Kim HS, Woo W, Choi YG, Bharat A, Chae YK. Novel association between graft rejection and post-transplant malignancy in solid organ transplantation. World J Transplant 2025; 15(2): 102384 [DOI: 10.5500/wjt.v15.i2.102384]
Corresponding Author of This Article
Young Kwang Chae, MD, Professor, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, 645 N. Michigan Avenue, Suite 1006, Chicago, IL 60611, United States. chaelabmeeting@gmail.com
Research Domain of This Article
Transplantation
Article-Type of This Article
Retrospective Cohort Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Author contributions: Kim HS and Woo W contributed equally to the following: Conceptualization, data curation, formal analysis, investigation, methodology, software, validation, visualization, original draft preparation, and review and editing of the manuscript; Choi YG contributed to formal analysis, investigation, methodology, visualization, and drafting and reviewing the manuscript; Bharat A contributed to conceptualization, supervision, project administration, and drafting and reviewing the manuscript; Chae YK contributed to conceptualization, supervision, project administration, investigation, methodology, and drafting and reviewing the manuscript. All authors have read and approved the final manuscript.
Institutional review board statement: The study was reviewed and approved by the Northwestern Institutional Review Board (IRB ID: STU00207117-MOD0009).
Informed consent statement: Written informed consent for participation was not mandated from participants or their legal guardians/next of kin, in line with national legislation and institutional protocols.
Conflict-of-interest statement: There are no conflicts of interest.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement- checklist of items.
Data sharing statement:sharing statement: Statistical reporting and analysis will be shared by the corresponding author upon reasonable request. To access these reports, please contact ychae@nm.org.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Young Kwang Chae, MD, Professor, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, 645 N. Michigan Avenue, Suite 1006, Chicago, IL 60611, United States. chaelabmeeting@gmail.com
Received: October 16, 2024 Revised: December 10, 2024 Accepted: January 9, 2025 Published online: June 18, 2025 Processing time: 127 Days and 11.9 Hours
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.
Core Tip: Our study uncovers a novel inverse relationship between rejection-induced graft failure (RGF) and post-transplant malignancy (PTM) in a cohort of 579905 solid organ transplant recipients. The findings suggest that immune activation during rejection enhances tumor surveillance and lowers malignancy risk, particularly in kidney transplants. In contrast, the immunosuppressive environment associated with PTM reduces the risk of RGF in all organs except the pancreas. These results underscore the need for tailored immunosuppressive strategies that balance the dual risks of rejection and malignancy to improve long-term outcomes in transplant recipients.
Citation: Kim HS, Woo W, Choi YG, Bharat A, Chae YK. Novel association between graft rejection and post-transplant malignancy in solid organ transplantation. World J Transplant 2025; 15(2): 102384
Over the past two decades, solid organ transplantation has become a life-saving procedure worldwide, driven by advancements in organ allocation systems, surgical techniques, immunosuppressive regimens, and post-transplant surveillance. As a result, one-year survival rates for transplanted organs now consistently range from 80% to 90% globally[1]. With an increasing number of transplant recipients living beyond five years, the medical community's focus has naturally shifted. Now, the emphasis is on overcoming the long-term clinical challenges these individuals encounter, especially issues related to graft rejection and post-transplant malignancy (PTM)[2].
Graft rejection, an immune response resulting in the damage to the transplanted organ and possibly even graft failure, is a major hurdle in achieving long-term success with solid organ transplantation[3,4]. Even with considerable progress in immunosuppressive therapies mitigating acute and chronic rejection, this issue persists as a complex challenge in transplantation medicine[5]. Simultaneously, PTM, increasingly recognized in the post-transplant landscape, contributes to recipient morbidity and mortality. The dynamic interplay of immune dysregulation and chronic immunosuppression leaves transplant recipients prone to a variety of malignancies, thereby adding another layer to the complexity of post-transplant care[6-8]. In-depth research has been conducted to understand the incidence, risk factors, and survival outcomes of graft rejection and PTM, primarily in the context of kidney transplantation. However, the relationship between these two severe complications remains largely enigmatic.
