Solid organ transplant recipients are at heightened risk of death from cancer. Indeed, the immunosuppressive treatment, which is paramount to avoid transplant rejection, heightens the risk of death from cancer among solid organ transplant recipients (1). Yet, evidence-based data regarding their cancer treatment are scarce because transplant recipients are usually excluded from clinical trials, and registries are limited (2, 3).

In recent years, the development of immune checkpoint inhibitors (ICIs), including cytotoxic T-lymphocyte-associated protein 4 (CTLA4) inhibitors and inhibitors of programmed cell death protein 1 or its ligand (PD1, PDL1), has considerably improved the survival of patients with certain advanced cancers (4). These monoclonal antibodies foster immune responses against malignancies, but sometimes lead to off-target immune adverse drug reactions (ADRs) (5). ICI unleash the breaks on the immune system and may trigger allograft rejection (AR) (6, 7).

Based on their similar mechanisms of action, different ICI classes are though to mediate the same effect on AR, however this has never been investigated (8). Besides, although AR associated with ipilimumab and pembrolizumab are mentioned in drug labels from both the Food and Drug Administration (FDA) (9, 10) and the European Medicines Agency (EMA) (11, 12), AR is only addressed in the FDA’s drug label for cemiplimab (13, 14). Similarly, regarding PDL1 inhibitors, AR risk is inconsistently mentioned in the FDA’s drug labels, and does not appear in the EMA’s drug labels. Therefore, we aimed to clarify the association of AR with the different ICI classes, through a disproportionality analysis of the pharmacovigilance database of the World Health Organization (WHO).

This analysis of real-world data, issued from the world pharmacovigilance database confirms that treatment of solid organ transplant recipients with ICIs is significantly associated with the risk of AR. This result seems plausible, due to the mechanisms of action of ICIs (19). It is also consistent with the results of previous studies (6, 7, 20). Our results suggest that AR occurs at an early stage of treatment and is associated with poor outcomes. Most reports or AR occurred in kidney transplant recipients, mostly because kidney transplantation is more prevalent than other solid organ transplantations. Moreover, clinicians might be less reluctant to use ICIs on kidney transplant recipients, because renal replacement therapy by dialysis is available. By contrast, liver (or heart) transplant rejection can be life-threatening on a short term.

In the literature, almost all reported cases occur in patients who have been transplanted for more than one year, and sometimes for more than 10 years, before the initiation of an ICI (20). This may be because clinicians are aware of the increased risk of rejection in the early post-transplantation period. Moreover, most patients probably undergo thorough screening for potential malignancies before being transplanted, so that it is rarely required to treat advanced cancer shortly after transplantation. According to the literature, when AR occurs, most patients receive high-dose corticosteroids, sometimes supplemented with intravenous immunoglobulins (in the case of antibody-mediated rejection) (21). For some patients, tacrolimus and/or mycophenolate are initiated or their dose are increased (20). Data from a systematic review report a mortality rate of 57.8% with a longer follow-up duration (median overall survival: 36 weeks) (7). Most deaths were due to cancer progression, although AR significantly impacted survival, particularly in liver recipients.

Interestingly, only one case of AR involving PDL1 inhibitors was reported in the WHO pharmacovigilance database, which is surprisingly low. Moreover, whereas CTLA4 and PD1 inhibitors were associated with statistically significant safety signals for AR in VigiBase^®, no signal was found with PDL1 inhibitors. The IC for PDL1 inhibitors was even negative, as 9 reports of ARs were expected considering the total number of reports with this class and with this ADR. Our findings are supported by a multicenter retrospective study, which focused on the safety and efficacy of ICIs in kidney transplant recipients. Among the 6 patients treated with PDL1 inhibitors, none developed AR, while almost half of the patients treated with PD1 inhibitors did (21). This class seemed associated with a lower risk of rejection, though the number of patients in this non-randomized cohort was too limited to draw definite conclusions.

Debate is still ongoing regarding the different safety profiles of PD1 and PDL1 inhibitors. Both molecules are involved in immune tolerance in transplant recipients (22). Therefore, the potentially lowered risk of AR in patients treated with PDL1 inhibitors might be underpinned by the fact that few lymphocytes are trafficking in the transplanted organ at a baseline state. Hence, PD1 inhibitors could potentially activate a larger proportion of lymphocytes overall, while PDL1 inhibitors may primarily activate lymphocytes at the tumor site, where PDL1 expression is significantly higher than in the graft (23). Another hypothesis is that the intensity of checkpoint inhibition may vary depending on the chosen class. This suggests a potential interest of therapeutic drug monitoring for ICIs, to reduce the risk of overexposure in at-risk patients (24).

Besides, PDL1 inhibitors do not disrupt the interaction between PD1 and PDL2, unlike PD1 inhibitors. As a result, the PDL2 pathway remains efficient in patients receiving PDL1 inhibitors, as a potential protective mechanism for the transplant (25). In fact, PDL2 is expressed on the human kidney and helps to regulate CD8 proliferation, while promoting Treg functions (26–30). From a different perspective, belatacept, a costimulation blocker targeting the CTLA4 pathway, is increasingly used in transplant recipients. A deeper understanding of the physiology of immune checkpoint blockade could, therefore, clear the path for harnessing these pathways to enhance allograft tolerance.

However, it is necessary to guard against overly speculative assertions. In fact, this study cannot definitely conclude that PDL1 inhibitors decrease the risk of AR, as compared to other ICIs. Indeed, limitations inherent to spontaneous reporting systems and pharmacovigilance approaches are hindering factors. Lacking data are frequent, preventing thorough causality assessment for each reported case of AR. Furthermore, we do not have access to the transplant biopsies and the details on the management of AR. The WHO safety database does not provide data regarding the interval between transplantation and the initiation of an ICI. The lack of case validation can induce false positives (31). Several confounding factors could not be addressed either, such as the indications of the treatment with ICIs, or the overall immunological risk status of the patients. Then, the available data do not allow for a distinction between cancer-related mortality and the direct consequences of rejection. The number of reports is low for some classes, with, for instance, only one report of AR involving PDL1 inhibitors in the WHO safety database. This may be due to PD-L1 inhibitors being less frequently used than other classes of ICIs. However, the disproportionality approach aims at mitigating the possible impact of varying prescribing rates (32, 33). In fact, when a drug is prescribed in a larger number of patients, the occurrence of all ADRs is expected to increase. Thus, the disproportionate reporting of a given ADR does not directly depend on the number of patients exposed to the drug. Anyway, reporting rates cannot be interpreted as incidence rates, hence the need for further confirmatory studies.

All in all, our exploratory study paves the way to further prospective studies investigating whether PDL1 inhibitors decrease the risk of AR compared to other classes of ICIs. Besides, the underlying mechanisms involved in this discrepancy warrant further investigation. If these data are confirmed, PDL1 inhibitors could become the preferred class of immune checkpoint inhibitors in solid organ transplant recipients.