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Immune modulation and epigenetic therapies for enhanced outcome of treatment in triple-negative breast cancer

Vitalis Chukwuemeka Okwor1 ,  Chika Juliet Okwor2 ,  Stephen Abiodun Musayayi3 ,  Tolulope Judah Gbayisomore3* ,  Innocent Joseph4 ,  Isaac Olamide Babalola5 ,  Lucky Aighowmanfe Ayeni6 ,  Abdul-Hanan Saani Inusah7 ,  Rufus Oluwagbemileke Ajayi8 ,  Feranmi Emmanuel Obe9 ,  Bertha Michael Akpan10
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1 Department of Radiation Medicine, University of Nigeria Teaching Hospital, Ituku/Ozalla, Enugu State, Nigeria
2 Department of Chemical Pathology, University of Nigeria Teaching Hospital, Ituku/Ozalla, Enugu State, Nigeria
3 Department of Anatomy, University of Medical Science, Ondo, Ondo State, Nigeria
4 Department of Computer Engineering and Informatics, Saint Petersburg Electrotechnical University, Saint Petersburg, Saint Petersburg, Russia
5 Department of Medical Laboratory Science, Faculty of Basic Medical Sciences, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria
6 Department of Chemistry, University of Wolverhampton, Wolverhampton, West Midlands, United Kingdom
7 School of Medicine, University for Development Studies, Tamale, Northern Region of Ghana, Ghana
8 Department of Public Health, University of Illinois Springfield, Springfield, Illinois, United States of America
9 Department of Biology, University of Texas at Tyler, Tyler, Texas, United States of America
10 Department of Biology and Ecological Sciences, Universita Della Calabria, Rende, Italy
Tumor Discovery 2024, 3(3), 3383 https://doi.org/10.36922/td.3383
Submitted: 8 April 2024 | Accepted: 16 July 2024 | Published: 4 October 2024
© 2024 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by the absence of human epidermal growth factor receptor 2, estrogen receptor, and progesterone receptor expression. While traditional TNBC treatment primarily relies on systemic chemotherapy, epigenetic modification has an important role in immune evasion and tumor progression. Recent classifications of TNBC into “hot” and “cold” tumors, based on immune activity and mutation burden, have revealed that poor response to immune checkpoint inhibitors (ICIs) in these tumors is due to low tumor-infiltrating lymphocytes and the presence of immunosuppressive cells. Emerging treatments such as ICIs and poly(ADP-ribose) polymerase inhibitors offer promising alternatives. The tumor microenvironment (TME) shapes immune responses in TNBC, and a limited subset of patients has shown encouraging responses to ICIs in treating TNBC at both early and advanced stages. However, combination therapies face challenges, including medication interactions and side effects. Epigenetic modulators, such as histone deacetylase and DNA methyltransferase inhibitors, also show promise in reversing epigenetic changes by enhancing anti-tumor immunity in TNBC. The frequent expression of indoleamine 2,3-dioxygenase 1 (IDO1) in TNBC, which catalyzes the conversion of tryptophan to kynurenine, contributes to immune suppression in TNBC patients. High IDO1 levels impair the tumoricidal activity of natural killer cells and correlate with poor responses to anti-PD-L1 therapy, which can be improved using IDO1 inhibitors. Targeting myeloid-derived suppressor cells, regulatory T-cells, and tumor-associated macrophage, along with utilizing epigenetic mechanisms, show promise in modulating the immunosuppressive TME in TNBC. Combining these approaches with standard therapies, along with biomarker-guided patient selection, can enhance treatment efficacy. Clinical trials and preclinical models are essential for optimizing these strategies. This study emphasizes the importance of understanding the mechanisms of modulation, tumor-immune interactions, and the potential of epigenetic therapies in improving treatment outcomes in TNBC.

Keywords
Triple-negative breast cancer
Epigenetic modifications
Immune modulation
Combination therapies
Funding
None.
Conflict of interest
The authors declare that they have no competing interests.
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Tumor Discovery, Electronic ISSN: 2810-9775 Print ISSN: 3060-8597, Published by AccScience Publishing
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