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Spiliopoulou et al. Cancer Drug Resist 2024;7:2 https://dx.doi.org/10.20517/cdr.2023.46 Page 11

Ratio was predictive in other tumor types as well, i.e.,
gastric cancer and melanoma
+
Renal cell 43 Flow cytometry using CD4 Treatment with nivolumab reduced T cells only in Santagata et al.
reg
+ - + [109]
carcinoma CD25 CD127 FOXP3 responders when assessed after 3 months 2020
Inhibition with CXCR4 antagonist blocked T cell
reg
function in vitro
Treatment with nivolumab reduced T cells only in
reg
responders when assessed after 3 months
+ +
Uveal 9 Mass cytometry using CD4 T cells reduced within 3 months, while CD8 and NK Di Giacomo et
reg
+
melanoma CD25 CD127 - cells increased al. 2022 [110]
T cells: T regulatory cells; FOXP3: forkhead box protein P3; OS: overall survival; IHC: immunohistochemistry; CCL: chemokine c-c-motif ligand;
reg
CCR: C-C chemokine receptor; NSCLC: non-small cell lung cancer; CTLA-4: cytotoxic T lymphocyte antigen-4; IL: interleukin; Th17 cells: T helper
17 cells; TGF-β: transforming growth factor beta; EGFR: epidermal growth factor receptor; PD-1: programmed death 1; NK: natural killer.
In 275 tumor specimens from patients with endometrial cancer, high FOXP3 expression was correlated with
poor OS . A similar observation was reported for patients with primary breast cancer, where T cells and
[93]
reg
[94]
CCL5 were co-expressed with standard prognostic markers for breast cancer . The authors postulated that
CCL5 engages the CCR5 on T cells and subsequently induces the production of TGF-β . Like the CCL5/
[94]
reg
CCR5 axis, the chemokine receptor CCR8 (its ligand being CCL1) also plays a critical role in upregulating
genes of intra-tumoral T cells as observed in patients with breast, colorectal, and lung cancer [112,113] . In each
reg
of these tumor types, the expression of CCR8 correlated with T cell signature and was associated with
reg
[114]
poor prognosis .
Oncogenic driver mutations are associated with a tumor microenvironment rich in immunosuppressive
mediators and T cells. For instance, Epidermal Growth Factor Receptor (EGFR) mutations in NSCLC are
reg
associated with high levels of T cells . The microenvironment of patients with EGFR-mutated NSCLC is
[102]
reg
[102]
immune-suppressed, as indicated by tissue expression of FOXP3 and PD-L1 . Furthermore, high numbers
of Fraction 2 T cells, low numbers of CD8 T cells (i.e., non-inflamed condition), and high levels of CCL22
+
reg
(the main ligand for CCR4) are observed in EGFR-mutated NSCLC patients . This immunosuppressive
[103]
state was reversed during combination treatment of EGFR inhibitors and PD-1 monoclonal antibodies,
leading to a reprogramming of the immune subsets, and consequently overcoming the resistance. Kirsten
Rat Sarcoma Virus (KRAS) mutated tumors are also associated with high numbers of T cells, for example,
reg
in KRAS-mutated colorectal cancers . KRAS-mutated tumors produce the immune suppressive mediators
[115]
[116]
IL-10 and TGF-β1 and thus drive a phenotype switch from naïve to T cells . Because of these
reg
observations in EGFR- and KRAS-mutated tumors, it is possible that other mutations are associated with
[117]
similar immunosuppressive mediators and T cells .
reg
In contrast to solid tumors, lymphoma patients may harbor four functionally distinct T cell groups: (1)
reg
Suppressor T cells: similar to solid tumors, this group of T cells is immunosuppressive; (2) Malignant
reg
reg
T cells: the malignant clone derived from precursors of T cells expresses FOXP3 as a marker for adult T
reg
cell leukemia/lymphoma (ATLL) and cutaneous T-cell lymphomas (CTCL); (3) Direct tumor-killing T
reg
cells: T cells with suppressive cytotoxicity capable of killing tumor cells; (4) Incompetent T cells: mostly
reg
reg
observed in angioimmunoblastic T-Cell lymphoma (AITL), and their presence is associated with
autoimmune symptoms . These different groups with distinct functions were not considered in a recent
[118]
meta-analysis of 23 lymphoma studies. In this meta-analysis, high numbers of T cells at baseline were
reg
associated with improved survival . However, in some subsets of T cell lymphoma and follicular
[119]
lymphoma, the high T cell counts were not associated with improved OS. Hence, additional
reg
differentiation markers are needed to accurately assess the functional role of T cells in lymphoma and its
reg
sub-types.