Review
. 2018 Mar; 22(4):353-363.
doi: 10.1080/14728222.2018.1451514.

FOXP3+ Treg as a therapeutic target for promoting anti-tumor immunity

Theresa L Whiteside 1 
Affiliations
  • PMID: 29532697
  •     109 References
  •     38 citations

Abstract

Regulatory T cells (Treg) characterized by expression of FOXP3 and strong immunosuppressive activity play a key role in regulating homeostasis in health and disease. Areas covered: Human Treg are highly diverse phenotypically and functionally. In the tumor microenvironment (TME), Treg are reprogrammed by the tumor, acquiring an activated phenotype and enhanced suppressor functions. No unique phenotypic markers for Treg accumulating in human tumors exist. Treg are heterogeneous and use numerous mechanisms to mediate suppression, which either silences anti-tumor immune surveillance or prevents tissue damage by activated T cells. Treg plasticity in the TME endows them with dual functionality. Treg frequency in tumors associates either with poor or improved survival. Treg responses to immune checkpoint inhibition (ICI) differ from the restorative effects ICIs induce in other immune cells. Therapies used to silence Treg, including ICIs, are only partly successful. Treg persistence and resistance to depletion are critical for maintaining homeostasis. Expert opinion: Treg emerge as a heterogeneous subset of immunosuppressive T cells, which usually, but not always, favor tumor progression. Treg are also engaged in non-immune activities that benefit the host. Therapeutic silencing of Treg in cancer requires a deeper understanding of Treg activities in human health and disease.

Keywords: Regulatory T cells (Treg); Treg and checkpoint inhibition; Treg phenotype; Treg suppressor functions; cancer; tumor microenvironment (TME).

Targeting adenosine in cancer immunotherapy: a review of recent progress.
Theresa L Whiteside.
Expert Rev Anticancer Ther, 2017 Apr 13; 17(6). PMID: 28399672    Free PMC article.
Review.
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.
Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance.
Xuefang Cao, Sheng F Cai, +4 authors, Timothy J Ley.
Immunity, 2007 Oct 09; 27(4). PMID: 17919943
Highly Cited.
The Regulatory T Cell: Jack-Of-All-Trades.
Ajithkumar Vasanthakumar, Axel Kallies.
Trends Immunol, 2015 Oct 30; 36(12). PMID: 26511762
Effects of adjuvant chemoradiotherapy on the frequency and function of regulatory T cells in patients with head and neck cancer.
Patrick J Schuler, Malgorzata Harasymczuk, +5 authors, Theresa L Whiteside.
Clin Cancer Res, 2013 Oct 08; 19(23). PMID: 24097865    Free PMC article.
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.
Regulatory T cell-derived exosomes: possible therapeutic and diagnostic tools in transplantation.
Akansha Agarwal, Giorgia Fanelli, +5 authors, Lesley A Smyth.
Front Immunol, 2014 Nov 22; 5. PMID: 25414702    Free PMC article.
Review.
Standardization, Evaluation, and Area-Under-Curve Analysis of Human and Murine Treg Suppressive Function.
Tatiana Akimova, Matthew H Levine, Ulf H Beier, Wayne W Hancock.
Methods Mol Biol, 2015 Nov 05; 1371. PMID: 26530794    Free PMC article.
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.
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.
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.
Rationale for anti-GITR cancer immunotherapy.
Deborah A Knee, Becker Hewes, Jennifer L Brogdon.
Eur J Cancer, 2016 Sep 04; 67. PMID: 27591414
Highly Cited. Review.
Preferential accumulation of regulatory T cells with highly immunosuppressive characteristics in breast tumor microenvironment.
Azharuddin Sajid Syed Khaja, Salman M Toor, +4 authors, Eyad Elkord.
Oncotarget, 2017 Apr 08; 8(20). PMID: 28388539    Free PMC article.
The effect of tumor-derived exosomes on immune regulation and cancer immunotherapy.
Theresa L Whiteside.
Future Oncol, 2017 Dec 05; 13(28). PMID: 29198150    Free PMC article.
Review.
First-in-Human Phase I Study of the Oral Inhibitor of Indoleamine 2,3-Dioxygenase-1 Epacadostat (INCB024360) in Patients with Advanced Solid Malignancies.
Gregory L Beatty, Peter J O'Dwyer, +8 authors, Thomas F Gajewski.
