 17099880
Highly Cited.
Peripherally induced tregs - role in immune homeostasis and autoimmunity.
Mahesh Yadav, Stephen Stephan, Jeffrey A Bluestone.
Front Immunol, 2013 Aug 24; 4. PMID: 23966994    Free PMC article.
Highly Cited.
Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer.
Marcus C B Tan, Peter S Goedegebuure, +6 authors, David C Linehan.
J Immunol, 2009 Jan 22; 182(3). PMID: 19155524    Free PMC article.
Highly Cited.
Deciphering and reversing tumor immune suppression.
Greg T Motz, George Coukos.
Immunity, 2013 Jul 31; 39(1). PMID: 23890064    Free PMC article.
Highly Cited. Review.
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.
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.
IFN-gamma controls the generation/activation of CD4+ CD25+ regulatory T cells in antitumor immune response.
Hiroyoshi Nishikawa, Takuma Kato, +6 authors, Hiroshi Shiku.
J Immunol, 2005 Sep 24; 175(7). PMID: 16177085
Cytokine levels correlate with immune cell infiltration after anti-VEGF therapy in preclinical mouse models of breast cancer.
Christina L Roland, Kristi D Lynn, +3 authors, Rolf A Brekken.
PLoS One, 2009 Nov 06; 4(11). PMID: 19888452    Free PMC article.
Regulatory T Cells: Molecular and Cellular Basis for Immunoregulation.
Yosuke Togashi, Hiroyoshi Nishikawa.
Curr Top Microbiol Immunol, 2017 Sep 08; 410. PMID: 28879523
Review.
The immunobiology of CD27 and OX40 and their potential as targets for cancer immunotherapy.
Sarah L Buchan, Anne Rogel, Aymen Al-Shamkhani.
Blood, 2017 Nov 10; 131(1). PMID: 29118006
Highly Cited. Review.
Neuropilin-1 expression on regulatory T cells enhances their interactions with dendritic cells during antigen recognition.
Milka Sarris, Kristian G Andersen, +2 authors, Alexander G Betz.
Immunity, 2008 Mar 11; 28(3). PMID: 18328743    Free PMC article.
Highly Cited.
The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity.
Chen Zhu, Ana C Anderson, +6 authors, Vijay K Kuchroo.
Nat Immunol, 2005 Nov 16; 6(12). PMID: 16286920
Highly Cited.
CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion.
Ann E Herman, Gordon J Freeman, Diane Mathis, Christophe Benoist.
J Exp Med, 2004 Jun 09; 199(11). PMID: 15184501    Free PMC article.
Highly Cited.
Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival.
Tyler J Curiel, George Coukos, +18 authors, Weiping Zou.
Nat Med, 2004 Aug 24; 10(9). PMID: 15322536
Highly Cited.
Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer.
Khaled Ali, Dalya R Soond, +11 authors, Bart Vanhaesebroeck.
Nature, 2014 Jun 12; 510(7505). PMID: 24919154    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.
Definition of target antigens for naturally occurring CD4(+) CD25(+) regulatory T cells.
Hiroyoshi Nishikawa, Takuma Kato, +8 authors, Hiroshi Shiku.
J Exp Med, 2005 Mar 09; 201(5). PMID: 15753203    Free PMC article.
Nonoverlapping roles of PD-1 and FoxP3 in maintaining immune tolerance in a novel autoimmune pancreatitis mouse model.
Baihao Zhang, Shunsuke Chikuma, +2 authors, Tasuku Honjo.
Proc Natl Acad Sci U S A, 2016 Jul 14; 113(30). PMID: 27410049    Free PMC article.
Highly Cited.
Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4.
Hye Sun Kuehn, Weiming Ouyang, +33 authors, Gulbu Uzel.
Science, 2014 Sep 13; 345(6204). PMID: 25213377    Free PMC article.
Highly Cited.
A novel splice variant of FR4 predominantly expressed in CD4+CD25+ regulatory T cells.
Zhengcai Jia, Ren Zhao, +7 authors, Yuzhang Wu.
Immunol Invest, 2009 Oct 29; 38(8). PMID: 19860584
Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody.
