Page 65 - Read Online

Page 8 of 14 Diab et al. J Cancer Metastasis Treat 2022;8:42 https://dx.doi.org/10.20517/2394-4722.2022.60

+
Figure 3. T lymphocytes within the TME of PDAC. Regulatory T cell (Tregs) and CD4 helper 17 (Th17) cells. Along with tumor-
associated macrophages, they inhibit cytotoxic T lymphocytes. Additionally, the dense stroma confers elevated intratumoral pressures
resulting in vascular compression, which reduces the recruitment of cytotoxic T lymphocytes to the TME. CTL: cytotoxic T lymphocyte;
TAM: tumor-associate macrophage; ECM: extracellular matrix; PDAC: pancreatic adenocarcinoma; Treg: regulatory T lymphocyte.
+
TH17, CD4 helper 17 lymphocyte. (Adopted from Carr et al., EMBO Mol Med. 2016;8:80-2. doi:10.15252/emmm.201505948).

+
+
[71]
CD4 T cells include Tregs and CD4 helper 17 (Th17), both of which exert tumor-promoting functions .
Tregs express a CD3 CD4 CD25 FoxP3 phenotype and are associated with poor prognosis [72,73] . Tregs
+
+
+
+
communicate intimately with MDSCs primarily through cell-cell interactions to promote their survival and
[74]
promote an immunosuppressive TME . Interestingly, depletion of Tregs in KC;Foxp3 and KC;CD4
DTR
-/-
mice resulted in an increase of MDSCs within tumors and pronounced tumor growth . These results
[74]
highlight the effects of one cell population on the rest of the whole population.
Th17 cells produce IL-17, a crucial cytokine in the development and progression of PDAC [75,76] . Oncogenic
Kras drives the expression of IL-17 receptor on PanIN lesions, and IL-17 from lymphocytes promotes
tumor progression and induces cancer stemness through pathways such as IL-6/STAT3 and NF-κB [75,76] .
-
+
Recent efforts showed that CD11b CD103 dendritic cells produce IL-23 and TGF-β and induce CD4 +
+
[77]
FOXP3 IL10 IL 17 IFNγ T cells . Identifying additional interactions these cells have with other
-
+
+
-
constituents of the TME can be exploited as therapeutic targets.
B cells
Contrary to other immune cells in the TME of PDAC, B lymphocytes are some of the least studied cell
populations and their role in the development of PDAC remains controversial [78,79] . Research shows the
presence of B cells in the early stages of PanIN lesions . Recent work shows that B cells can be found in
[78]
two main locations in PDAC : 1- scattered infiltrating the tumor-stromal surface and 2- organized in
[80]
ectopic lymph-node like structures called tertiary lymphoid tissue (TLT) . After affinity maturation of
[80]
[81]
+
CD20 naïve B cells in the germinal centers of TLT, circulating plasmablasts are produced . Those
plasmablasts have been shown to be the most potent subset of B cells to stimulate collagen production by