Breast cancer tumor microenvironment affects Treg/IL-17-producing Treg/Th17 cell axis: Molecular and therapeutic perspectives

Farhad Seif; Zahra Torki; Hamidreza Zalpoor; Mehran Habibi; Majid Pornour

doi:10.1016/j.omto.2023.01.001

Breast cancer tumor microenvironment affects Treg/IL-17-producing Treg/Th17 cell axis: Molecular and therapeutic perspectives

Mol Ther Oncolytics. 2023 Jan 11:28:132-157. doi: 10.1016/j.omto.2023.01.001. eCollection 2023 Mar 16.

Authors

Farhad Seif^{1

2}, Zahra Torki³, Hamidreza Zalpoor^{4

5}, Mehran Habibi⁶, Majid Pornour^{7

8}

Affiliations

¹ Department of Immunology and Allergy, Academic Center for Education, Culture (ACECR), and Research (ACECR), Tehran, Iran.
² Neuroscience Research Center, Iran University of Medical Sciences, Tehran, Iran.
³ Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
⁴ Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
⁵ Network of Immunity in Infection, Malignancy, and Autoimmunity (NIIMA), Universal Scientific Education, and Research Network (USERN), Tehran, Iran.
⁶ Department of Surgery, Johns Hopkins Breast Center at Bayview Campus, Baltimore, MD, USA.
⁷ Department of Photo Healing and Regeneration, Medical Laser Research Center, Yara Institute, Academic Center for Education, Culture, and Research (ACECR), Tehran, Iran.
⁸ Department of Oncology, School of Medicine, University of Maryland, Baltimore, MD, USA.

Abstract

The tumor microenvironment (TME) comprises a variety of immune cells, among which T cells exert a prominent axial role in tumor development or anti-tumor responses in patients with breast cancer (BC). High or low levels of anti-inflammatory cytokines, such as transforming growth factor β, in the absence or presence of proinflammatory cytokines, such as interleukin-6 (IL-6), delineate the fate of T cells toward either regulatory T (Treg) or T helper 17 (Th17) cells, respectively. The transitional state of RORγt⁺Foxp3⁺ Treg (IL-17-producing Treg) resides in the middle of this reciprocal polarization, which is known as Treg/IL-17-producing Treg/Th17 cell axis. TME secretome, including microRNAs, cytokines, and extracellular vesicles, can significantly affect this axis. Furthermore, immune checkpoint inhibitors may be used to reconstruct immune cells; however, some of these novel therapies may favor tumor development. Therefore, understanding secretory and cell-associated factors involved in their differentiation or polarization and functions may be targeted for BC management. This review discusses microRNAs, cytokines, and extracellular vesicles (as secretome), as well as transcription factors and immune checkpoints (as cell-associated factors), which influence the Treg/IL-17-producing Treg/Th17 cell axis in BC. Furthermore, approved or ongoing clinical trials related to the modulation of this axis in the TME of BC are described to broaden new horizons of promising therapeutic approaches.

Keywords: IL-17-producing Treg; Th17; Treg; breast cancer; cytokine; immune checkpoint inhibitor; microRNA; regulatory T cell; secretome; tumor microenvironment.

Publication types

Review