S Onizuka, I Tawara, +3 authors, E Nakayama.
Cancer Res, 1999 Jul 09; 59(13). PMID: 10397255
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.
TIGIT predominantly regulates the immune response via regulatory T cells.
Sema Kurtulus, Kaori Sakuishi, +6 authors, Ana C Anderson.
J Clin Invest, 2015 Sep 29; 125(11). PMID: 26413872    Free PMC article.
Highly Cited.
The role and significance of VEGFR2+ regulatory T cells in tumor immunity.
Panrong Zhu, Chenxi Hu, Kaiyuan Hui, Xiaodong Jiang.
Onco Targets Ther, 2017 Sep 19; 10. PMID: 28919780    Free PMC article.
Review.
Treg-mediated acquired resistance to immune checkpoint inhibitors.
Reem Saleh, Eyad Elkord.
Cancer Lett, 2019 May 13; 457. PMID: 31078738
Review.
Depletion of CD25(+) CD4(+) T cells and treatment with tyrosinase-related protein 2-transduced dendritic cells enhance the interferon alpha-induced, CD8(+) T-cell-dependent immune defense of B16 melanoma.
J Steitz, J Brück, +2 authors, T Tüting.
Cancer Res, 2001 Dec 26; 61(24). PMID: 11751377
Bach2 regulates homeostasis of Foxp3+ regulatory T cells and protects against fatal lung disease in mice.
Eui Ho Kim, David J Gasper, +3 authors, M Suresh.
J Immunol, 2013 Dec 25; 192(3). PMID: 24367030    Free PMC article.
Induction of FOXP3 expression in naive human CD4+FOXP3 T cells by T-cell receptor stimulation is transforming growth factor-beta dependent but does not confer a regulatory phenotype.
Dat Q Tran, Heather Ramsey, Ethan M Shevach.
Blood, 2007 Jul 24; 110(8). PMID: 17644734    Free PMC article.
Highly Cited.
The immune contexture in human tumours: impact on clinical outcome.
Wolf Herman Fridman, Franck Pagès, Catherine Sautès-Fridman, Jérôme Galon.
Nat Rev Cancer, 2012 Mar 16; 12(4). PMID: 22419253
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.
GITR triggering induces expansion of both effector and regulatory CD4+ T cells in vivo.
Ronald W van Olffen, Nathalie Koning, +6 authors, Martijn A Nolte.
J Immunol, 2009 Jun 06; 182(12). PMID: 19494272
Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade.
Rikke B Holmgaard, David A Schaer, +14 authors, Kyla E Driscoll.
J Immunother Cancer, 2018 Jun 06; 6(1). PMID: 29866156    Free PMC article.
Highly Cited.
OX40 is a potent immune-stimulating target in late-stage cancer patients.
Brendan D Curti, Magdalena Kovacsovics-Bankowski, +20 authors, Andrew D Weinberg.
Cancer Res, 2013 Nov 02; 73(24). PMID: 24177180    Free PMC article.
Highly Cited.
Inhibitory Receptors and Pathways of Lymphocytes: The Role of PD-1 in Treg Development and Their Involvement in Autoimmunity Onset and Cancer Progression.
Elena Gianchecchi, Alessandra Fierabracci.
Front Immunol, 2018 Nov 06; 9. PMID: 30386337    Free PMC article.
Highly Cited. Review.
Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation.
Ana C Anderson, Nicole Joller, Vijay K Kuchroo.
Immunity, 2016 May 19; 44(5). PMID: 27192565    Free PMC article.
Highly Cited. Review.
Regulatory T cells in cancer immunotherapy.
Hiroyoshi Nishikawa, Shimon Sakaguchi.
Curr Opin Immunol, 2014 Jan 15; 27. PMID: 24413387
Highly Cited. Review.
Discontinuation of dasatinib in patients with chronic myeloid leukaemia who have maintained deep molecular response for longer than 1 year (DADI trial): a multicentre phase 2 trial.
Jun Imagawa, Hideo Tanaka, +24 authors, DADI Trial Group.
Lancet Haematol, 2015 Dec 22; 2(12). PMID: 26686407
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.
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.
Regulatory T cells in tumor immunity.
