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.

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

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.

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.

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

• Graft rejection
• Post-transplant malignancy
• Transplantation
• Transplant immunology
• Immunosuppression
• Kidney transplant
• Liver transplant
• Heart transplant
• Lung transplant
• Pancreas transplant

• coronary artery bypass surgery
• coronary artery disease
• lung transplant evaluation
• percutaneous coronary intervention

• Actinic keratosis
• Skin cancers
• Solid organ transplant recipients

• Humans
• Retrospective Studies
• Skin Neoplasms
• Organ Transplantation
• Transplant Recipients

• kidney transplant recipients
• cutaneous squamous cell carcinoma
• immunosuppression
• sirolimus
• receptores de transplante renal
• carcinoma espinocelular cutâneo
• imunossupressão
• sirolimo

• Humans
• Male
• Middle Aged
• Aged
• Female
• Sirolimus/adverse effects
• Immunosuppressive Agents/adverse effects
• Kidney Transplantation/adverse effects
• Prospective Studies
• Carcinoma, Squamous Cell/drug therapy
• Carcinoma, Squamous Cell/chemically induced
• Skin Neoplasms/drug therapy
• Skin Neoplasms/epidemiology
• Skin Neoplasms/chemically induced
• Calcineurin Inhibitors/therapeutic use
• Graft Rejection/epidemiology
• Graft Rejection/prevention & control

• liver transplantation
• lung cancer
• meta-analysis
• standardized incidence ratio

• Humans
• Liver Transplantation/adverse effects
• Incidence
• Risk Factors
• Lung Neoplasms/epidemiology
• Lung Neoplasms/etiology
• North America

• Humans
• T-Lymphocytes, Regulatory
• Immune System
• Autoimmune Diseases
• Autoimmunity

• Gamma radiation
• Hepatocellular carcinoma
• Iron oxide nanocomposite
• MAPK
• PI3K/Akt/mTOR

• Rats
• Animals
• Carcinoma, Hepatocellular/chemically induced
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/pathology
• Liver Neoplasms/chemically induced
• Liver Neoplasms/drug therapy
• Chitosan/pharmacology
• Phosphatidylinositol 3-Kinases
• Diethylnitrosamine
• Models, Animal
• Nanocomposites
• Body Weight

• Egyptian Atomic Energy Authority

• Conversion
• Hepatocellular carcinoma
• Immunosuppressive agents
• Liver transplantation
• Sirolimus

• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/surgery
• Humans
• Immunosuppressive Agents/adverse effects
• Liver Neoplasms/drug therapy
• Liver Neoplasms/surgery
• Liver Transplantation/methods
• Multicenter Studies as Topic
• Neoplasm Recurrence, Local/drug therapy
• Prospective Studies
• Quality of Life
• Sirolimus/adverse effects
• Treatment Outcome

• cancer
• epidemiology
• kidney transplantation
• malignancy
• neoplasia
• nephrology
• science
• translational research

• Azathioprine
• Calcineurin inhibitors
• Cancer
• Cardiac
• Corticosteroid
• Cyclosporine
• Everolimus
• Heart
• Immune
• Immunosuppression
• Induction
• Maintenance
• Mycophenolate
• Orthotopic
• Prednisone
• Rejection
• Sirolimus
• Steroid
• Tacrolimus
• Transplant
• Vasculopathy
• mTOR inhibitors

• Calcineurin Inhibitors
• Cyclosporine
• Graft Rejection/prevention & control
• Heart Transplantation
• Humans
• Immunosuppression Therapy
• Immunosuppressive Agents/therapeutic use
• Mycophenolic Acid/pharmacology
• Sirolimus

• T cell biology
• basic (laboratory) research/science
• bone marrow/hematopoietic stem cell transplantation
• flow cytometry
• graft-versus-host disease (GVHD)
• graft-versus-leukemia (GVL)/graft versus tumor
• hematology / oncology
• immunosuppressant - mechanistic target of rapamycin: sirolimus
• immunosuppression/immune modulation
• translational research/science

