Novel association between graft rejection and post-transplant malignancy in solid organ transplantation

Abstract

Background: Advancements in immunosuppressive therapies have improved graft survival by enhancing graft tolerance and preventing organ rejection. However, the risk of malignancy associated with prolonged immunosuppression remains a concern, as it can adversely affect recipients' quality of life and survival. While the link between immunosuppression and increased cancer risk is well-documented, the specific interactions between graft rejection and post-transplant malignancy (PTM) remain poorly understood. Addressing this knowledge gap is crucial for devising immunosuppressive strategies that balance rejection prevention with cancer risk reduction.

Aim: To investigate whether immunosuppression in PTM reduces rejection risk, while immune activation during rejection protects against malignancy.

Methods: We analyzed data from the United Network for Organ Sharing's Organ Procurement and Transplantation Network database (1987-2023) on adult, first-time, single-organ transplant recipients with no prior history of malignancy (in donors or recipients). Landmark analyses at 1, 2, 3, 5, 10, 15, and 20 years post-transplant, Kaplan-Meier analyses, and time-dependent Cox proportional hazards regression models, each incorporating the temporal dimension of outcomes, assessed the association between rejection-induced graft failure (RGF) and PTM. Multivariate models were adjusted for clinical and immunological factors, including immunosuppression regimens.

Results: The cohort included 579905 recipients (kidney: 386878; liver: 108390; heart: 45046; lung: 37643; pancreas: 1948) with a mean follow-up of 7.3 years and a median age of 50.6 ± 13.2 years. RGF was associated with a reduction in PTM risk across all time points [hazard ratio (HR) = 0.07-0.20, P < 0.001], even after excluding mortality cases. Kidney transplant recipients exhibited the most pronounced reduction (HR = 0.22, P < 0.001). Conversely, among recipients with PTM, RGF risk decreased across all time points up to 15 years after excluding mortality cases (HR = 0.49-0.80, P < 0.001). This risk reduction was observed in kidney, liver, heart, and lung transplants (HRs = 0.90, 0.21, 0.21, and 0.18, respectively; P < 0.001) but not in pancreas transplants.

Conclusion: RGF reduces PTM risk, particularly in kidney transplants, while PTM decreases RGF risk in kidney, liver, heart, and lung transplants.

Keywords: Graft rejection; Heart transplant; Immunosuppression; Kidney transplant; Liver transplant; Lung transplant; Pancreas transplant; Post-transplant malignancy; Transplant immunology; Transplantation.

Figure 1

Flowchart of study inclusion and exclusion criteria. This study analyzed United Network for Organ Sharing’s Organ Procurement and Transplantation Network data on adult, first-time, single-organ transplant recipients from 1987 to 2023. Major exclusions were recipients of prior, multiorgan, or simultaneous transplants, and those with pre-transplant malignancy or donors with a malignancy history. UNOS-OPTN: United Network for Organ Sharing’s Organ Procurement and Transplantation Network.

Figure 2

Landmark analysis of post-transplant malignancy risk in rejection-induced graft failure. A: No landmark; B: 1-year landmark; C: 2-year landmark; D: 3-year landmark; E: 5-year landmark; F: 10-year landmark; G: 15-year landmark; H: 20-year landmark. Recipients with rejection-induced graft failure had a lower risk of developing malignancy over time compared to those without rejection. RGF: Rejection-induced graft failure.

Figure 3

Post-transplant malignancy-free survival in rejection-induced graft failure. A: All organ types; B: Kidney; C: Liver; D: Heart; E: Lung; F: Pancreas. Recipients with rejection-induced graft failure had higher malignancy-free rates after kidney, liver, heart, and lung transplants. RGF: Rejection-induced graft failure.

Figure 4

Immunological dynamics between graft rejection and post-transplant malignancy in solid organ transplantation. Our findings strongly indicate an inverse relationship between immune activation in graft rejection and the immunosuppressive state in malignancy. HR: Hazard ratio.