Hiroyoshi Nishikawa, Shimon Sakaguchi.
Int J Cancer, 2010 Jun 03; 127(4). PMID: 20518016
Highly Cited. Review.
Roles of regulatory T cells in cancer immunity.
Yoshiko Takeuchi, Hiroyoshi Nishikawa.
Int Immunol, 2016 May 11; 28(8). PMID: 27160722    Free PMC article.
Highly Cited. Review.
The blockade of immune checkpoints in cancer immunotherapy.
Drew M Pardoll.
Nat Rev Cancer, 2012 Mar 23; 12(4). PMID: 22437870    Free PMC article.
Highly Cited. Review.
TIM3+FOXP3+ regulatory T cells are tissue-specific promoters of T-cell dysfunction in cancer.
Kaori Sakuishi, Shin Foong Ngiow, +4 authors, Ana C Anderson.
Oncoimmunology, 2013 Jun 05; 2(4). PMID: 23734331    Free PMC article.
Highly Cited.
ICOS controls the pool size of effector-memory and regulatory T cells.
Yvonne Burmeister, Timo Lischke, +5 authors, Andreas Hutloff.
J Immunol, 2008 Jan 08; 180(2). PMID: 18178815
BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis.
Rahul Roychoudhuri, Kiyoshi Hirahara, +27 authors, Nicholas P Restifo.
Nature, 2013 Jun 04; 498(7455). PMID: 23728300    Free PMC article.
Highly Cited.
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.
FOXP3: of mice and men.
Steven F Ziegler.
Annu Rev Immunol, 2006 Mar 23; 24. PMID: 16551248
Highly Cited. Review.
The role of dendritic cells and regulatory T cells in the regulation of allergic asthma.
Jennifer T Burchell, Deborah H Strickland, Philip A Stumbles.
Pharmacol Ther, 2009 Aug 19; 125(1). PMID: 19686776
Review.
Adaptation of TCR repertoires to self-peptides in regulatory and nonregulatory CD4+ T cells.
Jamie Wong, Reinhard Obst, +3 authors, Christophe Benoist.
J Immunol, 2007 May 22; 178(11). PMID: 17513752
CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells.
Weihong Liu, Amy L Putnam, +11 authors, Jeffrey A Bluestone.
J Exp Med, 2006 Jul 05; 203(7). PMID: 16818678    Free PMC article.
Highly Cited.
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.
The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function.
Robert J Johnston, Laetitia Comps-Agrar, +9 authors, Jane L Grogan.
Cancer Cell, 2014 Dec 04; 26(6). PMID: 25465800
Highly Cited.
ICOS+ Foxp3+ TILs in gastric cancer are prognostic markers and effector regulatory T cells associated with Helicobacter pylori.
Hirotsugu Nagase, Tomohira Takeoka, +10 authors, Hisashi Wada.
Int J Cancer, 2016 Oct 28; 140(3). PMID: 27756099
PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations.
Weiping Zou, Jedd D Wolchok, Lieping Chen.
Sci Transl Med, 2016 Mar 05; 8(328). PMID: 26936508    Free PMC article.
Highly Cited. Review.
The inhibitory cytokine IL-35 contributes to regulatory T-cell function.
Lauren W Collison, Creg J Workman, +7 authors, Dario A A Vignali.
Nature, 2007 Nov 23; 450(7169). PMID: 18033300
Highly Cited.
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.
CD4+CD25high regulatory cells in human peripheral blood.
C Baecher-Allan, J A Brown, G J Freeman, D A Hafler.
J Immunol, 2001 Jul 24; 167(3). PMID: 11466340
Highly Cited.
Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells.
Stefani Spranger, Robbert M Spaapen, +4 authors, Thomas F Gajewski.
Sci Transl Med, 2013 Aug 30; 5(200). PMID: 23986400    Free PMC article.
Highly Cited.
Tim-3 and its role in regulating anti-tumor immunity.
Madhumita Das, Chen Zhu, Vijay K Kuchroo.
Immunol Rev, 2017 Mar 05; 276(1). PMID: 28258697    Free PMC article.
Highly Cited. Review.
Regulatory T cells increase the avidity of primary CD8+ T cell responses and promote memory.