• Kaposi's sarcoma
• Kidney transplantation
• Paclitaxel
• Sarcome de Kaposi
• Transplantation rénale

• everolimus
• kidney transplantation
• low-dose CNI
• secondary prevention
• skin cancer

Colorectal cancer (CRC) occurs with more aggressiveness in kidney transplant recipients compared to the general population. Immunosuppressive therapy plays a crucial role in the development of post-transplant malignancy. Concretely, cyclosporine A (CsA) has intrinsic pro-oncologic properties, while several studies report a regression of cancer after the introduction of rapamycin (RAPA). However, their effect on the extracellular vesicle (EV) content from CRC cell lines and their relevance in the pre-metastatic niche have not yet been studied. Here, we investigated the effect of RAPA and CsA in EV-miRNAs from metastatic and non-metastatic CRC cell lines and the role of relevant miRNAs transferred into a pre-metastatic niche model. EV-miRNA profiles showed a significant upregulation of miR-6127, miR-6746-5p, and miR-6787-5p under RAPA treatment compared to CsA and untreated conditions in metastatic cell lines that were not observed in non-metastatic cells. From gene expression analysis of transfected lung fibroblasts, we identified 22 shared downregulated genes mostly represented by the histone family involved in chromatin organization, DNA packaging, and cell cycle. These results suggest that EV-miR-6127, miR-6746-5p and miR-6787-5p could be a potential epigenetic mechanism induced by RAPA therapy in the regulation of the pre-metastatic niche of post-transplant colorectal cancer.

• Kaposi sarcoma
• chemotherapy
• immunosuppression
• mTOR inhibitor
• organ transplantation
• post-transplant malignancies

• Cancer incidence
• Immunosuppression
• Risk factors
• Solid organ transplantation

• mTOR
• mTORC1
• mTORC2

• Adult
• Aged
• Case-Control Studies
• Colorectal Neoplasms/mortality
• Colorectal Neoplasms/pathology
• Female
• Graft Rejection/prevention & control
• Humans
• Immunosuppressive Agents/adverse effects
• Immunosuppressive Agents/therapeutic use
• Liver Neoplasms/mortality
• Liver Neoplasms/secondary
• Liver Neoplasms/surgery
• Liver Transplantation
• Lung Neoplasms/mortality
• Lung Neoplasms/pathology
• Lung Neoplasms/secondary
• Lung Neoplasms/surgery
• Male
• Middle Aged
• Retrospective Studies
• Survival Analysis
• Treatment Outcome
• Tumor Burden/drug effects

• gene therapy
• mammalian target of rapamycin signaling pathway
• microRNA-144
• osteosarcoma

• cyclin E1
• isoflavones
• mTOR pathway
• retinoblastoma

In kidney transplant patients, skin cancer is the most commonly involved neoplasm. More than 90% of post-transplantation skin cancers are nonmelanoma skin cancers (NMSCs). The majority of them are squamous cell carcinomas and basal cell carcinomas. Calcineurin inhibitors (CNIs) such as cyclosporine and tacrolimus are immunosuppressive agents given after solid organ transplantation, but they can also promote tumor growth. Sirolimus is a novel class of immunosuppressants and has been proven to have antineoplastic properties. We review clinical trials and meta-analyses studying if conversion from CNI to sirolimus in post-renal transplantation patients decreases the development of NMSCs. A critical appraisal of the literature demonstrated that, while smaller scale studies tended to yield no clinically significant data, larger clinical trials and meta-analyses supported the conclusion that converting to sirolimus in post-renal transplant patients leads to reductions in skin cancer development. As a result, we conclude that conversion to sirolimus likely reduces NMSC in post-renal transplantation patients. Larger scale clinical trials with more rigorous stratification and less patient dropout rate are needed for more definitive conclusions.

