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Spiliopoulou et al. Cancer Drug Resist 2024;7:2 https://dx.doi.org/10.20517/cdr.2023.46 Page 9

[87]
In vivo imaging has been used to describe the dynamics of T cells in animals . While such studies in
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animals have shown important insights into T cell regulation in the presence of CTLA-4 inhibition, there
are no such specific imaging tools available for appropriate clinical investigation. The most advanced
+
imaging tool uses CD8-labeled PET imaging and reveals significant heterogeneity in CD8 T cell
distribution during immunotherapy in patients . Therefore, to date, such imaging tools still need to prove
[88]
their value to guide the drug development of novel agents.

While there are no regulatory-approved tests for assessing T cells or their function, FC is the most widely
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used laboratory test in clinical studies. In contrast to tissue-based tests, T cells in the blood can be
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monitored longitudinally either alone or in comparison to other blood-based immune cells.

CELLS DURING IMMUNOTHERAPY AND THEIR ROLE IN RESISTANCE
T reg
Background
T cells play an important role in tissue homeostasis and co-regulation of other immune cell subsets . In
[89]
reg
the following section, the role of T cells during immunotherapy will be reviewed and their potential as
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either prognostic (i.e., relevant to the disease progression and independent of therapies) or predictive (i.e.,
in assessing possible response to therapies) biomarkers .
[90]
Baseline levels of T cells in malignancies and their potential role as prognostic marker [Table 3]
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The prognostic value of T cells was examined by a systematic meta-analysis using data from 76 articles,
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which included 17 different types of cancers and 15,512 cancer cases . This study evaluated T cells as part
[91]
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of tumor-infiltrating lymphocytes (TILs). High numbers of T cells were associated with shorter overall
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survival (OS) in most tumor types (e.g., cervical, renal, melanoma, and breast cancer), but were associated
with longer OS in colorectal, head and neck, and esophageal cancer. The main parameters that influenced
the prognostic value included tumor location, stage of disease, and molecular subtype.
In addition to this meta-analysis, studies assessed the prognostic role of T cells in specific tumor types and
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a few important examples are described below.

In Non-small Cell Lung Cancer (NSCLC), the frequency of T cells in peripheral blood increases with the
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stage of NSCLC [96,97] . In 156 NSCLC patients, naïve T cells and not terminal T cells were correlated with
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reg
poor outcomes . These naïve T cells produced TGF-β and IL-10, indicating an immunosuppressive
[101]
reg
function. A study in the perioperative setting also found that T cells in peripheral blood increased with the
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stage of disease . This increase in T cells was independent of histology such as squamous and
[100]
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adenocarcinoma. The postoperative T cell frequency was not reduced to levels comparable to healthy
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subjects, suggesting that the immunosuppressive condition remained intact after surgery. Therefore, some
investigators proposed to use the presence of T cells in tumor tissue to assess the risk for relapse. For
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example, the T /TIL Combination Risk Index identified that patients with Stage I NSCLC and a high count
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of T cells were at risk of relapsing .
[95]
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While another study also reported that T cells increased with the stage of NSCLC, it found that serum
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[98]
levels of IL-17 and not IL-10 were negatively correlated with T cells . Gene expression of IL17 in
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lymphocytes was correlated with numbers of circulating T , suggesting that IL-17 is being produced by
reg
lymphocytes . Thus, serum levels of immunomodulatory factors may not always reflect the function of
[99]
T cells in patients. Consequently, for NSCLC patients receiving PD-1 therapies, counts of T cells need to
reg
reg
be combined with functional assays .
[111]