Oncotarget

Research Papers:

Preferential accumulation of regulatory T cells with highly immunosuppressive characteristics in breast tumor microenvironment

Azharuddin Sajid Syed Khaja, Salman M. Toor, Haytham El Salhat, Issam Faour, Navid Ul Haq, Bassam R. Ali and Eyad Elkord _

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Oncotarget. 2017; 8:33159-33171. https://doi.org/10.18632/oncotarget.16565

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Abstract

Azharuddin Sajid Syed Khaja1,2,*, Salman M. Toor1,2,*, Haytham El Salhat3,4, Issam Faour4, Navid Ul Haq5, Bassam R. Ali6, Eyad Elkord1,2,7

1Cancer Research Center, Qatar Biomedical Research Institute, College of Science and Engineering, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar

2Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates

3Oncology Department, Al Noor Hospital, Abu Dhabi, United Arab Emirates

4Surgery Department, Tawam Hospital, Al Ain, United Arab Emirates

5Pathology Department, Tawam Hospital, Al Ain, United Arab Emirates

6Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates

7Institute of Cancer Sciences, University of Manchester, Manchester, United Kingdom

*These authors contributed equally to this work

Correspondence to:

Eyad Elkord, email: eelkord@hbku.edu.qa, eyad.elkord@manchester.ac.uk

Keywords: regulatory T cells, FoxP3, helios, immune checkpoint receptors, primary breast cancer

Received: February 21, 2017     Accepted: March 16, 2017     Published: March 25, 2017

ABSTRACT

Immunosuppressive cells such as regulatory T cells (Tregs) have an ambiguous role in breast cancer prognosis, with studies reporting both positive and negative correlations between Treg infiltration and prognosis. This discrepancy could be due to the different immunosuppressive molecules present in these cells. In the present study, we phenotypically characterize different Treg subsets infiltrating the tumor microenvironment (TME), compared to adjacent normal tissue and peripheral blood of primary breast cancer (PBC) patients. We report that the majority of tumor-infiltrating CD4+ and CD8+ T cells have terminally exhaustive phenotype as assessed by CD39 and PD-1 expressions. We also show that Tregs are accumulated in breast TME compared to normal tissue. Further characterization of Tregs showed that these are mainly FoxP3+Helios+ and express high levels of CTLA-4 and PD-1. This preferential accumulation of FoxP3+Helios+ Treg subset with co-expression of different immune inhibitory molecules might have a negative effect on breast cancer prognosis. Taken together, our results suggest that breast tumor cells might utilize Tregs, and different suppressive pathways involving CD39, PD-1 and CTLA-4 molecules in creating an immune-subversive environment for them to survive, and a dual blockade of these immunosuppressive molecules might be considered as an effective method in breast cancer treatment.


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