Underpinning this study is the hypothesis that organ rejection is mechanistically equivalent to tumor rejection, implying an inverse relationship between rejection and malignancy in transplant recipients. As a result, the concurrent occurrence of both conditions is considered less likely. This premise guides our investigation into the incidence, demographics, and survival outcomes of these critical complications in solid organ transplant recipients, using data from the extensive United Network for Organ Sharing’s Organ Procurement and Transplantation Network (UNOS-OPTN) registry. The insights from this research could inspire novel approaches and support the development of organ-specific, personalized preventive and therapeutic strategies to improve outcomes for transplant recipients.
MATERIALS AND METHODS
Study population and outcomes of interest
This study utilized data from the UNOS-OPTN registry and included all adult, first-time, single-organ solid organ transplant recipients between October 1, 1987 and September 30, 2023. Recipients with a history of prior organ transplantation (including multiorgan or simultaneous transplants) or pre-transplant malignancy were excluded, as were those who received organs from donors with a history of malignancy (Figure 1). Key recipient and donor characteristics, such as recipient age, sex, race/ethnicity, body mass index (BMI), performance status, ABO blood group, ABO match status, human leukocyte antigen (HLA) match status, seropositivity for common oncogenic viruses [Cytomegalovirus (CMV), Epstein-Barr virus (EBV), hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus], donor type (living vs deceased), immunosuppressive therapies (induction, maintenance, and antirejection), were collected.
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.
The primary outcomes of interest were PTM and rejection-induced graft failure (RGF) in solid organ transplant recipients. PTM was classified according to the National Cancer Institute classification of cancers by body location and system[9]. For recipients with multiple PTM diagnoses, the first diagnosis was considered as the endpoint. Data on graft rejection and graft failure were obtained from the UNOS-OPTN registry. However, the dates provided in the registry were associated only with graft failure, not with graft rejection. To address this limitation in time-dependent analyses, the variable “RGF” was created to specifically capture cases where graft failure was caused by rejection. This approach enabled the accurate inclusion of rejection-related events in the statistical analyses, ensuring that the timing of rejection was appropriately reflected in relation to graft failure outcomes. RGF was classified as either acute RGF (ARGF) or chronic RGF (CRGF), according to the causes of failure recorded in the registry.
The risk of PTM following RGF was examined using multiple approaches. To minimize immortal time bias, which can arise when the time between an event (e.g., transplantation) and the start of follow-up (e.g., PTM diagnosis) is not properly accounted for, landmark analyses were performed at 1, 2, 3, 5, 10, 15, and 20 years post-transplant. These analyses evaluated the risk of developing PTM among recipients with or without a prior diagnosis of RGF at each time point, including only those alive at each landmark time. PTM-free survival analysis was performed to compare outcomes between recipients with and without RGF, stratified by organ type. A time-dependent Cox proportional hazards regression model was used to assess the hazard ratio (HR) of RGF on PTM development by organ type, treating RGF as a time-varying variable. Recipients who developed PTM before RGF were excluded to avoid false associations between rejection and malignancy.
Sensitivity analyses were conducted by excluding cases of rejection-related retransplantation or mortality. Subgroup analyses stratified by recipient age (≤ 51 vs > 51 years), BMI (< 25 vs ≥ 25), HLA matching (matched vs mismatched), donor type (living vs deceased), induction therapy (received vs not received), and transplant year (≤ 2005 vs > 2005) were performed to further explore the bidirectional relationship between RGF and PTM using time-dependent Cox proportional hazards regression models. Multivariate analysis adjusted for potential confounding factors, including age, sex, race/ethnicity, BMI, performance status, ABO blood group, ABO and HLA match status, viral seropositivity, donor type, and immunosuppressive regimen. In subgroup analyses, the variable under investigation (e.g., age in age-stratified analyses) was excluded from multivariate adjustment to avoid overcorrection.
Landmark analyses were conducted at 1, 2, 3, 5, 10, 15, and 20 years post-transplantation to assess the risk of RGF among recipients with or without a prior PTM diagnosis, including only those alive at each time point. RGF-free survival analysis was performed to compare outcomes between recipients with and without PTM, stratified by organ type. A time-dependent Cox proportional hazards regression model was used to evaluate the effect of PTM on RGF by organ type, treating PTM as a time-varying variable. Cases where RGF occurred prior to PTM were excluded to avoid false negative associations between PTM and rejection.
