Immune checkpoint inhibitors in kidney transplantation

Abstract

Purpose of review: The development of immune checkpoint inhibitor (ICI) immunotherapy has revolutionized the treatment of several cancers. Malignancies are one of the leading causes of death in solid organ transplant recipients (SOTRs). Although ICI treatment may be an effective option in treating malignancies in SOTRs, concerns about triggering allograft rejection have been raised in this population. Herein, we will review currently available data regarding patients, allograft and malignancy outcomes in SOTRs who received ICI therapy.

Recent findings: Cancer incidence is three to five-fold higher among SOTRs, compared with the general population. Skin cancer is the most prevalent cancer after transplant, followed by kidney cancer, lymphoma and Kaposi sarcoma. There are no large prospective studies evaluating ICI therapy's use for treating cancers in SOTRs. However, retrospective studies have shown that ICI treatment may be associated with improved malignancy outcomes and overall survival (OS). However, the risk of allograft rejection is high (around 40%) of whom about half lose their allograft. Maintaining higher levels of immunosuppression may be associated with a lower risk of allograft rejection, but potentially worse malignancy outcomes.

Summary: Although ICI treatment may be associated with improved patient and malignancy outcomes, the risk of allograft rejection and loss are high. Prospective studies are needed to confirm the benefits of ICI therapy in SOTRs and to evaluate the optimal immunosuppression regimen modifications, if any, to improve patient, malignancy and allograft outcomes in transplant recipients.

Figure 1.

Main immune checkpoint receptors on T cells and their respective ligands. Immune checkpoints such as PD-1, CTLA-4, when bound with their respective ligands on APCs and/or tumor cells, can trigger a negative signal to T cells. Abbreviations in the legend: CTLA-4: Cytotoxic T-Lymphocyte-Associated protein-4; PD-1: programmed cell death protein-1; TCR: T-cell receptor; MHC: major histocompatibility complex; PD-L1/2: programmed cell death ligand 1/2.

Figure 2.. Immune evasion by tumor cells and allograft rejection.

Checkpoint proteins, such as PD-L1 on antigen-presenting cells and PD-1 on T cells, keep the immune response in check. (A) When PD-L1 is expressed by tumor cells, the binding of PD-L1 to PD-1 provides a coinhibitory signal that prevents T cells from killing tumor cells in the body (cancer immune evasion). (B, C) Blocking the binding of PD-L1 to PD-1 with an immune checkpoint inhibitor (e.g. anti-PD-L1 or anti-PD-1) unleashes the “break” allowing T cells to be activated and kill tumor cells. Since this process is broad and affects all T cells, it may also expand T cells that may recognize donor HLA peptides in transplantation. (D) These alloreactive T cells, unleashed by checkpoint inhibitors, could then lead to rejection of the transplanted kidney. Abbreviations in the legend: PD-1: programmed cell death protein-1; PD-L1: programmed cell death protein-Ligand 1. TCR: T cell receptor.