Clin Cancer Res, 2017 Jan 06; 23(13). PMID: 28053021    Free PMC article.
Highly Cited.
The PTEN pathway in Tregs is a critical driver of the suppressive tumor microenvironment.
Madhav D Sharma, Rahul Shinde, +12 authors, David H Munn.
Sci Adv, 2015 Nov 26; 1(10). PMID: 26601142    Free PMC article.
Highly Cited.
Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression.
Tobias Bopp, Christian Becker, +13 authors, Edgar Schmitt.
J Exp Med, 2007 May 16; 204(6). PMID: 17502663    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.
Adenosine and prostaglandin e2 production by human inducible regulatory T cells in health and disease.
Theresa L Whiteside, Edwin K Jackson.
Front Immunol, 2013 Jul 31; 4. PMID: 23898333    Free PMC article.
The role of regulatory T cells in cancer immunology.
Theresa L Whiteside.
Immunotargets Ther, 2015 Jan 01; 4. PMID: 27471721    Free PMC article.
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.
Home sweet home: the tumor microenvironment as a haven for regulatory T cells.
Beatrice Ondondo, Emma Jones, Andrew Godkin, Awen Gallimore.
Front Immunol, 2013 Jul 23; 4. PMID: 23874342    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.
Differential pattern and prognostic significance of CD4+, FOXP3+ and IL-17+ tumor infiltrating lymphocytes in ductal and lobular breast cancers.
Raoul Droeser, Inti Zlobec, +5 authors, Coya Tapia.
BMC Cancer, 2012 Apr 05; 12. PMID: 22471961    Free PMC article.
T-Regulating Hair Follicle Stem Cells.
Maria Maryanovich, Paul S Frenette.
Immunity, 2017 Jun 22; 46(6). PMID: 28636968
Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.
Naiyer A Rizvi, Matthew D Hellmann, +21 authors, Timothy A Chan.
Science, 2015 Mar 15; 348(6230). PMID: 25765070    Free PMC article.
Highly Cited.
Denileukin diftitox (ONTAK) induces a tolerogenic phenotype in dendritic cells and stimulates survival of resting Treg.
Andreas S Baur, Manfred B Lutz, +17 authors, Gerold Schuler.
Blood, 2013 Aug 21; 122(13). PMID: 23958949
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.
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.
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.
Correlation of high numbers of intratumoral FOXP3+ regulatory T cells with improved survival in germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin's lymphoma.
Alexandar Tzankov, Cecile Meier, +3 authors, Stephan Dirnhofer.
Haematologica, 2008 Jan 29; 93(2). PMID: 18223287
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.
A Distinct Function of Regulatory T Cells in Tissue Protection.
Nicholas Arpaia, Jesse A Green, +5 authors, Alexander Y Rudensky.
Cell, 2015 Sep 01; 162(5). PMID: 26317471    Free PMC article.
Highly Cited.
Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide.
M S Jordan, A Boesteanu, +5 authors, A J Caton.
Nat Immunol, 2001 Mar 29; 2(4). PMID: 11276200
Highly Cited.
Definition of two pathways for generation of suppressor T-cell activity.
S K Hu, D D Eardley, H Cantor, R K Gershon.
Proc Natl Acad Sci U S A, 1983 Jun 01; 80(12). PMID: 6222382    Free PMC article.
Indoleamine 2,3-Dioxygenase and Tolerance: Where Are We Now?
Andrew L Mellor, Henrique Lemos, Lei Huang.
Front Immunol, 2017 Nov 23; 8. PMID: 29163470    Free PMC article.
Review.
Interaction of TNF with TNF receptor type 2 promotes expansion and function of mouse CD4+CD25+ T regulatory cells.
Xin Chen, Monika Bäumel, +2 authors, Joost J Oppenheim.
J Immunol, 2007 Jun 21; 179(1). PMID: 17579033
Highly Cited.
Effect of nasopharyngeal carcinoma-derived exosomes on human regulatory T cells.
Dhafer Mrizak, Nathalie Martin, +9 authors, Nadira Delhem.
J Natl Cancer Inst, 2014 Dec 17; 107(1). PMID: 25505237
Highly Cited.
Targeting CD73 in the tumor microenvironment with MEDI9447.
Carl M Hay, Erin Sult, +15 authors, Kris F Sachsenmeier.