Sensitivity analyses excluded cases of malignancy-related mortality, while subgroup analyses stratified by recipient and donor characteristics examined the main outcomes of interest using time-dependent Cox models. Multivariate analyses adjusted for confounders and excluded the stratifying variable in subgroup analyses.
Statistical analysis
Continuous variables were reported as mean and standard deviation (SD), with comparisons made using the t-test. Categorical variables were compared using the χ2 test. Landmark analyses were performed at 1, 2, 3, 5, 10, 15, and 20 years post-transplant, and survival curves were estimated and compared using the Kaplan–Meier method and the log-rank test. Time-dependent Cox proportional hazards regression models were used to assess risk factors over time. All statistical analyses were conducted using R version 4.0.4 (R Core Team, R Foundation for Statistical Computing, Vienna, Austria), with statistical significance defined as a two-tailed P value of less than 0.05. The manuscript was reviewed for statistical accuracy by co-author Young-Geun Choi, PhD, an Associate Professor in the Department of Mathematics Education at Sungkyunkwan University.
RESULTS
This cohort included 579905 total organ recipients, comprising kidney (386878), liver (108390), heart (45046), lung (37643), and pancreas (1948) transplants (Figure 1). The mean follow-up duration was 7.3 years. The mean age of recipients was 50.6 years (SD 13.2), and 38% were female (Table 1).
Table 1 Peri-transplant clinical and immunological characteristics, n (%)/mean ± SD.
Recipient demographics, donor characteristics, and approaches to induction, maintenance, and antirejection therapy varied across different organ types (P < 0.001) (Table 1). Lung transplant recipients had the highest mean age (55.0 years, SD 12.9), while pancreas recipients were the youngest (mean 41.2 years, SD 9.9). Whites were the predominant race for all organ types, though kidney and heart recipients had a notably higher proportion of Black individuals (26.2% and 19.2%, respectively), and kidney and liver recipients had a higher proportion of Hispanic individuals (15.9% and 13.5%, respectively). Recipients with a BMI under 25 were more common in lung (48.5%) and pancreas (48.2%) transplants. Recipients with poor performance status were more frequently recipients of lung (72.9%), heart (64.9%), and liver (55.1%) transplants. Blood type mismatches were rare (0.8%), while HLA mismatches were prevalent across all organ types (82.3%), with the highest rates in pancreas (98.2%) and kidney (91.8%) transplants. More than half of the recipients were positive for CMV and EBV (51.4% and 61.1%, respectively), while HBV and HCV positivity was more commonly observed in liver transplants (4.1% and 28.5%, respectively).
Following transplantation, most recipients received immunosuppressive therapies tailored to prevent and manage graft rejection. Induction therapy was administered to 76.6% of recipients, with the highest rates in pancreas (85.0%) and kidney (80.6%) transplant recipients. Glucocorticoid was the most common agent used (62.7%), particularly in lung (64.8%), heart (64.5%), and kidney (64.4%) transplants. Rabbit anti-thymocyte globulin (rATG) was used in 28.2% of recipients, with its highest utilization in pancreas transplants (56.0%). Basiliximab was used less frequently, administered to 18.6% of recipients, primarily in lung transplants (45.5%). Maintenance therapy was given to 97.4% of recipients, with glucocorticoid (78.8%), mycophenolate mofetil (77.8%), and tacrolimus (25.0%) being the mainstay treatments. Cyclosporine was used in 20.9% of recipients overall, with reduced usage in pancreas (6.3%) and liver (12.1%) transplants. Azathioprine, used in 10.7% of recipients, was notably more common in lung transplant recipients (25.4%). Antirejection therapy as a therapeutic intervention following the diagnosis of graft rejection was required in 5.8% of recipients. Glucocorticoid was the most used agent (5.2%). Heart (11.2%) and lung transplants (9.4%) had the highest frequencies of antirejection therapy use.
