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Spiliopoulou et al. Cancer Drug Resist 2024;7:2 Cancer
DOI: 10.20517/cdr.2023.46
Drug Resistance

Review Open Access

Targeting T regulatory (T ) cells in immunotherapy-
reg
resistant cancers

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1,2
3
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Pavlina Spiliopoulou , Paramjit Kaur , Tracey Hammett , Giusy Di Conza , Michael Lahn 3
1
Department of Drug Development Program, Phase I Unit, Beatson West of Scotland Cancer Center, Glasgow G12 0YN, UK.
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School of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
3
Department of Oncology Clinical Development, iOnctura SA, Geneva 1202, Switzerland.
Correspondence to: Dr. Michael Lahn, Department of Oncology Clinical Development, iOnctura SA, Avenue Sécheron 15,
Geneva 1202, Switzerland. E-mail: m.lahn@ionctura.com
How to cite this article: Spiliopoulou P, Kaur P, Hammett T, Di Conza G, Lahn M. Targeting T regulatory (T ) cells in
reg
immunotherapy-resistant cancers. Cancer Drug Resist 2024;7:2. https://dx.doi.org/10.20517/cdr.2023.46
Received: 13 May 2023 First Decision: 16 Jun 2023 Revised: 11 Dec 2023 Accepted: 9 Jan 2024 Published: 12 Jan 2024
Academic Editor: Godefridus J. Peters Copy Editor: Pei-Yun Wang Production Editor: Pei-Yun Wang

Abstract
Primary or secondary (i.e., acquired) resistance is a common occurrence in cancer patients and is often associated
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with high numbers of T regulatory (T ) cells (CD4 CD25 FOXP3 ). The approval of ipilimumab and the
reg
development of similar pharmacological agents targeting cell surface proteins on T cells demonstrates that such
reg
intervention may overcome resistance in cancer patients. Hence, the clinical development and subsequent
approval of Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) targeting agents can serve as a prototype for similar
agents. Such new agents aspire to be highly specific and have a reduced toxicity profile while increasing effector T
cell function or effector T/T regulatory (T /T ) ratio. While clinical development with large molecules has shown
eff
reg
the greatest advancement, small molecule inhibitors that target immunomodulation are increasingly entering early
clinical investigation. These new small molecule inhibitors often target specific intracellular signaling pathways
[e.g., phosphoinositide-3-kinase delta (PI3K-δ)] that play an important role in regulating the function of T cells.
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This review will summarize the lessons currently applied to develop novel clinical agents that target T cells.
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Keywords: Primary and secondary resistance, T regulatory cells, flow cytometry, mass cytometry,
hyperprogression

© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0
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