Oncoimmunology, 2016 Sep 14; 5(8). PMID: 27622077    Free PMC article.
Highly Cited.
Regulatory T cells: recommendations to simplify the nomenclature.
Abul K Abbas, Christophe Benoist, +12 authors, Steve F Ziegler.
Nat Immunol, 2013 Mar 20; 14(4). PMID: 23507634
Highly Cited.
Tumor-derived exosomes regulate expression of immune function-related genes in human T cell subsets.
Laurent Muller, Masato Mitsuhashi, +2 authors, Theresa L Whiteside.
Sci Rep, 2016 Feb 05; 6. PMID: 26842680    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.
Human T regulatory cells can use the perforin pathway to cause autologous target cell death.
William J Grossman, James W Verbsky, +3 authors, Timothy J Ley.
Immunity, 2004 Oct 16; 21(4). PMID: 15485635
Highly Cited.
Human CD4+ CD39+ regulatory T cells produce adenosine upon co-expression of surface CD73 or contact with CD73+ exosomes or CD73+ cells.
P J Schuler, Z Saze, +8 authors, T L Whiteside.
Clin Exp Immunol, 2014 Apr 23; 177(2). PMID: 24749746    Free PMC article.
Highly Cited.
Targeting cancer-derived adenosine: new therapeutic approaches.
Arabella Young, Deepak Mittal, John Stagg, Mark J Smyth.
Cancer Discov, 2014 Jul 19; 4(8). PMID: 25035124
Highly Cited. Review.
Treg depletion potentiates checkpoint inhibition in claudin-low breast cancer.
Nicholas A Taylor, Sarah C Vick, +10 authors, Jonathan S Serody.
J Clin Invest, 2017 Aug 22; 127(9). PMID: 28825599    Free PMC article.
Highly Cited.
MicroRNA-Containing T-Regulatory-Cell-Derived Exosomes Suppress Pathogenic T Helper 1 Cells.
Isobel S Okoye, Stephanie M Coomes, +5 authors, Mark S Wilson.
Immunity, 2014 Sep 18; 41(3). PMID: 28903020    Free PMC article.
Human tumor-derived exosomes (TEX) regulate Treg functions via cell surface signaling rather than uptake mechanisms.
Laurent Muller, Patricia Simms, +4 authors, Theresa L Whiteside.
Oncoimmunology, 2017 Sep 19; 6(8). PMID: 28919985    Free PMC article.
Highly Cited.
CD39: A complementary target to immune checkpoints to counteract tumor-mediated immunosuppression.
Nathalie Bonnefoy, Jérémy Bastid, +2 authors, Jean-François Eliaou.
Oncoimmunology, 2015 Jul 15; 4(5). PMID: 26155397    Free PMC article.
Human circulating CD4+CD25highFoxp3+ regulatory T cells kill autologous CD8+ but not CD4+ responder cells by Fas-mediated apoptosis.
Laura Strauss, Christoph Bergmann, Theresa L Whiteside.
J Immunol, 2009 Jan 22; 182(3). PMID: 19155494    Free PMC article.
What are regulatory T cells (Treg) regulating in cancer and why?
Theresa L Whiteside.
Semin Cancer Biol, 2012 Apr 03; 22(4). PMID: 22465232    Free PMC article.
Highly Cited. Review.
Regulatory T Cells in Skin Facilitate Epithelial Stem Cell Differentiation.
Niwa Ali, Bahar Zirak, +18 authors, Michael D Rosenblum.
Cell, 2017 May 30; 169(6). PMID: 28552347    Free PMC article.
Highly Cited.
IDO, PTEN-expressing Tregs and control of antigen-presentation in the murine tumor microenvironment.
David H Munn, Madhav D Sharma, Theodore S Johnson, Paulo Rodriguez.
Cancer Immunol Immunother, 2017 May 11; 66(8). PMID: 28488123    Free PMC article.
Review.
Foxp3 expression in T regulatory cells and other cell lineages.
Christel Devaud, Phillip K Darcy, Michael H Kershaw.
Cancer Immunol Immunother, 2014 Jul 27; 63(9). PMID: 25063364
Review.
Interleukin-35: Expanding Its Job Profile.
Deepali V Sawant, Kristia Hamilton, Dario A A Vignali.