Clinical outcomes by organ type
The clinical outcomes of transplant recipients varied based on the type of organ transplanted (P < 0.001) (Table 2). RGF occurred in 9.5% of recipients overall, with kidney (12.1%) and lung (12.0%) transplants showing the highest rates, while liver transplants had the lowest (1.8%). Acute rejection was observed in 2.1% of all recipients, but it was more common in pancreas (8.4%) and kidney (2.7%) transplants. Chronic rejection affected 7.4% of recipients, with the highest rates in lung (11.2%) and kidney (9.4%) transplants. Retransplantation was necessary for 6.3% of recipients, particularly among pancreas (10.5%) and kidney (7.8%) transplants, whereas heart (1.7%), lung (3.2%), and liver (3.8%) transplants showed lower rates of retransplantation. PTM was identified in 12.0% of recipients, with lung (22.6%) and heart (20.9%) transplants carrying the highest risk. Kidney transplants had a lower incidence of PTM (9.9%), while liver transplants were closer to the overall average (12.4%). Skin cancer, including Kaposi sarcoma, was the most common malignancy (6.4%), especially in lung (14.7%) and heart (12.8%) recipients. Genitourinary cancer (1.7%) was most prevalent in heart transplant (3.3%). Hematologic cancers (1.4%) were more common in lung transplants (2.6%), while digestive cancers (1.2%) were more frequent in lung (2.0%), liver (1.6%), and heart (1.6%) transplants. Neurologic cancer was the least common type of PTM (0.0%). Mortality affected 39.5% of all recipients, with lung transplants having the highest rate (58.5%), followed by heart (41.2%) and kidney transplants (38.4%). Pancreas transplants had the lowest mortality rate (28.4%).
Relationship between rejection and PTM by organ type
In landmark analyses, recipients with RGF across all organ types exhibited a lower risk of developing malignancy over time compared to those without a history of rejection: At 1 year (HR = 0.20, 95%CI: 0.16-0.26, P < 0.001), 2 years (HR = 0.16, 95%CI: 0.13-0.21, P < 0.001), 3 years (HR = 0.14, 95%CI: 0.11-0.18, P < 0.001), 5 years (HR = 0.11, 95%CI: 0.08-0.14, P < 0.001), 10 years (HR = 0.09, 95%CI: 0.07-0.12, P < 0.001), 15 years (HR = 0.11, 95%CI: 0.07-0.16, P < 0.001), and 20 years (HR = 0.07, 95%CI: 0.03-0.16, P < 0.001) (Figure 2, Table 3). This trend persisted after excluding rejection-related retransplantation and mortality. In PTM-free survival analyses, recipients with RGF had higher rates of being free of malignancy years after transplantation for kidney, liver, heart, and lung transplants (log-rank P < 0.001) but not for pancreas transplants (Figure 3). Time-dependent Cox proportional hazards regression model identified kidney and lung transplants as having a reduced PTM risk after RGF (kidney: HR = 0.21, 95%CI: 0.18-0.23, P < 0.001; lung: HR = 0.44, 95%CI: 0.22-0.89, P = 0.02) (Table 4). This protective pattern remained after excluding rejection-related retransplantations, but only kidney transplants retained this effect when excluding rejection-related mortality cases (HR = 0.25, 95%CI: 0.20-0.31, P < 0.001). Both acute and chronic cases of RGF were strongly associated with reduced PTM risk in kidney transplant recipients (ARGF: HR = 0.22, 95%CI: 0.18-0.29, P < 0.001; CRGF: HR = 0.21, 95%CI: 0.18-0.24, P < 0.001).
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.
Conversely, solid organ transplant recipients with PTM and no prior history of graft rejection had a lower risk of developing RGF over time compared to those without PTM after excluding deaths attributed to PTM: 1 year (HR = 0.51, 95%CI: 0.44-0.58, P < 0.001), 2 years (HR = 0.49, 95%CI: 0.44-0.56, P < 0.001), 3 years (HR = 0.49, 95%CI: 0.44-0.55, P < 0.001), 5 years (HR = 0.56, 95%CI: 0.50-0.61, P < 0.001), 10 years (HR = 0.67, 95%CI: 0.60-0.74, P < 0.001), and 15 years (HR = 0.80, 95%CI: 0.70-0.91, P < 0.001) (Table 5). Time-dependent Cox proportional hazards regression model with malignancy-related mortality excluded showed PTM as a protective factor for most organs (kidney: HR = 0.90, 95%CI: 0.84-0.95, P < 0.001; liver: HR = 0.21, 95%CI: 0.11-0.38, P < 0.001; heart: HR = 0.21, 95%CI: 0.14-0.31, P < 0.001; lung: HR = 0.18, 95%CI: 0.14-0.23, P < 0.001), except for pancreas transplants (Table 6).
