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TARGETING CDC1S FOR HCC INTERVENTION
Some patients with a variety of cancers, including HCC, benefit from immune checkpoint inhibitors [44,45] .
Since not all HCC patients are sensitive to this therapy, research has found that WNT activation correlated
with T cell exclusion and resistance to anti-PD1 therapy [46,47] . By using a murine autochthonous liver cancer
model based on hydrodynamic tail vein delivery of different genetic elements, it was found that WNT
activation led to defective DC recruitment, mainly cDC1s. As a consequence, the anti-tumor immune
response was impaired. The impaired immunity in HCC from WNT activation might be due to decreased
[48]
CCL5 secretion by the tumor . These investigations pointed to the importance of cDC1 recruitment in
HCC immunotherapy.

[49]
HCCs arising in cirrhosis are usually preceded by the appearance of malignant precancerous nodules .
The liver of a cirrhotic patient may harbor either a single, benign or precancerous malignant nodule,
or even both. HCC progression could be interfered with if the malignant progenitors in cirrhosis were
eliminated. At this stage, it is difficult to treat with conventional means such as surgery, radiation, and
chemotherapy. However, it may still be controllable by stimulating the immune response through cancer
vaccines. Tumor-associated antigens, which are re-expressed in tumor and not/lowly expressed in normal
[50]
tissues, might potentially be appropriate targets . Previous studies have documented that inducing the
generation of specific T cells to alpha-fetoprotein (AFP), which is re-expressed in most HCCs, led to tumor
[51]
regression and prevented carcinogen-induced murine autochthonous HCC . However, in regenerating
[50]
[52]
mouse liver significant hepatocyte damage was observed . Two decades ago, glypican-3 (GPC3) was
[53]
identified as a new HCC-associated antigen . Different from AFP, it is undetectable in cirrhotic livers, or
even in benign hepatic lesions. Tissue expression of GPC3 was used to discriminate the nature of a < 2 cm
hepatocellular lesion lacking HCC radiological features detected in a cirrhotic patient under surveillance.
Up to 60% of early HCCs showed immunoreactivity to GPC3, either as membranous and/or cytoplasmic
staining in biopsy material . We therefore hypothesized that eliciting the host’s own specific T cell
[53]
immunity against GPC3 could interfere with disease progression in cirrhosis patients.

With the growing importance of cDC1s in initiating effective anti-tumor immunity, and the selective
expression of XCR1 on these cDC1s, the XCL1-GPC3 fusion protein may be an efficient cancer vaccine.
We have linked the XCL1 chemokine to GPC3 for in vivo targeting to induce GPC3-specific CTLs for
eliminating GPC3-positive HCC. Our results showed that the expressed XCL1-GPC3 chemoattracted
+
+
+
+
murine XCR1 CD8α DCs and human XCR1 CD141 DCs in vitro and promoted IL-12 production.
After the mXCL1-GPC3 plasmid was injected subcutaneously, the expressed mXCL1-GPC3 protein was
+
detected mainly in CD8α DCs of mice draining lymph nodes. XCL1-GPC3-targeted DCs enhanced
+
antigen-specific CD8 T cell proliferation and induced the de novo generation of GPC3-specific CD8 T
+
cells, which abolished GPC3-expressing tumor cells both in the murine and human systems. In a murine
autochthonous liver cancer model of AlBlHBV mice, the 3-dose (30-μg in total) immunization suspended
tumor development with significantly reduced tumor incidence and tumor load compared with GPC3-
immunized mice. Notably, the mouse livers have increased infiltration of GPC3-specific CD8 T cells,
+
activated NK cells and NKT cells after mXCL1-GPC3 immunization. The antitumor effects of these cells
[40]
were further enhanced by the administration of anti-PD-1 . Therefore, the XCL1-GPC3, which targets
cDC1s, might be a promising cancer vaccine to compensate for the deficiency of checkpoint blockades in
HCC immunotherapy.

SUMMARY
The presence of cDC1s in the tumor microenvironment is often associated with a good prognosis in cancer
patients and better response to immune checkpoint inhibitors. This cell population is an attractive target for
delivering HCC tumor antigens to induce antitumor specific T cell responses. The combination of cDC1-