J Interferon Cytokine Res, 2015 Apr 29; 35(7). PMID: 25919641    Free PMC article.
Review.
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.
A nonimmune function of T cells in promoting lung tumor progression.
Jesse A Green, Nicholas Arpaia, +2 authors, Alexander Y Rudensky.
J Exp Med, 2017 Oct 19; 214(12). PMID: 29038367    Free PMC article.
Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters.
Markus Feuerer, Laura Herrero, +8 authors, Diane Mathis.
Nat Med, 2009 Jul 28; 15(8). PMID: 19633656    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.
Regulatory T Cells: Molecular Actions on Effector Cells in Immune Regulation.
Asiel Arce-Sillas, Diana Denisse Álvarez-Luquín, +6 authors, Laura Adalid-Peralta.
J Immunol Res, 2016 Jun 15; 2016. PMID: 27298831    Free PMC article.
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.
PD-L1 regulates the development, maintenance, and function of induced regulatory T cells.
Loise M Francisco, Victor H Salinas, +4 authors, Arlene H Sharpe.
J Exp Med, 2009 Dec 17; 206(13). PMID: 20008522    Free PMC article.
Highly Cited.
A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism.
Janine L Coombes, Karima R R Siddiqui, +4 authors, Fiona Powrie.
J Exp Med, 2007 Jul 11; 204(8). PMID: 17620361    Free PMC article.
Highly Cited.
Tumor-derived microvesicles induce, expand and up-regulate biological activities of human regulatory T cells (Treg).
Marta Szajnik, Malgorzata Czystowska, +2 authors, Theresa L Whiteside.
PLoS One, 2010 Jul 28; 5(7). PMID: 20661468    Free PMC article.
Highly Cited.
High frequency of tumor-infiltrating FOXP3(+) regulatory T cells predicts improved survival in mismatch repair-proficient colorectal cancer patients.
Daniel M Frey, Raoul A Droeser, +7 authors, Luigi Tornillo.
Int J Cancer, 2009 Oct 27; 126(11). PMID: 19856313
Highly Cited.
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
Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.
S Sakaguchi, N Sakaguchi, +2 authors, M Toda.
J Immunol, 1995 Aug 01; 155(3). PMID: 7636184
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.
Exosomes carrying immunoinhibitory proteins and their role in cancer.
T L Whiteside.
Clin Exp Immunol, 2017 Apr 04; 189(3). PMID: 28369805    Free PMC article.
Highly Cited. Review.
A special population of regulatory T cells potentiates muscle repair.
Dalia Burzyn, Wilson Kuswanto, +8 authors, Diane Mathis.
Cell, 2013 Dec 10; 155(6). PMID: 24315098    Free PMC article.
Highly Cited.
Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma.
Jeffrey J Wallin, Johanna C Bendell, +19 authors, David F McDermott.
Nat Commun, 2016 Aug 31; 7. PMID: 27571927    Free PMC article.
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.
Introduction to Extracellular Vesicles: Biogenesis, RNA Cargo Selection, Content, Release, and Uptake.
Erik R Abels, Xandra O Breakefield.
Cell Mol Neurobiol, 2016 Apr 08; 36(3). PMID: 27053351    Free PMC article.
Highly Cited. Review.
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.
Molecular pathways: targeting the TGF-β pathway for cancer therapy.
Anna L Smith, Tyler P Robin, Heide L Ford.
Clin Cancer Res, 2012 Jun 20; 18(17). PMID: 22711703
Review.
Cancer-derived matrix metalloproteinase-9 contributes to tumor tolerance.
Bin-Quan Wang, Chun-Ming Zhang, +3 authors, Ping-Chang Yang.
J Cancer Res Clin Oncol, 2011 Aug 13; 137(10). PMID: 21833719
CD26 expression and adenosine deaminase activity in regulatory T cells (Treg) and CD4(+) T effector cells in patients with head and neck squamous cell carcinoma.
Magis Mandapathil, Miroslaw Szczepanski, +7 authors, Theresa L Whiteside.
Oncoimmunology, 2012 Aug 31; 1(5). PMID: 22934258    Free PMC article.
Adenosine and prostaglandin E2 cooperate in the suppression of immune responses mediated by adaptive regulatory T cells.
Magis Mandapathil, Miroslaw J Szczepanski, +6 authors, Theresa L Whiteside.
