Journal Article
. 2016 May; 1(5):.

PD-1 marks dysfunctional regulatory T cells in malignant gliomas

Daniel E Lowther 1 Brittany A Goods 2 Liliana E Lucca 1 Benjamin A Lerner 1 Khadir Raddassi 1 David van Dijk 3 Amanda L Hernandez 1 Xiangguo Duan 1 Murat Gunel 4 Vlad Coric 5 Smita Krishnaswamy 3 J Christopher Love 6 David A Hafler 7 
Affiliations
  • PMID: 27182555
  •     61 References
  •     84 citations

Abstract

Immunotherapies targeting the immune checkpoint receptor programmed cell death protein 1 (PD-1) have shown remarkable efficacy in treating cancer. CD4+CD25hiFoxP3+ Tregs are critical regulators of immune responses in autoimmunity and malignancies, but the functional status of human Tregs expressing PD-1 remains unclear. We examined functional and molecular features of PD-1hi Tregs in healthy subjects and patients with glioblastoma multiforme (GBM), combining functional assays, RNA sequencing, and cytometry by time of flight (CyTOF). In both patients with GBM and healthy subjects, circulating PD-1hi Tregs displayed reduced suppression of CD4+ effector T cells, production of IFN-γ, and molecular signatures of exhaustion. Transcriptional profiling of tumor-resident Tregs revealed that several genes coexpressed with PD-1 and associated with IFN-γ production and exhaustion as well as enrichment in exhaustion signatures compared with circulating PD-1hi Tregs. CyTOF analysis of circulating and tumor-infiltrating Tregs from patients with GBM treated with PD-1-blocking antibodies revealed that treatment shifts the profile of circulating Tregs toward a more exhausted phenotype reminiscent of that of tumor-infiltrating Tregs, further increasing IFN-γ production. Thus, high PD-1 expression on human Tregs identifies dysfunctional, exhausted Tregs secreting IFN-γ that exist in healthy individuals and are enriched in tumor infiltrates, possibly losing function as they attempt to modulate the antitumoral immune responses.

