Immunotherapy for hepatocellular carcinoma recurrence after liver transplantation, can we harness the power of immune checkpoint inhibitors?

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death globally and liver transplantation (LT) can serve as the best curative treatment option. However, HCC recurrence after LT remains the major obstacle to the long-term survival of recipients. Recently, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many cancers and provided a new treatment strategy for post-LT HCC recurrence. Evidence has been accumulated with the real-world application of ICIs in patients with post-LT HCC recurrence. Notably, the use of these agents as immunity boosters in recipients treated with immunosuppressors is still controversial. In this review, we summarized the immunotherapy for post-LT HCC recurrence and conducted an efficacy and safety evaluation based on the current experience of ICIs for post-LT HCC recurrence. In addition, we further discussed the potential mechanism of ICIs and immunosuppressive agents in regulating the balance between immune immunosuppression and lasting anti-tumor immunity.

Keywords: hepatocellular carcinoma; immune checkpoint inhibitor; immunosuppression; liver transplantation; transplant tolerance.

Figure 1

The balance between cancer immunology and transplant tolerance. Through the activation of effector T cells, the ICIs can not only reduce tumor burden but also increase the risk of graft rejection. IL-2, interleukin-2; IFN-γ, interferon-γ; TNF-α, tumor necrosis factor-α.

Figure 2

The co-stimulatory and co-inhibitory pathways in T cells. The PD-1 axis could phosphorylate ITIM and ITSM, recruit SHP1 and SHP2, and further inhibit ZAP 70. Similarly, CTLA-4 pathway recruited SHP2 and PP2A, and attenuated the mTOR signaling. Fyn is another motif on the cytoplasmic tail of Tim-3, promoting the inhibitory function by inhibiting the NFAT and mTOR activity. The unique KIEELE motif is essential for the inhibitory function of Lag-3. When implemented with ICIs, the co-inhibitory pathway is inhibited and T cell is activated. Immunosuppressive agents, such as CNIs and mTOR inhibitors, can obstruct T cell activation by different mechanisms. PD-1, programmed cell death protein-1; PD-L1, programmed cell death ligand 1; CTLA-4, cytotoxic T lymphocyte antigen 4; PP2A, protein phosphatase 2A; ITIM, immune-receptor tyrosine based inhibitory motif; ITSM, immune-receptor tyrosine based switch motif; ZAP 70, zeta-chain-associated protein kinase 70; SHP, src homology 2 domain- containing protein tyrosine phosphatase; NFAT, nuclear factor of activated T cells; mTOR, mammalian target of rapamycin; Tim-3, T cell immunoglobulin-3; Lag-3, lymphocyte activation gene-3; TIGIT, T cell immunoglobulin and ITIM domain; TAC, tacrolimus.