J Biol Chem, 2010 Jun 19; 285(36). PMID: 20558731    Free PMC article.
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.
Regulatory T-cell modulation using cyclophosphamide in vaccine approaches: a current perspective.
Dung T Le, Elizabeth M Jaffee.
Cancer Res, 2012 Jul 05; 72(14). PMID: 22761338    Free PMC article.
Highly Cited. Review.
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.
Expression of ICOS on human melanoma-infiltrating CD4+CD25highFoxp3+ T regulatory cells: implications and impact on tumor-mediated immune suppression.
Laura Strauss, Christoph Bergmann, +3 authors, Theresa L Whiteside.
J Immunol, 2008 Feb 23; 180(5). PMID: 18292519
Generation and accumulation of immunosuppressive adenosine by human CD4+CD25highFOXP3+ regulatory T cells.
Magis Mandapathil, Benedict Hilldorfer, +7 authors, Theresa L Whiteside.
J Biol Chem, 2009 Oct 28; 285(10). PMID: 19858205    Free PMC article.
Highly Cited.
The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets.
Bertrand Allard, Maria Serena Longhi, Simon C Robson, John Stagg.
Immunol Rev, 2017 Mar 05; 276(1). PMID: 28258700    Free PMC article.
Highly Cited. Review.
TNF activates a NF-kappaB-regulated cellular program in human CD45RA- regulatory T cells that modulates their suppressive function.
Meital Nagar, Jasmine Jacob-Hirsch, +7 authors, Itamar Goldstein.
J Immunol, 2010 Feb 26; 184(7). PMID: 20181891
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.
Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma.
Udaya K Liyanage, Todd T Moore, +8 authors, David C Linehan.
J Immunol, 2002 Aug 24; 169(5). PMID: 12193750
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
CTLA-4⁺ Regulatory T Cells Increased in Cetuximab-Treated Head and Neck Cancer Patients Suppress NK Cell Cytotoxicity and Correlate with Poor Prognosis.
Hyun-Bae Jie, Patrick J Schuler, +5 authors, Robert L Ferris.
Cancer Res, 2015 Apr 03; 75(11). PMID: 25832655    Free PMC article.
Highly Cited.
Cutting edge: IL-2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function.
Angela M Thornton, Erin E Donovan, Ciriaco A Piccirillo, Ethan M Shevach.
J Immunol, 2004 May 22; 172(11). PMID: 15153463
Highly Cited.
Tumor-derived microvesicles promote regulatory T cell expansion and induce apoptosis in tumor-reactive activated CD8+ T lymphocytes.
Eva U Wieckowski, Carmen Visus, +3 authors, Theresa L Whiteside.
J Immunol, 2009 Aug 21; 183(6). PMID: 19692638    Free PMC article.
Highly Cited.
Immunosuppressive effect of regulatory T lymphocytes in lung cancer, with special reference to their effects on the induction of autologous tumor-specific cytotoxic T lymphocytes.
Yoshiki Shigematsu, Takeshi Hanagiri, +8 authors, Fumihiro Tanaka.
Oncol Lett, 2012 Dec 04; 4(4). PMID: 23205074    Free PMC article.
Expansion of human T regulatory type 1 cells in the microenvironment of cyclooxygenase 2 overexpressing head and neck squamous cell carcinoma.
Christoph Bergmann, Laura Strauss, +2 authors, Theresa L Whiteside.
Cancer Res, 2007 Sep 19; 67(18). PMID: 17875728
Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer.
E Y Woo, C S Chu, +6 authors, C H June.
Cancer Res, 2001 Jun 19; 61(12). PMID: 11406550
Highly Cited.
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.
The VEGF receptor, neuropilin-1, represents a promising novel target for chronic lymphocytic leukemia patients.
Agnieszka Piechnik, Anna Dmoszynska, +5 authors, Krzysztof Giannopoulos.
Int J Cancer, 2013 Mar 01; 133(6). PMID: 23447383
Expression of PD-1 by CD4(+)CD25(+)CD127(low) Treg cells in the peripheral blood of lung cancer patients.
AnYuan Zhong, Xue Pan, MinHua Shi.
Onco Targets Ther, 2015 Aug 01; 8. PMID: 26229490    Free PMC article.
Tremelimumab (CP-675,206), a cytotoxic T lymphocyte associated antigen 4 blocking monoclonal antibody in clinical development for patients with cancer.
