Immune checkpoint inhibitors for solid organ transplant recipients: clinical updates

Abstract

Transplant care continues to advance with increasing clinical experience and improvements in immunosuppressive therapy. As the population ages and long-term survival improves, transplant patient care has become more complex due to comorbidities, frailty, and the increased prevalence of cancer posttransplantation. Immune checkpoint inhibitors (ICIs) have become a standard treatment option for many cancers in non-transplant patients, but the use of ICIs in transplant patients is challenging due to the possibility of disrupting immune tolerance. However, over the past few years, ICIs have gradually started to be used in transplant patients as well. In this study, we review the current use of ICIs after all solid organ transplantation procedures (kidney, liver, heart, and lung). Increasing data suggest that the type and number of immunosuppressants may affect the risk of rejection after immunotherapy. Immunotherapy for cancer in transplant patients may be a feasible option for selected patients; however, prospective trials in specific organ transplant recipients are needed.

Keywords: Cytotoxic T-lymphocyte-associated protein 4; Graft rejection; Immune checkpoint inhibitor; Programmed cell death protein 1; Transplantation.

Fig. 1

(A) Mechanism of action of immune checkpoint inhibitors (ICIs). When programmed cell death protein 1 (PD-1) on T cells binds to programmed cell death ligand 1 (PD-L1) or 2 on cancer cells or antigen-presenting cells, T cell activation is suppressed, causing immune escape of cancer cells. Anti-PD-1 antibodies bind to PD-1 on T cells and inhibit the binding of PD-1 to PD-L1/PD-L2, thereby blocking the transmission of inhibitory signals, maintaining T cell activation and restoring the anti-tumor effect. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is expressed on activated T cells and Treg cells, and inhibits T cell activation by binding to B7 on antigen-presenting cells. By inhibiting the binding of CTLA-4 to B7, the anti-CTLA-4 antibody enables the binding of CD28 to B7, thereby reactivating T cells. (B) Mechanism of rejection caused by ICIs. In posttransplant patients, donor cells produce donor antigens, and immunosuppressants are used to suppress T cell activation and regulate immunological tolerance. In patients with cancer after organ transplant, a reduction in the dose of immunosuppressants is often considered to avoid overimmunosuppression and to recover adequate tumor immunity. In addition, ICIs have the potential to disrupt the equilibrium of immunological tolerance and lead to acute rejection. MHC, major histocompatibility complex; TCR, T-cell receptor; LAG3, lymphocyte activation gene 3; CNI, calcineurin inhibitor; MMF, mycophenolate mofetil; mTORi, mammalian target of rapamycin inhibitor.