Page 103 - Read Online

Page 8 of 16 Cadamuro et al. Hepatoma Res 2022;8:11 https://dx.doi.org/10.20517/2394-5079.2021.140

able to activate the DC compartment and decrease tumor burden, an effect dramatically reduced by DC
[69]
depletion .
Myeloid-derived suppressor cells
[70]
A family of immune cells only recently studied in CCA is that of the MDSCs . MDSCs are a large group of
myeloid-derived cells whose number expands in diseases such as cancer or chronic inflammation and can
exert an immunosuppressive effect [70,71] . MDSCs inhibit the action of cytotoxic T cells and NK cells by
producing indoleamine 2,3-dioxygenase, reactive oxygen species (ROS), inducible nitric oxide synthase,
prostaglandin E , arginase, and immunomodulatory cytokines such as IL-10 and TGFβ . A study
[70]
2
performed on a very small cohort of 17 patients with CCA showed an increase in circulating MDSCs
compared to controls , an observation confirmed in a more recent study . Zhang et al. , using an
[72]
[74]
[73]
-/-
Mdr2 mouse in which iCCA was induced by hydrodynamic tail injection of plasmids known to favor its
development (NICD + AKT and YAP + AKT), showed that accumulation of MDSCs favored tumor
progression. Notably, gut sterilization was able to reduce MDSC recruitment. This observation
demonstrates that hepatic recruitment of MDSCs can be modulated by the gut microbiota. Furthermore,
using a different mouse model of iCCA [LSL-Kras G12D ; Trp53 Flox/Flox ; Alb-Cre (KPPC) mouse], it was shown
that neoplastic cells can recruit MDSCs via GM-CSF and that administering a blocking monoclonal
[73]
antibody halts the recruitment of myeloid cells and decreases the growth and spread of the tumor . In
addition, the use of antibodies targeting a specific ApoE MDSC subset, coupled with TAM depletion, can
increase the antitumoral effect of immune checkpoint blockade monotherapy .
[75]

Adaptive immunity
TILs are T cells that accumulate within the tumor stroma and counteract tumor development in an antigen-
specific manner. The TIL population is composed by different cell types and includes CD4 T cells (T helper
+
or Th lymphocytes), CD4 CD25 regulatory T cells (Tregs), CD8 T cells (cytotoxic T lymphocytes), and
+
+
+
CD20 B lymphocytes. In general, in biliary tract tumors, the cells that mount the adaptive response tend to
+
decrease during the process that goes from dysplasia to frank tumor and are also more numerous in eCCA
than in iCCA . The different components of TILs accumulate in specific areas of the tumor. While CD20
+
[76]
B cells are present throughout the tumor, CD4 cells accumulate in the peritumor area and CD8 T cells on
+
+
+
the tumor front [62,76,77] . Several studies showed that an enrichment in CD4 , CD8 , and CD20 cells correlates
+
+
with a better overall survival and lower recurrence rates in patients with both iCCA and eCCA [63,76,78-81] .
The adaptive immune response is also finely tuned by a set of stimulatory or inhibitory molecules expressed
on the membrane of T cells called immune checkpoints that mostly function to avoid autoimmune
reactions against self-cells. The downside of this mechanism is that it can be used by cancer cells to avoid
being recognized by immune surveillance, a mechanism known as immune escape [13,82] . The main
stimulatory molecules belonging to immune checkpoints include CD27, CD28, CD40, CD137, CD278,
OX40, and glucocorticoid-induced TNF receptor, while among the inhibitory ones the best known and
studied are cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1) and its ligand PD-L1,
lymphocyte activation gene-3, T-cell immunoglobulin, and mucin protein-3 . Pharmacological blockage of
[83]
inhibitory checkpoint molecules is currently exploited for the development of anti-tumor drugs, and there
are several anti PD-1, PD-L1, and CTLA-4 molecules approved for use or currently in clinical trials for the
treatment of several solid cancers, including CCA [84-88] . Data regarding the predictive value of PD-1 and PD-
L1 expression on patient outcome are discordant and conflicting. One recent meta-analysis of 11 studies
with more than 1000 patients showed that the expression of PD-L1 by tumor cells does not correlate with a
worse overall survival of the patients even after stratifying by type of CCA , but another meta-analysis
[89]
[90]
+
provided opposite results . As for PD-1, recent work has shown that, in iCCA, the increase in CD68
[91]
macrophages and CD8 T lymphocytes expressing PD-1 correlates with a worse postoperative survival .
+