Antoni Ribas, Douglas C Hanson, +6 authors, Jesus Gomez-Navarro.
Oncologist, 2007 Aug 04; 12(7). PMID: 17673618
Review.
PD-1 upregulated on regulatory T cells during chronic virus infection enhances the suppression of CD8+ T cell immune response via the interaction with PD-L1 expressed on CD8+ T cells.
Hyo Jin Park, Joon Seok Park, +8 authors, Sang-Jun Ha.
J Immunol, 2015 May 03; 194(12). PMID: 25934860
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.
The prognostic value of FoxP3+ tumor-infiltrating lymphocytes in cancer: a critical review of the literature.
Ronald J deLeeuw, Sara E Kost, Juzer A Kakal, Brad H Nelson.
Clin Cancer Res, 2012 Apr 19; 18(11). PMID: 22510350
Highly Cited. Systematic Review.
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.
Antigen-specific regulatory T-cell responses to intestinal microbiota.
E V Russler-Germain, S Rengarajan, C-S Hsieh.
Mucosal Immunol, 2017 Aug 03; 10(6). PMID: 28766556    Free PMC article.
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.
A unique subset of CD4+CD25highFoxp3+ T cells secreting interleukin-10 and transforming growth factor-beta1 mediates suppression in the tumor microenvironment.
Laura Strauss, Christoph Bergmann, +3 authors, Theresa L Whiteside.
Clin Cancer Res, 2007 Aug 03; 13(15 Pt 1). PMID: 17671115
Highly Cited.
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.
Toward Precision Radiotherapy for Use with Immune Checkpoint Blockers.
Claire Vanpouille-Box, Silvia C Formenti, Sandra Demaria.
Clin Cancer Res, 2017 Jul 29; 24(2). PMID: 28751442    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.
Generation of induced regulatory T cells from primary human naïve and memory T cells.
Gavin I Ellis, Mary Catherine Reneer, +2 authors, Francesc Martí.
J Vis Exp, 2012 Apr 25; (62). PMID: 22525890    Free PMC article.
How little is known about the role of human FOXP3+ Tregs in tumors.
Tatiana Akimova, Wayne W Hancock.
Expert Opin Ther Targets, 2018 Jul 11; 22(8). PMID: 29989842    Free PMC article.
The Role of Long Non-coding RNAs in Immunotherapy Resistance.
Yuwen Zhou, Yajuan Zhu, Yao Xie, Xuelei Ma.
Front Oncol, 2019 Dec 19; 9. PMID: 31850199    Free PMC article.
Review.
Immune Checkpoints in Circulating and Tumor-Infiltrating CD4+ T Cell Subsets in Colorectal Cancer Patients.
Salman M Toor, Khaled Murshed, +3 authors, Eyad Elkord.
Front Immunol, 2020 Jan 11; 10. PMID: 31921188    Free PMC article.
Effect of pembrolizumab on CD4+ CD25+ , CD4+ LAP+ and CD4+ TIM-3+ T cell subsets.
S M Toor, V Sasidharan Nair, G Pfister, E Elkord.
Clin Exp Immunol, 2019 Jan 30; 196(3). PMID: 30693485    Free PMC article.
PCC0208025 (BMS202), a small molecule inhibitor of PD-L1, produces an antitumor effect in B16-F10 melanoma-bearing mice.
Zhengping Hu, Pengfei Yu, +7 authors, Jingwei Tian.
PLoS One, 2020 Mar 28; 15(3). PMID: 32214351    Free PMC article.
Lessons to Learn From Low-Dose Cyclosporin-A: A New Approach for Unexpected Clinical Applications.
Camila Flores, Guillemette Fouquet, +2 authors, Olivier Hermine.
Front Immunol, 2019 Apr 16; 10. PMID: 30984176    Free PMC article.
Review.
Complementary Roles of GCN5 and PCAF in Foxp3+ T-Regulatory Cells.
Yujie Liu, Chunrong Bao, +6 authors, Wayne W Hancock.
Cancers (Basel), 2019 Apr 21; 11(4). PMID: 31003455    Free PMC article.
α-GalCer and iNKT Cell-Based Cancer Immunotherapy: Realizing the Therapeutic Potentials.
Yingting Zhang, Ryan Springfield, +5 authors, Weiming Yuan.