• calcineurin inhibitor
• kaposi sarcoma
• kidney transplant
• non melanoma skin cancer
• renal transplant
• sirolimus

• Excision
• Histology
• Management
• Skin neoplasms
• Treatment

• Adolescent
• Adult
• Aged
• Databases as Topic
• Demography
• Female
• Follow-Up Studies
• Humans
• Liver Transplantation/statistics & numerical data
• Logistic Models
• Male
• Middle Aged
• Neoplasms/pathology
• Registries/statistics & numerical data
• Risk Factors
• Survival Analysis
• Transplant Recipients/statistics & numerical data
• Young Adult

• the National S&T Major Project
• the Foundation for Innovative Research Groups of the National Natural Science Foundation of China
• Medical and health platform project of Zhejiang Province (A level backbone talent)

• kidney transplantation
• malignancy
• mammalian target of rapamycin
• non-melanoma skin cancer

Liver transplantation (LT) is associated with a 2 to 7 fold higher, age and gender adjusted, risk of de novo malignancy. The overall incidence of de novo malignancy post LT ranges from 2.2% to 26%, and 5 and 10 years incidence rates are estimated at 10% to 14.6% and 20% to 32%, respectively. The main risk factors for de novo malignancy include immunosuppression with impaired immunosurveillance, and a number of patient factors which include; age, latent oncogenic viral infections, tobacco and alcohol use history, and underlying liver disease. The most common cancers after LT are non-melanoma skin cancers, accounting for approximately 37% of de novo malignancies, with a noted increase in the ratio of squamous to basal cell cancers. While these types of skin cancer do not impact patient survival, post-transplant lymphoproliferative disorders and solid organ cancer, accounting for 25% and 48% of malignancies, are associated with increased mortality. Patients developing these types of cancer are diagnosed at more advanced stages, and their cancers behave more aggressively compared with the general population. Patients undergoing LT for primary sclerosing cholangitis (particularly with inflammatory bowel disease) and alcoholic liver disease have high rates of malignancies compared with patients undergoing LT for other indications. These populations are at particular risk for gastrointestinal and aerodigestive cancers respectively. Counseling smoking cessation, skin protection from sun exposure and routine clinical follow-up are the current approach in practice. There are no standardized surveillance protocol, but available data suggests that regimented surveillance strategies are needed and capable of yielding cancer diagnosis at earlier stages with better resulting survival. Evidence-based strategies are needed to guide optimal surveillance and safe minimization of immunosuppression.

• Liver transplant
• Immunosuppression
• Risk
• Outcomes
• Malignancy

Deregulated expression of the MET receptor tyrosine kinase has been reported in up to 50% of patients with hepatocellular carcinoma, the most abundant form of liver cancers, and is associated with decreased survival. Consequently, MET is considered as a molecular target in this malignancy, whose progression is highly dependent on extensive angiogenesis. Here we studied the impact of MET small molecule inhibitors on angiogenesis-associated parameters and growth of xenograft liver models consisting of cells expressing MET-mutated variants M1268T and Y1248H, which exhibit constitutive kinase activity. We demonstrate that MET mutations expression is associated with significantly increased production of vascular endothelial growth factor, which is blocked by MET targeting only in cells expressing the M1268T inhibitor-sensitive but not in the Y1248H inhibitor-resistant variant. Decrease in vascular endothelial growth factor production is also associated with reduction of tyrosine phopshorylation of the vascular endothelial growth factor receptor 2 expressed on primary liver sinusoidal endothelial cells and with inhibition of vessel formation. Furthermore, MET inhibition demonstrated an efficient anti-tumor activity and considerable reduction in microvessel density only against the M1268T-derived intrahepatic tumors. Collectively, our data support the role of targeting MET-associated angiogenesis as a major biological determinant for liver tumor growth control.

• MET
• activating mutations
• angiogenesis
• liver cancer
• small molecule inhibitors

Everolimus (EVE), a mammalian target of rapamycin inhibitor, has been proposed as liver transplant immunosuppressive drug, gaining wide interest also for the treatment of cancer. Although an appropriate tolerance, it may induce several adverse effects, such as fibro-interstitial pneumonitis due to the acquisition of activated myofibroblasts. The exact molecular mechanism associated with epithelial to mesenchymal transition (EMT) may be crucial also in the liver context. This work examines the role and the molecular mediators of EMT in hepatic stellate cell (HSC) and human liver cancer cells (HepG2) and the potential role of EVE to maintain the epithelial phenotype rather than to act as a potential initiators of EMT.

