Page 106 - Read Online

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

[110]
patients with CCA were treated with infusions of EGFR-targeting CART cells (NCT01869166) , while in a
second clinical trial (NCT01935843) patients were infused with specific CARTs for human epidermal
[111]
growth factor receptor 2 . Both trials resulted in an increase in disease-free survival with respect to
patients treated with chemotherapy drug only. Several recent studies used new and improved (fourth-
generation) CARTs that target proteins highly expressed by CCA, such as CD133 , MUC-1 , and
[113]
[112]
integrin αVβ6 ; these have been shown to be extremely efficient both in the expansion of the CART
[114]
population and in the lysis of different CCA cell lines, in vitro.
CONCLUSION
Despite the increased interest of the scientific community, treatment of cholangiocarcinomas remains an
unmet need. Currently, a therapeutic option that has shown good efficacy is liver transplantation, which,
only in very recent years, is being proposed for patients with iCCA and pCCA without distant metastases
and with an early disease . Aside from this option, there are no other truly effective treatment options.
[115]
The genetic and phenotypic diversity that characterizes this family of rare cancers has negatively affected the
progress in this field. An important strategy to overcome this impasse is to better understand the
mechanisms that mediate the crosstalk between tumor cells, the variety of TME cells described above, and
the components of the ECM. In recent years, several studies have aimed at classifying CCA on the basis of
not only of their immunohistochemical and anatomopathological phenotype but also their genetics, signal
pathways, and actionable targets. A seminal work by Sia et al. classifies iCCAs into proliferation class and
[116]
inflammation class, based on specific signaling pathways and mutations. Notably, proliferation class shows a
worse outcome with respect to the inflammatory one. Using a similar approach, mixed hepatocellular CCA
[118]
(HCC/CCA) and eCCA have also been subcategorized. Using a molecular approach, eCCAs were
[117]
classified in metabolic, mesenchymal, proliferative, and immune classes, all characterized in terms of
mutations and modulation of different actionable targets. Furthermore, the development of single-cell RNA
[119]
sequencing now allows analysis of the discrete cell populations in the TRS, including CAFs and immune
response cells , and to study in more detail the crosstalk between these cell milieus . Finally, a recent
[120]
[121]
study used nano liquid chromatography coupled to matrix-assisted laser desorption/ionization-time of
flight (MALDI-TOF/TOF) analysis to study the composition of the matrix (or matrisome) in CCA .
[122]
Using this approach, these authors demonstrated that the aberrant deposition of collagen type III alpha 1
chain directly stimulates the migration of neoplastic cells . Such studies will not only lead to a better
[122]
understanding of the mechanisms of development and growth of the CCA but also open new avenues for a
better allocation of patients to the most appropriate treatments. For example, when planning combination
treatment with immune checkpoint inhibitors and other molecularly targeted drugs, a personalized
approach based on genetic mutations and signaling pathways deregulated in specific CCA subclasses may
confer a therapeutic advantage.

DECLARATIONS
Authors’ contributions
Made substantial contributions to conception and writing of the manuscript: Cadamuro M, Fabris L, Zhang
X, Strazzabosco M

Availability of data and materials
Not applicable.

Financial support and sponsorship
This project was supported in part by the Yale Liver Center award NIH P30 DK034989 Clinical -
Translational core.