Front Immunol, 2019 Jun 28; 10. PMID: 31244823    Free PMC article.
Review.
Differential expression of Helios, Neuropilin-1 and FoxP3 in head and neck squamous cell carcinoma (HNSCC) patients.
A A Mohamed Adil, Anil Kumar Bommanabonia, +4 authors, Neesar Ahmed.
3 Biotech, 2019 Apr 19; 9(5). PMID: 30997315    Free PMC article.
Transcriptomic Profiling of Tumor-Infiltrating CD4+TIM-3+ T Cells Reveals Their Suppressive, Exhausted, and Metastatic Characteristics in Colorectal Cancer Patients.
Varun Sasidharan Nair, Salman M Toor, +8 authors, Eyad Elkord.
Vaccines (Basel), 2020 Feb 12; 8(1). PMID: 32041340    Free PMC article.
Immune Microenvironment of Thyroid Cancer.
Hongyu Yin, Yemei Tang, Yujia Guo, Shuxin Wen.
J Cancer, 2020 Jul 07; 11(16). PMID: 32626535    Free PMC article.
Review.
Human regulatory T cells (Treg) and their response to cancer.
Theresa L Whiteside.
Expert Rev Precis Med Drug Dev, 2019 Jan 01; 4(4). PMID: 32953989    Free PMC article.
Circulating exosomes measure responses to therapy in head and neck cancer patients treated with cetuximab, ipilimumab, and IMRT.
Marie-Nicole Theodoraki, Saigopalakrishna Yerneni, +5 authors, Theresa L Whiteside.
Oncoimmunology, 2019 May 31; 8(7). PMID: 31143513    Free PMC article.
Highly Cited.
Tumor Infiltrating Regulatory T Cells in Sporadic and Colitis-Associated Colorectal Cancer: The Red Little Riding Hood and the Wolf.
Massimo Claudio Fantini, Agnese Favale, Sara Onali, Federica Facciotti.
Int J Mol Sci, 2020 Sep 18; 21(18). PMID: 32937953    Free PMC article.
Review.
Transcriptional Control of Regulatory T Cells in Cancer: Toward Therapeutic Targeting?
Pierre Stéphan, Raphaëlle Lautraite, Allison Voisin, Yenkel Grinberg-Bleyer.
Cancers (Basel), 2020 Nov 05; 12(11). PMID: 33143070    Free PMC article.
Review.
Tumor Microenvironment and Immunotherapy Response in Head and Neck Cancer.
Panagiota Economopoulou, Ioannis Kotsantis, Amanda Psyrri.
Cancers (Basel), 2020 Nov 19; 12(11). PMID: 33203092    Free PMC article.
Review.
Mechanisms and Future of Non-Small Cell Lung Cancer Metastasis.
Tianhao Zhu, Xunxia Bao, +6 authors, Sibo Zhu.
Front Oncol, 2020 Dec 03; 10. PMID: 33262947    Free PMC article.
Review.
Anti-Tumorigenic Activities of IL-33: A Mechanistic Insight.
Sara Andreone, Adriana Rosa Gambardella, +6 authors, Fabrizio Mattei.
Front Immunol, 2020 Dec 18; 11. PMID: 33329534    Free PMC article.
Review.
Antitumor Effect and Immune Response of Nanosecond Pulsed Electric Fields in Pancreatic Cancer.
Jing Zhao, Shuochun Chen, +5 authors, Tian'an Jiang.
Front Oncol, 2021 Feb 27; 10. PMID: 33634030    Free PMC article.
The analysis of Treg lymphocyte blood percentage changes in patients with head and neck cancer during combined oncological treatment: a preliminary report.
Magdalena Dutsch-Wicherek, Katarzyna Chaberek, +4 authors, Łukasz Wicherek.
Cent Eur J Immunol, 2020 Jan 01; 45(4). PMID: 33658889    Free PMC article.
Adiponectin-expressing Treg facilitate T lymphocyte development in thymic nurse cell complexes.
Yiwei Zhang, Handi Cao, +3 authors, Yu Wang.
Commun Biol, 2021 Mar 18; 4(1). PMID: 33727658    Free PMC article.
Industrializing engineered autologous T cells as medicines for solid tumours.
Cedrik M Britten, Aiman Shalabi, Axel Hoos.