Table 5 Landmark analysis of rejection-induced graft failure risk in post-transplant malignancy, n (%).
Relationship between rejection and PTM by clinical characteristics
In a time-dependent Cox proportional hazards regression model across various patient subgroups (age ≤ 51 vs > 51, BMI < 25 vs ≥ 25, HLA-matched vs HLA-mismatched, living vs. deceased donor, with vs. without induction therapy, transplant year pre-2005 vs post-2005), RGF was consistently associated with a reduction in PTM risk (HRs = 0.20- 0.26, all P < 0.001) (Table 7).
Table 7 Time-dependent Cox proportional hazards regression analysis of post-transplant malignancy risk in rejection-induced graft failure stratified by clinical characteristics.
In contrast, the relationship between PTM and RGF risk was more variable across subgroups (Table 8). Younger recipients demonstrated a stronger association (HR = 1.17, 95%CI: 1.11–1.23, P < 0.001) compared to older recipients (HR = 1.06, 95%CI: 1.00–1.11, P = 0.04). Both BMI subgroups, BMI < 25 (HR = 1.11, 95%CI: 1.05-1.17, P < 0.001) and BMI ≥ 25 (HR = 1.12, 95%CI: 1.07-1.18, P < 0.001), were associated with increased RGF risk among recipients with PTM. Among HLA-mismatched cases, PTM increased the risk of RGF (HR = 1.13, 95%CI: 1.09-1.18, P < 0.001), while no association was observed for HLA-matched cases. For donor type, both liver donors (HR = 1.13, 95%CI: 1.05-1.21, P < 0.001) and deceased donors (HR = 1.12, 95%CI: 1.08-1.17, P < 0.001) showed increased RGF risk associated with PTM. The absence of induction therapy was linked to stronger associations (HR = 1.16, 95%CI: 1.08-1.23, P < 0.001) compared to those who received induction therapy (HR = 1.10, 95%CI: 1.06-1.15, P < 0.001). The year of transplant (pre-2005 vs post-2005) did not show an association between PTM and RGF risk.
Table 8 Time-dependent Cox proportional hazards regression analysis of rejection-induced graft failure risk in post-transplant malignancy stratified by clinical characteristics.
Our study is the first to investigate the relationship between graft rejection and malignancy in the post-transplant setting, highlighting their incidence, demographics, and survival outcomes using real-world data from the UNOS/OPTN registry. Expanding beyond prior research that primarily focused on kidney transplants, we demonstrate the effects of rejection and cancer across multiple solid organ transplants. Importantly, our findings provide compelling evidence of an inverse relationship between the immune activation seen in graft rejection and the immunosuppressive state that fosters cancer development. This suggests that the same biological mechanisms responsible for rejecting graft cells may also serve to target and eliminate cancer cells (Figure 4).
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.
Decreased risk of PTM after RGF
Our study reveals that RGF is consistently associated with a reduction in PTM risk across various patient subgroups, including those stratified by age, BMI, HLA matching, donor type, induction therapy, and transplant year. In organ-specific analyses, this protective association was most pronounced kidney transplant recipients, where rejection is more prevalent than in other organ types.
This inverse relationship raises intriguing possibilities about the role of immune activation during rejection in promoting tumor surveillance, though the mechanisms remain speculative and require further investigation. A plausible hypothesis is that the elevated immune activity during graft rejection may inadvertently trigger antitumor responses. Evidence from studies on tumor-infiltrating lymphocytes (TILs) indicates that high levels of CD3+, CD4+, and CD8+ TILs correlate with improved overall survival in patients with cancer[10]. Alloreactive T cell activation during rejection may infiltrate growing tumors and cross-react with tumor antigens, facilitating tumor control at early stages. Cytokines, such as IFN-γ and TNF-α, released by activated T cells, may have direct antitumor effects and simultaneously activate other immune cells, such as natural killer (NK) cells. This process may be further amplified by the maturation and cellular composition of tertiary lymphoid structures (TLS), particularly the development of germinal centers, which have been associated with stronger antitumor responses and improved clinical outcomes[11]. Within TLS, B cells activated during graft rejection could contribute to antitumor immunity by producing antibodies targeting tumor-derived antigens[11]. Moreover, NK cell activation within tumor-associated TLS is increasingly recognized as a critical element of antitumor immunity[11]. Supporting this dynamic, preclinical studies using genetically modified mice lacking T, B, and NK cells have demonstrated increased susceptibility to both chemically induced and naturally occurring epithelial cancers, emphasizing the essential role of immune cells in preventing malignancy[12].