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Cytometry A, 2020 Jul 01; 97(8). PMID: 32602650    Free PMC article.
Review.
Safety and efficacy of sintilimab combined with oxaliplatin/capecitabine as first-line treatment in patients with locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma in a phase Ib clinical trial.
Haiping Jiang, Yulong Zheng, +12 authors, Nong Xu.
BMC Cancer, 2020 Aug 17; 20(1). PMID: 32795349    Free PMC article.
Nanomedicine-based immunotherapy for central nervous system disorders.
Sumaira Hanif, Pir Muhammad, +4 authors, Bing-Yang Shi.
Acta Pharmacol Sin, 2020 May 30; 41(7). PMID: 32467570    Free PMC article.
Review.
Validation of CyTOF Against Flow Cytometry for Immunological Studies and Monitoring of Human Cancer Clinical Trials.
Ramy Gadalla, Babak Noamani, +14 authors, David G Brooks.
Front Oncol, 2019 Jun 06; 9. PMID: 31165047    Free PMC article.
Hyperprogression: A novel response pattern under immunotherapy.
Xue-Jiao Han, Aqu Alu, +2 authors, Xia-Wei Wei.
Clin Transl Med, 2020 Oct 01; 10(5). PMID: 32997401    Free PMC article.
Review.
IL-1β-MyD88-mTOR Axis Promotes Immune-Protective IL-17A+Foxp3+ Cells During Mucosal Infection and Is Dysregulated With Aging.
Natarajan Bhaskaran, Fady Faddoul, +5 authors, Pushpa Pandiyan.
Front Immunol, 2020 Nov 27; 11. PMID: 33240286    Free PMC article.
Regulatory T Cells: From Discovery to Autoimmunity.
Alexandra Kitz, Emily Singer, David Hafler.
Cold Spring Harb Perspect Med, 2018 Jan 10; 8(12). PMID: 29311129    Free PMC article.
Review.
Expression of TIGIT/CD155 and correlations with clinical pathological features in human hepatocellular carcinoma.
Xiangguo Duan, Juanxi Liu, +6 authors, Chunxia Su.
Mol Med Rep, 2019 Sep 06; 20(4). PMID: 31485637    Free PMC article.
Hyper-Progressive Disease: The Potential Role and Consequences of T-Regulatory Cells Foiling Anti-PD-1 Cancer Immunotherapy.
Christopher Tay, Yamin Qian, Shimon Sakaguchi.
Cancers (Basel), 2020 Dec 31; 13(1). PMID: 33375291    Free PMC article.
Review.
Sustained Helicobacter pylori infection accelerates gastric dysplasia in a mouse model.
Valerie P O'Brien, Amanda L Koehne, +8 authors, Nina R Salama.
Life Sci Alliance, 2020 Dec 15; 4(2). PMID: 33310760    Free PMC article.
IFN-γ and CD38 in Hyperprogressive Cancer Development.
Stefania Angelicola, Francesca Ruzzi, +6 authors, Arianna Palladini.
Cancers (Basel), 2021 Jan 21; 13(2). PMID: 33467713    Free PMC article.
Review.
Understanding and Targeting Human Cancer Regulatory T Cells to Improve Therapy.
H Ryan Kolb, Nicholas Borcherding, Weizhou Zhang.
Adv Exp Med Biol, 2021 Feb 02; 1278. PMID: 33523451
Modulation of regulatory T cell function and stability by co-inhibitory receptors.
Liliana E Lucca, Margarita Dominguez-Villar.
Nat Rev Immunol, 2020 Apr 10; 20(11). PMID: 32269380
Review.
Metabolic support of tumour-infiltrating regulatory T cells by lactic acid.
McLane J Watson, Paolo D A Vignali, +14 authors, Greg M Delgoffe.
Nature, 2021 Feb 17; 591(7851). PMID: 33589820    Free PMC article.
Emerging dynamics pathways of response and resistance to PD-1 and CTLA-4 blockade: tackling uncertainty by confronting complexity.
Allan Relecom, Maysaloun Merhi, +4 authors, Said Dermime.
J Exp Clin Cancer Res, 2021 Feb 20; 40(1). PMID: 33602280    Free PMC article.
Review.
Non-canonical PD-1 signaling in cancer and its potential implications in clinic.
Haoran Zha, Ying Jiang, +10 authors, Zhaoxia Li.
J Immunother Cancer, 2021 Feb 18; 9(2). PMID: 33593825    Free PMC article.
Review.
TP53 mutations in myelodysplastic syndromes and secondary AML confer an immunosuppressive phenotype.
David A Sallman, Amy F McLemore, +18 authors, Alan F List.
Blood, 2020 Jul 31; 136(24). PMID: 32730593    Free PMC article.
Immune Cell Profiling of Peripheral Blood as Signature for Response During Checkpoint Inhibition Across Cancer Types.
Vinicius Araujo B de Lima, Morten Hansen, +4 authors, Inge Marie Svane.
Front Oncol, 2021 Apr 13; 11. PMID: 33842304    Free PMC article.
Notch4 signaling limits regulatory T-cell-mediated tissue repair and promotes severe lung inflammation in viral infections.
Hani Harb, Mehdi Benamar, +30 authors, Talal A Chatila.
Immunity, 2021 Apr 30; 54(6). PMID: 33915108    Free PMC article.
Targeting STAT3 Abrogates Tim-3 Upregulation of Adaptive Resistance to PD-1 Blockade on Regulatory T Cells of Melanoma.
Lili Huang, Yu Xu, +4 authors, Qing Xu.
Front Immunol, 2021 May 04; 12. PMID: 33936081    Free PMC article.
The Role of Dectin-1 Signaling in Altering Tumor Immune Microenvironment in the Context of Aging.
Natarajan Bhaskaran, Sangeetha Jayaraman, +6 authors, Pushpa Pandiyan.
Front Oncol, 2021 May 11; 11. PMID: 33968777    Free PMC article.