Nat Rev Drug Discov, 2021 Apr 10; 20(6). PMID: 33833444
Review.
TNFR2: Role in Cancer Immunology and Immunotherapy.
Yang Yang, Md Sahidul Islam, Yuanjia Hu, Xin Chen.
Immunotargets Ther, 2021 Apr 29; 10. PMID: 33907692    Free PMC article.
Review.
The landscape and prognostic value of immune characteristics in uterine corpus endometrial cancer.
Wenli Liu, Lisha Sun, +3 authors, Hong Wang.
Biosci Rep, 2021 Mar 31; 41(4). PMID: 33782686    Free PMC article.
Regulatory T-Cells as an Emerging Barrier to Immune Checkpoint Inhibition in Lung Cancer.
Daniel R Principe, Lauren Chiec, Nisha A Mohindra, Hidayatullah G Munshi.
Front Oncol, 2021 Jun 19; 11. PMID: 34141625    Free PMC article.
Review.
Treg: A Promising Immunotherapeutic Target in Oral Diseases.
Yujing Zhang, Jihua Guo, Rong Jia.
Front Immunol, 2021 Jun 29; 12. PMID: 34177907    Free PMC article.
Review.
Identification of LIPH as an unfavorable biomarkers correlated with immune suppression or evasion in pancreatic cancer based on RNA-seq.
Hongkai Zhuang, Xinming Chen, +4 authors, Baohua Hou.
Cancer Immunol Immunother, 2021 Jul 20; 71(3). PMID: 34279685
PI3Kα inhibitor CYH33 triggers antitumor immunity in murine breast cancer by activating CD8+T cells and promoting fatty acid metabolism.
Pu Sun, Xi Zhang, +9 authors, Ling-Hua Meng.
J Immunother Cancer, 2021 Aug 11; 9(8). PMID: 34373258    Free PMC article.
PD-L1+NEUT, Foxp3+Treg, and NLR as New Prognostic Marker with Low Survival Benefits Value in Hepatocellular Carcinoma.
Lin Zhou, Jing Wang, +4 authors, Qiang He.
Technol Cancer Res Treat, 2021 Oct 05; 20. PMID: 34605709    Free PMC article.
Comprehensive Analysis of Inflammatory Response-Related Genes, and Prognosis and Immune Infiltration in Patients With Low-Grade Glioma.
Tao Han, Zhifan Zuo, +3 authors, Hongjin Wang.
Front Pharmacol, 2021 Oct 30; 12. PMID: 34712139    Free PMC article.
Targeting regulatory T cells for immunotherapy in melanoma.
Lili Huang, Yeye Guo, +4 authors, Xiaowei Xu.
Mol Biomed, 2021 Nov 23; 2(1). PMID: 34806028    Free PMC article.
Review.
Immunotherapy for Triple-Negative Breast Cancer.
Yifeng Cao, Chuyang Chen, +2 authors, Ping Wang.
Pharmaceutics, 2021 Dec 29; 13(12). PMID: 34959285    Free PMC article.
Review.
Resistance to Immunotherapy: Mechanisms and Means for Overcoming.
Mohamad A Salkeni, John Y Shin, James L Gulley.
Adv Exp Med Biol, 2022 Jan 02; 1342. PMID: 34972962

;. PMID: 35006459
Cell-mediated immune resistance in cancer.
Yuhao Wang, Emily Hays, Martina Rama, Benjamin Bonavida.
Cancer Drug Resist, 2020 Jan 01; 3(2). PMID: 35310881    Free PMC article.
The impact of CCR8+ regulatory T cells on cytotoxic T cell function in human lung cancer.
Miya Haruna, Azumi Ueyama, +13 authors, Hisashi Wada.
Sci Rep, 2022 Apr 01; 12(1). PMID: 35354899    Free PMC article.
Genomic and immunological profiles of small-cell lung cancer between East Asians and Caucasian.
Anqi Lin, Ningning Zhou, +5 authors, Jian Zhang.
Cancer Cell Int, 2022 May 01; 22(1). PMID: 35488336    Free PMC article.
Integrating single-cell RNA sequencing with spatial transcriptomics reveals immune landscape for interstitial cystitis.
Liao Peng, Xi Jin, +13 authors, De-Yi Luo.
Signal Transduct Target Ther, 2022 May 20; 7(1). PMID: 35589692    Free PMC article.