Additional hypothesized mechanisms involve improved tumor recognition during rejection. Inflammation-induced dendritic cell maturation and MHC molecule upregulation may enhance tumor antigen presentation, while activated antigen-presenting cells with increased co-stimulatory molecule expression may lower the activation threshold for T cells targeting tumor antigens[11,13,14]. Epitope spreading during rejection may allow the immune system to recognize a broader range of tumor antigens[15]. Together, these interconnected processes illustrate how the immune activation seen during graft rejection may incidentally bolster tumor surveillance.
In kidney transplants specifically, the reduced malignancy risk may also be explained by the high frequency of HLA mismatches in this cohort. HLA mismatches lead to chronic immune stimulation, which may facilitate the detection and elimination of tumor cells. This hypothesis is supported by studies demonstrating that HLA mismatches can activate tumor surveillance mechanisms that protect against certain cancers, such as skin cancers[16]. Additionally, kidney transplant recipients were more frequently treated with mTOR inhibitors, a class of immunosuppressive agents known for their dual role in controlling both graft rejection and malignancy[17-21]. These agents inhibit tumor angiogenesis and have shown a protective effect against cancer, which is particularly pronounced in kidney transplant recipients. An important factor is the reduction of immunosuppressive therapy in recipients with failing allografts. As patients who experience graft failure following a kidney transplant frequently resume dialysis, the resulting decrease in immunosuppression may foster a more immune-activated state that is less conducive to cancer development[22].
Liver, heart, lung, and pancreas transplants did not show an association between RGF and PTM reduction after excluding mortality cases related to graft rejection. These organs are more susceptible to developing “cold” tumors, such as breast, prostate, and pancreatic cancers, which are non-immunogenic and do not trigger robust immune responses[23,24]. The prevalence of these tumor types likely weakens the impact of RGF on PTM, even with heightened immune activation during graft rejection.
In liver and heart transplants, the low incidence of RGF, combined with the exclusion of rejection-related deaths, likely reduced the statistical power needed to detect a meaningful association. Furthermore, liver transplants, characterized by lower rates of HLA mismatches and the organ’s inherent immunotolerance, tend to have a diminished immune response to tumors[25]. Heart transplants frequently use mycophenolate mofetil, which has been associated with a 27% reduction in PTM risk[26]. However, this protective effect may be offset by the use of azathioprine in some patients, a drug linked to higher malignancy risks in heart transplantation, contributing to the overall lack of association with PTM[27].
In lung transplants, PTM reduction was observed when only rejection-related retransplantations were excluded, but not when mortality cases related to rejection were removed. Lung transplant recipients face a higher risk of graft rejection due to constant exposure to environmental agents and the presence of a large reservoir of donor antigen-presenting cells, necessitating more intensive immunosuppressive regimens[28,29]. These recipients are particularly vulnerable to chronic rejection, which severely impacts survival rates, falling behind those observed in other solid organ transplantations. The exclusion of mortality cases from rejection in lung transplants likely weakened the observed association, as severe cases of rejection often result in early death. Transplant recipients surviving with milder or controlled rejection may not exhibit the same level of immune surveillance required to suppress malignancy, thus diminishing the association in analyses excluding mortality. Notably, despite aggressive immunosuppression in lung transplants, our study found no increased PTM risk following RGF. This may be due to the widespread use of basiliximab for induction therapy, as it has been demonstrated to lower the incidence of acute rejection without increasing the risk of PTM[30]. The widespread use of glucocorticoids for maintenance therapy raises concerns about their potential role in promoting neoplasms. However, this remains a topic of contention due to limited clinical trial data and their long-standing history in clinical practice[31].