Antigen-Specific Regulatory T Cell Therapy in Autoimmune Diseases and Transplantation.
Claudia Selck, Margarita Dominguez-Villar.
Front Immunol, 2021 Jun 01; 12. PMID: 34054826    Free PMC article.
Review.
Not-so-opposite ends of the spectrum: CD8+ T cell dysfunction across chronic infection, cancer and autoimmunity.
Jenna L Collier, Sarah A Weiss, +2 authors, Arlene H Sharpe.
Nat Immunol, 2021 Jun 19; 22(7). PMID: 34140679
Review.
A new predictive biomarker enables more accurate PD-1 blockade therapy.
Kuojun Zhang, Sheng Jiang.
Cell Mol Immunol, 2021 Feb 10; 18(7). PMID: 33558685    Free PMC article.
Immune checkpoint blockade impairs immunosuppressive mechanisms of regulatory T cells in B-cell lymphoma.
Vera Bauer, Fatima Ahmetlić, +3 authors, Ralph Mocikat.
Transl Oncol, 2021 Jul 07; 14(9). PMID: 34229208    Free PMC article.
The presence of TIM-3 positive cells in WHO grade III and IV astrocytic gliomas correlates with isocitrate dehydrogenase mutation status.
Mia D Sørensen, Ole Nielsen, Guido Reifenberger, Bjarne W Kristensen.
Brain Pathol, 2020 Nov 28; 31(3). PMID: 33244787    Free PMC article.
Harnessing Treg Homeostasis to Optimize Posttransplant Immunity: Current Concepts and Future Perspectives.
Shuntaro Ikegawa, Ken-Ichi Matsuoka.
Front Immunol, 2021 Sep 17; 12. PMID: 34526990    Free PMC article.
Review.
Regulatory T Cells in Autoimmunity and Cancer: A Duplicitous Lifestyle.
Aikaterini Hatzioannou, Athina Boumpas, +4 authors, Panayotis Verginis.
Front Immunol, 2021 Sep 21; 12. PMID: 34539668    Free PMC article.
Review.
Oral immune dysfunction is associated with the expansion of FOXP3+PD-1+Amphiregulin+ T cells during HIV infection.
N Bhaskaran, E Schneider, +9 authors, P Pandiyan.
Nat Commun, 2021 Aug 28; 12(1). PMID: 34446704    Free PMC article.
Distinct immune signatures discriminate between asymptomatic and presymptomatic SARS-CoV-2pos subjects.
Shanhe Yu, Caixia Di, +17 authors, Jieming Qu.
Cell Res, 2021 Sep 26; 31(11). PMID: 34561618    Free PMC article.
CD177 modulates the function and homeostasis of tumor-infiltrating regulatory T cells.
Myung-Chul Kim, Nicholas Borcherding, +32 authors, Weizhou Zhang.
Nat Commun, 2021 Oct 03; 12(1). PMID: 34599187    Free PMC article.
The Multifaceted Role of Regulatory T Cells in Breast Cancer.
Kevin Kos, Karin E de Visser.
Annu Rev Cancer Biol, 2021 Oct 12; 5. PMID: 34632244    Free PMC article.
Emerging concepts in PD-1 checkpoint biology.
Kristen E Pauken, James A Torchia, +2 authors, Gordon J Freeman.
Semin Immunol, 2021 May 20; 52. PMID: 34006473    Free PMC article.
Review.
CD4 T-Cell Exhaustion: Does It Exist and What Are Its Roles in Cancer?
Alexandra M Miggelbrink, Joshua D Jackson, +4 authors, Peter E Fecci.
Clin Cancer Res, 2021 Jun 16; 27(21). PMID: 34127507    Free PMC article.
Review.
Dendritic Cell Vaccination of Glioblastoma: Road to Success or Dead End.
Angeliki Datsi, Rüdiger V Sorg.
Front Immunol, 2021 Nov 20; 12. PMID: 34795675    Free PMC article.
Review.
Role of the PD-1/PD-L1 Signaling in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis: Recent Insights and Future Directions.
Yan Mi, Jinming Han, Jie Zhu, Tao Jin.
Mol Neurobiol, 2021 Sep 05; 58(12). PMID: 34480337    Free PMC article.
Review.
Differential Role of PD-1 Expressed by Various Immune and Tumor Cells in the Tumor Immune Microenvironment: Expression, Function, Therapeutic Efficacy, and Resistance to Cancer Immunotherapy.
Myeong Joon Kim, Sang-Jun Ha.
Front Cell Dev Biol, 2021 Dec 14; 9. PMID: 34901012    Free PMC article.
Review.
Systematic analysis of CD39, CD103, CD137, and PD-1 as biomarkers for naturally occurring tumor antigen-specific TILs.
Monika A Eiva, Dalia K Omran, Jessica A Chacon, Daniel J Powell.
Eur J Immunol, 2021 Sep 11; 52(1). PMID: 34505280    Free PMC article.
The oxygen sensor prolyl hydroxylase domain 2 regulates the in vivo suppressive capacity of regulatory T cells.
Yousra Ajouaou, Abdulkader Azouz, +7 authors, Oberdan Leo.
Elife, 2022 Feb 23; 11. PMID: 35192456    Free PMC article.
Key Players of the Immunosuppressive Tumor Microenvironment and Emerging Therapeutic Strategies.
Kevin Park, Mysore S Veena, Daniel Sanghoon Shin.
Front Cell Dev Biol, 2022 Mar 30; 10. PMID: 35345849    Free PMC article.
Review.
Intraperitoneal oncolytic virotherapy for patients with malignant ascites: Characterization of clinical efficacy and antitumor immune response.
Yalei Zhang, Ling Qian, +5 authors, Peng Wang.
Mol Ther Oncolytics, 2022 Apr 12; 25. PMID: 35399603    Free PMC article.
CyTOF® for the Masses.
Akshay Iyer, Anouk A J Hamers, Asha B Pillai.
Front Immunol, 2022 May 03; 13. PMID: 35493491    Free PMC article.
Review.