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Anugwom et al. Hepatoma Res 2022;8:7 https://dx.doi.org/10.20517/2394-5079.2021.123 Page 5 of 13

[33]
atezolizumab/bevacizumab group . This led to the approval of this combination by the FDA as first-line
therapy for advanced HCC in 2020. Sintilimab (PD-L1 inhibitor) combined with a bevacizumab biosimilar
(a biologic medical product highly similar to the already approved biological) has been compared to
sorafenib in the ORIENT-32 trial. The overall survival and progression-free survival were both higher in the
sintilimab/bevacizumab-biosimilar group (HR = 0.57 for both outcomes) . Other combinations including
[34]
ICIs in ongoing trials include: atezolizumab/cabozantinib (COSMIC-312, NCT03755791),
lenvatinib/pembrolizumab (LEAP-002, NCT03713593) nivolumab/ipilimumab (CHECKMATE-9DW,
NCT04039607) and durvalumab/bevacizumab (EMERALD-2, NCT03847428) . It is expected that these
[35]
additional ICIs will expand the immunologic treatment options for patients with HCC in the near future.

THE IMMUNOLOGICAL MILLEU OF THE TRANSPLANT RECIPIENT
Immunosuppression is essential to long-term patient and graft survival after LT. Compared to
transplantation for other solid organs, the liver is quite immune tolerant, and this is related to the unique
immunologic microenvironment created by the liver-derived dendritic cells, liver sinusoidal endothelial
[36]
cells, liver-derived natural killer cells, and Kupffer cells . This unique environment is crucial in
maintaining organ homeostasis and keeping a balance between immune tolerance and inflammation when
exposed to infectious and tumorigenic triggers [37,38] . In the LT recipient, this unique immune-environment
may explain the need for less overall systemic immunosuppression and potential for immunosuppression
withdrawal after LT [38,39] .

There has been significant advancement in the strategies aimed at successfully preventing rejection of the
allograft since the first successful liver transplantation by Starzl et al. [40,41] in the 1960’s. In the early days of
LTs, corticosteroids and azathioprine were used as the primary immunosuppression strategy and this has
evolved to more recent immunosuppression modalities such as calcineurin inhibitors (CNIs), anti-
metabolites, mammalian targets of Rapamycin inhibitors (mTORs), T-cell depleting and T-cell inhibiting
antibodies [42,43] .

The consequent effect of transplantation on the native immune system is the reduction of T-cell
stimulation, proliferation and differentiation, impairment of natural killer cell proliferation, and significant
downregulated production of co-stimulatory molecules by antigen-presenting cells with a decrease in the
production of pro-inflammatory cytokines [44-46] . These changes, though necessary for long-term allograft
survival, have a deleterious effect on the ability of the immune system to actively detect and attack cancer
cells, so it is no surprise that the risk of some malignancies increases in the post-LT period. As previously
alluded to, in those transplanted for HCC, tumor recurrence can be as high as 20%, and this risk is affected
by immunosuppression, obesity, donor age, etiology of liver disease [47-49] . The de-novo cancer risk in patients
post-LT, based on over 108,000 recipients between 1987 and 2015, was obtained from the United States
Scientific Registry of Transplant Recipients database, and this estimated the cumulative incidence of de novo
extrahepatic cancer to be about 1.3% (95%CI: 1.3-1.4) in the first year after LT; and up to 18.8% (18.4-19.3)
at 20 years . The most common de-novo malignancies in the LT population include Non-Hodgkin’s
[47]
lymphoma, keratinocyte skin cancer (basal cell cancer and squamous cell cancer), cervical cancer and
head/neck cancers; and so, strategies such as judicious use of immunosuppression with reduction when
possible, cancer screening (dermatologic visits, regular pap smears) and avoidance of excessive sun exposure
may promote early detection [50,51] .