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

A variety of factors may affect the development of rejection of liver allograft during ICI therapy. The timing
of ICI use has been implicated by a few studies. In the LT population, the use of ICIs in those with a median
interval of ~2 to 8 years post-LT has been associated with little to no reports of ACR, but rejection seems
much higher when used in the early post-transplant period, up to a year following transplantation [74-76] . This
phenomenon may be explained by the development of transplant immunological tolerance, which refers to
[77]
the decreased immune activity against the allograft, and thus reduced immunosuppression needs . Being
an immunologically privileged organ, liver allograft immune tolerance can occur many years post-LT and is
evidenced by maturation and depletion of self-reactive T-cells, progressive upregulation of CD4+ regulatory
T-cells (which can suppress the injurious activity of Th cells) and regulatory dendritic cells, as well as the
ongoing interaction of these alloreactive cells with hepatocytes and cholangiocytes in the allograft [78,79] . This
reduced immune activity against the allograft is responsible for the decline in basal immune activity in those
with more remote transplantation as opposed to those in the early post-transplant period, hence the
importance of considering the time interval from LT in the use of ICIs.

Modification of immunosuppression in LT recipients undergoing treatment with ICI is somewhat unclear.
Data suggests that immunosuppression could be reduced in LT patients prior to starting ICIs; as a robust T-
cell response is required for successful activity of ICIs and less stringent immunosuppression could facilitate
this [28,80] . Different approaches to achieving this goal have been documented. The use of prophylactic
corticosteroids in a patient maintained on Tacrolimus and Everolimus, with close monitoring was reported
[56]
in a case by Biondani et al. . This patient was managed successfully with no evidence of ACR or IRAEs.
Systemic corticosteroids serve as a potent treatment for IRAEs or ACR, and this may explain the utility of
their use . De Toni et al. reported a patient who was managed by progressive tapering of
[57]
[67]
immunosuppression while being closely monitored on ICIs with no apparent adverse effects. A few studies
showed improved survival in patients managed with ICIs and mTOR inhibitors. Compared to the CNIs, the
mTOR inhibitors have been postulated as having significant anti-neoplastic, anti-angiogenetic and anti-
proliferative properties, related to the selective inhibition of protein synthesis required for cancer cell
growth and proliferation, with the induction of G1 cell cycle arrest, promoting cancer cell apoptosis,
decreased translation of DNA damage, as well as restoration of radiosensitivity in some radioresistant
tumors [81,82] . It has been suggested that these properties may be responsible for the improved survival shown
in these studies [83,84] . However, all these observations are based on case reports and small series, and there is
no consensus recommendation for an immunosuppression strategy prior to initiating ICIs.

Interestingly, in a study reviewing liver biopsies of persons who were post-LT and on ICIs, Munker et al.
[70]
demonstrated that liver biopsies with ACR had increased levels of PD-1 expression, whereas those without
ACR did not have increased PD-1 expression. This suggested a relationship between PD-1 expression and
risk of acute cellular rejection following treatment with ICIs that could be further studied to better
[70]
implement treatment in these patients (as this study evaluated only seven samples) .

IMPORTANT CONSIDERATIONS FOR THE USE OF CHECKPOINT INHIBITORS AFTER
LIVER TRANSPLANTATION
Although there are no societal recommendations on the strategies for the use of ICIs in the treatment of
HCC in LT recipients, some guidance can be drawn from published studies. The timing of ICI use should
be considered. Based on the limited data available, initiating ICIs should be approached with caution in the
early years post-LT for HCC or other tumors [74,75,85] . However, the choice of agent or agent combinations
should be guided primarily by the tumor type, as well as available data behind its safety, efficacy and
response. Moreover, in the case of HCC, choosing ICIs should be considered after other systemic therapies
have failed. Where possible, a liver biopsy should be performed prior to initiation of ICIs in post-transplant