Real time-PCR and western blot have been used to assess the capability of EVE at low-therapeutic (10 nM) and high (100 nM) dose to induce an in vitro EMT in HSC and HepG2.

Biomolecular experiments demonstrated that low concentration of EVE (10 nM) did not modify the gene expression of alpha-smooth muscle actin (α-SMA), Vimentin (VIM), Fibronectin (FN) in both HSC and HepG2 cells, whereas EVE at 100 nM induced a significant over-expression of all the three above-mentioned genes and an increment of α-SMA and FN protein levels. Additionally, 100 nM of EVE induced a significant phosphorylation of AKT and an up-regulation of TGF-β expression in HSC and HepG2 cells.

Our data, although obtained in an in vitro model, revealed, for the first time, that high concentration of EVE may induce EMT in liver cells confirming previous published evidences obtained in renal cells. Additionally, they suggested that mTOR-I should be administered at the lowest dose able to maximize their important and specific therapeutic properties minimizing or avoiding fibrosis-related adverse effects.

In summary, if confirmed by additional studies, our results could be useful for researchers to standardize new therapeutic immunosuppressive and anticancer drugs protocols.

De novo neoplasms account for almost 30% of deaths 10 years after liver transplantation and are the most common cause of mortality in patients surviving at least 1 year after transplant. The risk of malignancy is two to four times higher in transplant recipients than in an age- and sex-matched population, and cancer is expected to surpass cardiovascular complications as the primary cause of death in transplanted patients within the next 2 decades. Since exposure to immunosuppression is associated with an increased frequency of developing neoplasm, long-term immunosuppression should be therefore minimized. Promising results in the prevention of hepatocellular carcinoma (HCC) recurrence have been reported with the use of mTOR inhibitors including everolimus and sirolimus and the ongoing open-label prospective randomized controlled SILVER. Study will provide more information on whether sirolimus-containing vs mTOR-inhibitor-free immunosuppression is more efficacious in reducing HCC recurrence.

• Liver transplantation
• De novo neoplasms
• Immunosuppression
• mTOR inhibitors
• Hepatocellular carcinoma

• Donor Selection
• Humans
• Immunocompromised Host
• Immunosuppressive Agents/administration & dosage
• Immunosuppressive Agents/adverse effects
• Liver Transplantation/adverse effects
• Liver Transplantation/mortality
• Neoplasms/diagnosis
• Neoplasms/etiology
• Neoplasms/mortality
• Neoplasms/prevention & control
• Risk Assessment
• Risk Factors
• Time Factors
• Tissue Donors
• Treatment Outcome

• chemotherapy
• renal transplantation
• urothelial carcinoma

Primary liver cancer is one of the commonest causes of death. Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers. For patients with unresectable or metastatic HCC, conventional chemotherapy is of limited or no benefit. Sorafenib is the only systemic treatment to demonstrate a statistically significant but modest overall survival benefit, leading to an era of targeted agents. Many clinical trials of targeted drugs have been carried out with many more in progress. Some drugs like PTK787 showed potential benefits in the treatment of HCC. Despite these promising breakthroughs, patients with HCC still have a dismal prognosis. Recently, both a phase III trial of everolimus and a phase II clinical trial of trebananib failed to demonstrate effective antitumor activity in advanced HCC. Sorafenib still plays a pivotal role in advanced HCC, leading to further explorations to exert its maximum efficacy. Combinations targeted with chemotherapy or transarterial chemoembolization is now being tested and might bring about advances. New targeted agents such as mammalian target of rapamycin inhibitors are under investigation, as well as further exploration of the mechanism of hepatocarcinogenesis.

• Hepatocellular carcinoma
• Ramucirumab
• Regorafenib
• Tivantinib
• Molecular targeted therapy
• Sorafenib
• Linifanib
• Erlotinib
• Everolimus
• Sunitinib
• Brivanib