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

therapies targeting T cells.
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1. Soluble Factors: IL-10 is secreted by T cells and is one of the key cytokines contributing to immune
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[52]
suppression in cancer . IL-10 also acts on T cells themselves by expanding their number and increasing
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[53]
CTLA-4 expression . TGF-β signaling is another cytokine that is associated with immunosuppression by
T cells [54,55] . Like IL-10, TGF-β signaling can also induce T cells . Its significance might surpass that of
[56]
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IL-10 in the function of T cells, as it also inhibits the differentiation and function of Th1 and Th2 cells.
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TGF-β signaling promotes the differentiation of Th17 and Th9 cells, differentiation of tissue-resident
memory CD8 T cells, generation of natural killer (NK) cells, and other tissue-resident cells, e.g., γδ T cells,
+
innate lymphoid cells, and gut intraepithelial lymphocytes . Given the tissue distribution of TGF-β
[57]
signaling proteins and its feedback loop on T cells, it may be one factor contributing to the tissue-
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dependent functionality of T cells [Table 2].
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2. Inhibitory Receptors: Perhaps the most recognized inhibitory receptor expressed on T cells is the
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CTLA-4 [35,58] . Because of its role in competing with CD28 for the co-stimulatory molecules CD80 (B7.1) and
CD86 (B7.2) on antigen presenting cells (APCs), CTLA-4 can induce cell cycle arrest, inhibit the production
of IL-2, and down-regulate ligands needed for the activation of T effector cells. Hence, it was termed an
immune checkpoint inhibitor (ICI) and this critical discovery was recognized through the Nobel Prize
awarded to James Allison and Tasuku Honjo . This observation led to the discovery of similar receptors
[59]
with inhibitory function, such as CD73 [60,61] . The expression of CD73 in conjunction with TGF-β signaling
contributes to a significant increase in T cells and renders ICI therapies ineffective.
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3. Competition for Growth Factors: Interleukin-2 (IL-2) is not only produced by activated CD4 and CD8
+
T cells, but also by Dendritic Cells (DCs) and thymic cells . IL-2 engages with the IL-2R, which consists of
[62]
[62]
IL-2Rα (=CD25), IL-2Rβ and common γ-chain . T cells express CD25 constitutively in contrast to T
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effector cells [63,64] . Persistent IL-2 signaling is needed to sustain the T cell inhibitory function and
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survival . Insulin Growth Factor was found to act synergistically with IL-2 to achieve persistent T cell
[65]
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activity, which suggests that pro-inflammatory conditions support T cells . Other pro-inflammatory
[66]
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conditions are observed in patients with glioblastoma after receiving a single administration of a Chimeric
[67]
Antigen Receptor T cell (CAR-T) directed against Epithelial Growth Factor Receptor III . After the
administration of the CAR-T in patients with glioblastoma, an increase of T cells in the tumor
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microenvironment was observed, which was associated with a lack of treatment response. In another study,
children receiving an IL13 CAR-T intracranially showed no reduction in T cells in their cerebrospinal
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fluid . Other soluble drivers may originate from metabolic pathways. For example, the fatty acid
[68]
transporter CD36 sustains mitochondria fitness and the suppressive function of T cells in the tumor
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microenvironment . Therefore, T cells may not only be influenced by soluble factors, such as cytokines
[69]
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or chemokines, but indirectly affected by factors from the metabolic pathways embedded in the
microenvironment.
Overall, these few examples demonstrate that T cell function can be induced and maintained by a variety
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of factors. Hence, activating or blocking these functions is relevant to therapeutic drug development. To
appropriately assess the responses to therapies directed against T cells, it is necessary to detect and
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monitor the T cells in either tumor tissue or peripheral blood. This assumes that most T cells are selected
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in the periphery and that, regardless of their ontogeny, they share similar mechanisms of action.
METHODS TO MEASURE T CELLS
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There are several methods to determine T cells in cancer patients. Multiparametric cellular flow cytometry
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