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Page 12 Spiliopoulou et al. Cancer Drug Resist 2024;7:2 https://dx.doi.org/10.20517/cdr.2023.46

While the above-mentioned examples show how T cells are associated with survival, it remains unclear
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whether the presence of T cells is merely an epiphenomenon or a key driver of immune suppression in
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cancer patients. Therefore, changes in T cells after clinically meaningful responses to therapies may help to
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recognize where T cells are key drivers of tumor progression.
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T cells as potential drivers of tumor progression and their potential role as predictive biomarkers
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[Table 3]
Studies of immunotherapy and other anti-cancer treatments were selected to determine whether T cells
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[120]
are potentially related to treatment outcomes, either as a negative or positive predictive marker . For
example, patients with hyperprogression during immunotherapy have elevated T cells, which is associated
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with treatment failure [121,122] . In such patients, T cells expand and copious amounts of immune suppressive
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cytokines (e.g., TGF-β1, IL-10) are secreted. Furthermore, T cells upregulate PD-1 expression during
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[123]
PD-1/PD-L1-targeting therapies, generating highly immunosuppressive T cells . This observation is not
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limited to peripheral blood T cells. PD-1 expression on T cells is also observed in the tumor
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[108]
microenvironment of patients with NSCLC . While the expression of PD1 on T cells is already
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+
+
predictive for PD-1-based therapies, the ratio of PD1 T cells and CD8 T effector (T ) has a superior
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eff
predictive value than PDL-1 staining alone . Hence, detecting PD1 T cells by either FC in blood or IHC
[108]
+
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in tissue can predict the efficacy of ICI therapies.
T cell dynamics are not always associated with poor outcomes. For example, PD-L1-treated patients with
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NSCLC had high frequencies of circulating T cells one week after therapy. These levels were correlated
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with a high response rate, longer progression-free survival, and overall survival . At the same time, TGF-β
[107]
levels were elevated and associated with a favorable response to anti-PD-1 immunotherapy. A second study
in patients with cutaneous melanoma also reported an association of high levels of T cells with improved
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outcomes after adjuvant PD-1-based therapies . Several reasons may explain this difference between
[124]
T cells as a predictive marker of poor or improved outcomes. First, the mere phenotypic description of
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T cells may ignore certain functional characteristics of T cells, which can miss the degree of immune
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suppression. For instance, T cells expressing signal transducer and activator of transcription 3 (STAT3)
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appear to be less immune suppressive . By adding a STAT3 inhibitor to such T cells, their suppressive
[124]
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[124]
function was enhanced . Hence, it is possible that studies reporting increased T cells are capturing a
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broader T cell population, including T cells, with reduced immunosuppressive function. Second, levels
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of T cells may differ between early and later stages of immunotherapy. Most studies assessed the levels of
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T cells several weeks after starting immunotherapies. Patients with renal cell carcinoma (RCC) treated
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with nivolumab had a reduction in peripheral T cells once they were treated for 3 months, indicating a
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[109]
response to the therapy . Similarly, patients with cutaneous melanoma had a significant reduction in
T cells after three consecutive doses of ipilimumab . In uveal melanoma, the peripheral T cell
[104]
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population began to decrease after approximately 2 months of treatment with the PI3K-δ inhibitor
roginolisib . Patients with endometrial cancer who did not respond to immunotherapy had increased T
[110]
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[92]
cells after several treatment cycles in their blood, indicating a treatment failure . Given these differences, it
is important to characterize the T cell population during a novel therapy before drawing a conclusion on
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whether T cells can serve as a prediction marker. Third, an increase in T cells early in therapy may
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represent a mobilization of the T cells from the tumor tissue into the periphery and consequently have
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limited value for a prediction. Using in vitro co-cultures of peripheral blood mononuclear cells (PBMCs)
from healthy volunteers, adding them to endometrial cancer cell lines led to an increase of T cells within a
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few hours, suggesting a prompt migratory response of T cells . Hence, it is possible that once tumor cells
[93]
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are prevented from producing chemoattractant factors as a result of therapeutic intervention, T cells may
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migrate away from the tumor tissue and subsequently be detected in peripheral blood. As mentioned
previously, a numerical increase in T cells needs to be accompanied by appropriate functional tests to
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