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Page 2 Spiliopoulou et al. Cancer Drug Resist 2024;7:2 https://dx.doi.org/10.20517/cdr.2023.46

INTRODUCTION
Immunotherapy with immune checkpoint inhibitors (ICI) has become the backbone of several treatment
[1]
regimens for cancer and has resulted in unprecedented benefits for patients . Notwithstanding this
progress, many patients eventually experience disease progression while undergoing treatment with ICI,
[2]
and the mechanisms of the underlying resistance remain elusive . One important contributor to such
[3-5]
resistance is the immunosuppressive tumor microenvironment . Based on the state and quality of
immune cells, the tumor microenvironment has been classified as immune-inflamed, immune-excluded,
[6,7]
and immune-deserted . A second classification incorporates the role of cancer-associated fibrosis to
describe the response to ICI . A third classification integrates the role of epithelial-mesenchymal
[8,9]
transition (EMT) as a key factor for resistance to ICI . T regulatory (T ) cells emerge as key contributors
[10]
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of resistance to ICI and are included in each of the three above-mentioned classifications, primarily in
immune-excluded or immune-enriched fibrosis conditions [Figure 1]. Considering that T cells play an
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important function in tissue homeostasis, responses to infections, and the control of autoimmunity, their
involvement in immune-excluded or immune-enriched fibrosis conditions is perhaps expected .
[11]
Furthermore, T cells are no longer recognized as a single group of T cells, but instead consist of different
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subgroups with varied immunosuppressive properties against which distinct inhibitors can be developed .
[12]
This review will discuss the advances in drug development of large and small molecule agents to overcome
T cell-mediated resistance to ICI.
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BIOLOGY AND CHARACTERIZATION OF T CELLS
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Early discovery of T cell biology
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Originally described as T suppressor cells [13-16] , T cells play a specific role in different phases of immune
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responses . T cells were first identified as a subset of CD4 T cells by their cell surface expression of CD25
[17]
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+
[18]
(alpha chain of the IL-2 receptor) and consequently labeled as CD4 CD25 T cells . Functionally,
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T cells were initially characterized by the production of interleukin (IL)-10 and Transforming Growth
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Factor beta (TGF-β1) . Ongoing studies have demonstrated that T cells have a high degree of
[19]
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diversity . In humans, of all circulating CD4 T cells, approximately 1%-3% are CD4 CD25 T cells .
+
+
[20]
[17]
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They are often overlooked in clinical studies with respect to their contribution to treatment outcomes of
new agents.
Ontogeny of T cells [Figure 2]
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T cells were defined by their anatomical site of differentiation and the detection of the Forkhead box
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protein P3 (FOXP3) : (1) natural T cells (nT ) are T cells that develop in the thymus and subsequently
[21]
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migrate to the periphery ; (2) induced T cells (iT ) are those that evolve from naïve CD4 FOXP3 T cells
[22]
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upon stimulation in the periphery [21,23] . Unfortunately, T cells induced in vitro were also labeled as iT
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(i.e., inducible T ). This has led to some confusion regarding the nomenclature of T cells. Therefore, the
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3rd International Conference on regulatory T cells has recommended the following nomenclature to
[24]
resolve the existing confusion:
1. Thymus-derived T cells (tT ) - in lieu of nT .
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2. Peripherally-derived T cells (pT - i.e., FOXP3 T cells that differentiate in the periphery) - in lieu of
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induced or adaptive T cells.
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3. In vitro-iT - i.e., to differentiate T cells derived in vitro studies from those investigated during in vivo
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studies.
The above-mentioned classifications of T cells are based on ontogeny studies and two models are used to
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describe the generation of T cells. The first model is called “instructive model”. According to the
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