No association was found between RGF and PTM reduction in pancreas transplants. Although this cohort had a moderately high incidence of RGF, the small sample size for pancreas transplants likely limited the statistical power of the analysis. The frequent use of rATG, a potent agent associated with higher malignancy risks, for induction therapy in pancreas transplants may have also confounded the analysis[32-34]. Earlier dosing protocols, which involved higher doses of rATG, along with increased exposure to maintenance immunosuppressants and the absence of antiviral prophylaxis in the past, may have contributed to an inflated malignancy risk in the data analyzed from 1987 onwards.
Decreased risk of RGF after PTM
The reduction in RGF risk following PTM, observed across kidney, liver, heart, and lung transplants, may be attributed to the immunosuppressive effects of the tumor microenvironment (TME). This immunosuppressive state, characterized by a complex network of cellular and molecular interactions, dampens both anti-tumor and alloimmune responses, thereby reducing the likelihood of graft rejection.
One mechanism is T cell exhaustion, where chronic antigen exposure in the TME leads to decreased effector functions and reduced cytotoxicity. Tumors often induce the expansion of regulatory T (Treg) cells, which suppress NK and CD8+ T cells, further inhibiting immune responses against tumors and allografts[35,36]. Similarly, myeloid-derived suppressor cells, abundant in the TME, foster immunosuppression by generating reactive oxygen species and nitric oxide while depleting amino acids essential for T cell function[36,37]. T cells in an exhausted state exhibit diminished production of effector cytokines, such as IFN-γ, and impaired cytotoxic activity, facilitating tumor progression and potentially lowering the likelihood of graft rejection[38].
The TME also employs mechanisms of immune evasion that contribute to the diminished alloimmune response. Tumors overexpressing programmed death-ligand 1 (PD-L1) suppress T cell activity through the PD-1/PD-L1 axis, while the enzyme indoleamine 2,3-dioxygenase depletes tryptophan, an amino acid critical for T cell proliferation, creating a hostile environment for immune activation[10,39]. Furthermore, tumors secrete immunosuppressive cytokines, including transforming growth factor-β and interleukin-10, that inhibit T cell proliferation, enhance Treg differentiation, and reduce antigen presentation by dendritic cells[10]. Collectively, these mechanisms not only facilitate tumor progression but also protect transplanted grafts from immune-mediated rejection.
Liver transplant recipients, who typically experience lower rates of immune activation due to the liver’s immunomodulatory properties, may benefit from the additional immune suppression associated with PTM. In addition, nearly all recipients of kidney, liver, heart, and lung received maintenance therapy, which may help maintain immune tolerance and prevent graft rejection. Moreover, individuals diagnosed with PTM are typically subject to heightened surveillance and more meticulous management practices. This increased oversight likely plays a crucial role in minimizing the incidence of overlooked or suboptimally addressed rejection episodes.
In contrast, pancreas transplants did not show a reduction in RGF risk after PTM, likely due to the high rates of HLA mismatches, which increase the risk of rejection. Additionally, the smaller sample size for pancreas transplants may have limited the statistical power to detect a significant reduction in RGF risk following PTM.
Increased risk of RGF after PTM
Unlike organ-specific analyses that focus on mechanisms unique to each organ, subgroup analyses stratified by recipient and donor characteristics reflect the heterogeneity introduced by systemic factors and variations in clinical practices across all organ types. Younger recipients faced a higher risk of RGF after PTM, potentially due to their more robust immune responses and alloimmune activation, while older recipients, often experiencing immunosenescence, were less likely to develop rejection. BMI below 25 was associated with increased RGF risk, which may reflect frailty or poor nutritional status in underweight individuals, potentially impairing immune function and recovery. On the other hand, the increased risk in high BMI may be linked to chronic systemic and adipose tissue inflammation that exacerbates alloimmune responses[40]. HLA mismatches raised RGF risk in PTM cases due to heightened alloimmune activation, whereas no association was observed in HLA-matched cases.
Recipients without induction therapy exhibited a stronger association between PTM and RGF risk, likely reflecting the lack of robust initial immunosuppressive regimens. Deceased donors were linked to higher rejection risks compared to living donors, potentially due to longer ischemic times, ischemia-reperfusion injury, and suboptimal graft quality, which amplify alloimmune responses. Notably, the year of transplant (pre-2005 vs post-2005) did not influence the PTM-RGF relationship, suggesting that advancements in transplant practices, including improved immunosuppressive regimens and organ allocation policies, have not meaningfully altered this dynamic.