Luigia Pace, Andy Tempez, +5 authors, Sebastian Amigorena.
Science, 2012 Nov 01; 338(6106). PMID: 23112334
Targeting VEGFR2 with Ramucirumab strongly impacts effector/ activated regulatory T cells and CD8+ T cells in the tumor microenvironment.
Yasuko Tada, Yosuke Togashi, +7 authors, Kohei Shitara.
J Immunother Cancer, 2018 Oct 14; 6(1). PMID: 30314524    Free PMC article.
Induction of peripheral T cell tolerance in vivo requires CTLA-4 engagement.
V L Perez, L Van Parijs, +3 authors, A K Abbas.
Immunity, 1997 Apr 01; 6(4). PMID: 9133420
Highly Cited.
VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors.
Thibault Voron, Orianne Colussi, +15 authors, Magali Terme.
J Exp Med, 2015 Jan 21; 212(2). PMID: 25601652    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.
Tumor immunotherapy directed at PD-1.
Antoni Ribas.
N Engl J Med, 2012 Jun 05; 366(26). PMID: 22658126
Highly Cited.
Clinical experience with denileukin diftitox (ONTAK).
Francine Foss.
Semin Oncol, 2006 Mar 07; 33(1 Suppl 3). PMID: 16516670
Review.
Prognostic role of FOXP3+ regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer.
Sylvain Ladoire, François Martin, François Ghiringhelli.
Cancer Immunol Immunother, 2011 Jun 07; 60(7). PMID: 21644034
Highly Cited. Review.
Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase.
Catherine Uyttenhove, Luc Pilotte, +5 authors, Benoît J Van den Eynde.
Nat Med, 2003 Sep 23; 9(10). PMID: 14502282
Highly Cited.
Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor.
Makoto Miyara, Yumiko Yoshioka, +15 authors, Shimon Sakaguchi.
Immunity, 2009 May 26; 30(6). PMID: 19464196
Highly Cited.
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Eui-Cheol Shin.
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The Resistance Mechanisms of Checkpoint Inhibitors in Solid Tumors.
Evangelos Koustas, Panagiotis Sarantis, Athanasios G Papavassiliou, Michalis V Karamouzis.
Biomolecules, 2020 Apr 30; 10(5). PMID: 32344837    Free PMC article.
Review.
Senescent Tumor CD8+ T Cells: Mechanisms of Induction and Challenges to Immunotherapy.
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Cancers (Basel), 2020 Oct 04; 12(10). PMID: 33008037    Free PMC article.
Review.
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Stefan Forster, Ramin Radpour.
Front Oncol, 2020 Nov 27; 10. PMID: 33240813    Free PMC article.
Review.
Immunotherapy in Solid Tumors and Gut Microbiota: The Correlation-A Special Reference to Colorectal Cancer.
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Cancers (Basel), 2020 Dec 31; 13(1). PMID: 33375686    Free PMC article.
Review.
Polyvinyl Alcohol Carbazate as a Polymer-Based Antitumoral Agent.
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Front Oncol, 2021 Jan 29; 10. PMID: 33505913    Free PMC article.
Inflammation-Driven Breast Tumor Cell Plasticity: Stemness/EMT, Therapy Resistance and Dormancy.
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Front Oncol, 2021 Feb 16; 10. PMID: 33585241    Free PMC article.
Review.
Oncolytic virotherapy reverses the immunosuppressive tumor microenvironment and its potential in combination with immunotherapy.
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Review.
Expression and clinicopathological significance of Foxp3 and VISTA in cervical cancer.
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Am J Transl Res, 2021 Oct 16; 13(9). PMID: 34650712    Free PMC article.
[Peripheral Blood Inflammation Indicators as Predictive Indicators in 
Immunotherapy of Advanced Non-small Cell Lung Cancer].
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Zhongguo Fei Ai Za Zhi, 2021 Sep 16; 24(9). PMID: 34521188    Free PMC article.
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Payal Grover, Peeyush N Goel, Mark I Greene.
Front Immunol, 2021 Oct 23; 12. PMID: 34675933    Free PMC article.
Review.
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Review.
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Review.
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Review.
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