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Page 6 of 18 Qin et al. Hepatoma Res 2020;6:24 I http://dx.doi.org/10.20517/2394-5079.2020.04

Table 1. Major immunotherapeutic approaches for HCC
Approach Subject Agent
Vaccines Antigen peptide AFP, GPC3, SSX-2, Htert
Dendritic cells Tumor antigens on DCs and tumor lysate on DCs
HCC cells HCC cells or lysates
Oncolytic virus CVV, JX-594, GLV-1h68 and G47delta
Checkpoint inhibitors CTLA-4 Tremelimumab, tremelimumab with TACE or RFA
PD-1 Nivolumab, pembrolizumab and pidilizumab
PD-L1 Atezolizumab
Adoptive cells CAR-T GPC3, GPC3 and ASGR1
TILs
NK cells NK with K562-mb15-41BBL, sorafenib and NKG2D
CIK CD3 /CD56 T cells, CIK combination with TACE + RFA
+
+
HCC: hepatocellular carcinoma; CIK: cytokine induced killer; NK: natural killer; CAR-T: chimeric antigen receptor T cell; CTLA-4: cytotoxic
T lymphocyte-associated antigen-4; CVV: cowpox virus; RFA: radiofrequency ablation; TILs; tumor-infiltrating lymphocytes; DCs:
dendritic cells; TACE: transcatheter arterial chemoembolization

malignant invasion and metastasis. Previous studies have shown that various angiogenic receptors are
expressed in endothelial cells, such as epidermal growth factor homology domains-2 (Tie-2), VEGF
receptors, platelet-derived growth factor receptor, epidermal growth factor receptor and C-X-C chemokine
receptors, which promote the formation of new blood vessels [72,73] . Liver sinus endothelial cells are special
[74]
endothelial cells that can collect sample portal venous blood and act as APCs to cross-prime T cells . In
addition, the synergistic induction of tumor-derived VEGF-A and prostaglandin E2 (PGE2) can reduce
[45]
antitumor immune response through excessive turnover of CD8 T cells .
+
Kupffer cells are hepatocyte macrophages that form the first line of defense against pathogens and promote
[75]
local tolerance . When stimulated by inflammatory cytokines, Kupffer cells are also stimulated (TNF-α,
IL-1, PDGF) to produce excess osteopontin, which plays an important part in different cellular signaling
[76]
pathways, promoting inflammation, tumor invasion and metastasis . Kupffer cells produce large amounts
[77]
of IL-6 in response to hepatocyte death, which contributes to compensatory proliferation of hepatocytes .
In addition, IL-10 inhibits the expression of Kupffer cell-derived inflammatory TNF-α, and works in concert
[78]
with NO to reduce liver inflammation .
CURRENT STAGES OF IMMUNOTHERAPY
In view of the important role of the immune microenvironment in liver tumors, immunotherapy for liver
cancer has become the focus in current research. According to the present study, immunotherapeutic
approaches are divided into vaccines, cytokines, adoptive cell therapies, immune checkpoint inhibitors, and
oncolytic viruses [Table 1].

Vaccines in HCC management
The essence of cancer vaccination is the body’s own immune system activated by an antigenic substance
and then attacks the tumor. With the progress of immunology and technology, tumor vaccine therapy has
become the frontier in tumor treatment research. Recently, some studies showed that HCC vaccines mainly
include vaccines based on antigen peptides, DCs, cancer cells and DNA.

Antigen peptide vaccines
Antigen peptide vaccines are accurate targets for HCC and are based on TAAs. Recently, the most frequently
reported peptide vaccines have been AFP peptide vaccines [79,80] . AFP is a glycoprotein belonging to the
albumin family, and is normally expressed in abundance in fetal blood while aberrantly expressed on the
surface of HCC cells. However, due to the immune tolerance of the liver, the immune response to AFP
[81]
is limited . It is difficult for AFP to produce an effective immune response when it is synthesized in the