Study limitations and strengths
The findings of our study should be interpreted with caution, as its retrospective design is inherently susceptible to potential biases and unaccounted confounders. Key factors, such as advancements in medical care, changing treatment protocols, and environmental exposures, that may influence recipient outcomes were not included in the analysis. The reliance on the UNOS-OPTN transplant information database is another limitation, as the data are derived from transplant center reports, which may be incomplete or inconsistently documented[41]. For example, transplant recipients may be followed less closely after graft failure than before, potentially leading to an artifactual decrease in the observed incidence of PTMs. Additionally, the study did not have access to detailed antimicrobial regimens, such as voriconazole, which is known to increase cancer risk in solid organ transplant recipients, thereby omitting an important factor related to cancer development[42]. Subgroup analyses based on comorbidities, such as persistent pulmonary fibrosis, chronic obstructive pulmonary disease, and primary sclerosing cholangitis—conditions strongly associated with cancer—were not conducted due to their varying prevalence across different transplant types[43-45]. The small sample size for pancreas transplants is a limitation of the database and study criteria. Adjusting the criteria risks introducing selection bias, while using additional data sources may increase heterogeneity and reduce internal validity. Future studies could overcome this limitation through collaboration across transplant registries, enabling larger sample sizes with consistent data collection and definitions.
The study has several strengths that effectively counterbalance these limitations. The sample size of 579905 solid organ transplant recipients allows for a more comprehensive understanding of the relationship between graft rejection and malignancy in the post-transplant setting across a variety of organ types. Furthermore, our inclusion of detailed induction, maintenance, and antirejection treatment histories in all multivariate analyses strengthens the reliability of the study by accounting for the impact of immunosuppression regimens on recipient outcomes. The consistency of our findings across multiple analytical approaches further strengthens the robustness of our results. This was demonstrated through landmark analyses at different time points, time-dependent Cox proportional hazards regression analyses, subgroup analyses, and sensitivity analyses. The sensitivity analyses involved: (1) Excluding rejection-related retransplantation to mitigate biases from repeated transplantations; (2) Excluding rejection-related mortality; and (3) excluding malignancy-related mortality to focus on the direct interaction between the main outcomes without the confounding effect of death. Notably, the trend of reduced PTM risk following RGF persisted across all data subsets, reinforcing the reliability of our conclusions and providing a solid foundation for future research and advancements in transplant medicine.
CONCLUSION
In conclusion, this nationwide cohort study offers important insights into the dynamic relationship between RGF and PTM in solid organ transplantation. Our findings support the hypothesis that increased immune activation during graft rejection enhances immune surveillance, thereby lowering the risk of malignancy. On the other hand, the immunosuppressive environment associated with malignancy in the post-transplant setting may lower the risk of graft rejection in certain organ types. The observed organ-specific differences in this relationship underscore the importance of tailoring immunosuppressive regimens to the tissue-specific immune environments of each organ type. Moreover, the variations across recipient and donor characteristics suggest that the interplay between alloimmune activation, immunosuppression, and systemic inflammation is highly context-dependent. These results emphasize the need for prospective studies to elucidate the immunological mechanisms driving the RGF-PTM relationship. Such research could involve dynamic tracking of immune changes, including T cell activation, cytokine production, and metabolic reprogramming, and identifying biomarkers predictive of rejection or malignancy risk. Additionally, detailed subgroup analyses within each organ type could offer deeper insights into how recipient and donor characteristics influence these outcomes, enabling proactive risk stratification and personalized interventions to optimize transplant care.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Corresponding Author's Membership in Professional Societies: American Society of Clinical Oncology, 148776; American Association for Cancer Research, 273566; Society for Immunotherapy of Cancer, 24504; International Association for the Study of Lung Cancer, 417079.
Specialty type: Transplantation
Country of origin: United States
Peer-review report’s classification
Scientific Quality: Grade A, Grade A
Novelty: Grade A, Grade B
Creativity or Innovation: Grade A, Grade A
Scientific Significance: Grade A, Grade A
P-Reviewer: Li MY S-Editor: Liu H L-Editor: A P-Editor: Zhang XD
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