Effector Antitumor and Regulatory T Cell Responses Influence the Development of Nonmelanoma Skin Cancer in Kidney Transplant Patients

Crespo, Elena; Fernandez, Loreto; Lúcia, Marc; Melilli, Edoardo; Lauzurica, Ricardo; Penín, R.M.; Quer, Ariadna; Luque, Sergio; Quero, María; Manonelles, Anna; Torrás, Joan; Cruzado, Josep M.; Cañas, Laura; Grinyó, Josep M.; Bestard, Oriol

doi:10.1097/tp.0000000000001759

Cited by 19 publications

(17 citation statements)

References 49 publications

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“…Among patients with nonmelanoma skin cancer history, mTOR inhibitors lessened the incidence of postrenal transplant skin cancer rather than CNI . At the same time, more than 12 months of use of mTOR inhibitors also lowered the incidence of nonmelanoma skin cancer in recipients previously treated with CNI . The cohort studies based on the national registry database provided a clue that mTOR inhibitors provide a protective role in treating the most common malignancy after transplantation.…”

Section: Discussionmentioning

confidence: 99%

“…Definition of maintenance user of specific immunosuppressive agents: The steady use of CNI, mTOR inhibitors, mycophenolate mofetil, steroid, or azathioprine is defined as continuous use of these drugs for more than 12 months after the ICD code v42.0. 25 As the user of mTOR inhibitors, the definition of mTORi users is as follows: (a) continuous use more than 1 year and (b) prescribed within 1 year after transplantation performed. Those with the started prescription after the occurrence of malignancy were regarded as nonuser for mTOR inhibitors.…”

Section: The Use Of Immunosuppressant Agentsmentioning

confidence: 99%

“…35 At the same time, more than 12 months of use of mTOR inhibitors also lowered the incidence of nonmelanoma skin cancer in recipients previously treated with CNI. 25 The cohort studies based on the national registry database provided a clue that mTOR inhibitors provide a protective role in treating the most common malignancy after transplantation. Among urothelial carcinoma, PTEN-PI3K-AKT pathway was important in tumorigenesis.…”

Section: T a B L E 2 Demographic And Clinical Characteristics Of Mtmentioning

confidence: 99%

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Effect of mechanistic target of rapamycin inhibitors on postrenal transplantation malignancy: A nationwide cohort study

et al. 2018

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BackgroundPost‐transplantation malignancy influenced graft survival and overall survival in the patients receiving renal transplantation. Immunosuppressants influenced the immune surveillance, but whether immunosuppressive agents have impact for incidence of post‐transplantation malignancy is still elusive in Taiwan.MethodWe conducted a nationwide population‐based study. Patients who did not have malignancy history and received kidney transplantation between 2000 and 2010 were enrolled. Specific immunosuppressive users are defined as sustained use (more than 12 months) after renal transplantation. The primary outcome is the development of cancer after kidney transplantation. A Cox proportional hazards model was used to determine the risk of cancer development.ResultAmong 4438 recipients, 559 of them were diagnosed with malignancy after 1 year of transplantation. A total of 742 of recipients were as user of mechanistic target of rapamycin (mTOR) inhibitors. The mTOR users had higher rate of receiving pulse therapy. The hazard ratios (HR) for mTOR inhibitor users with exposure more than 5 years for overall malignancy and urothelial malignancy were 0.68 (95% CI: 0.48‐0.95, P = 0.02) and 0.60 (95% CI: 0.36‐0.99, P = 0.02), respectively. For the overall mortality and reentry of dialysis, the probability of both groups was similar (overall mortality: P = 0.53; reentry of dialysis: P = 0.77).ConclusionAmong the recipients of renal transplantation in Taiwan, mTOR inhibitors with exposure more than 5 years provided a protective role in reducing the risk of overall neoplasm and urothelial malignancy. The probability of reentry of dialysis and overall mortality was similar between the mTORi users and nonusers.

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Section: Discussionmentioning

confidence: 99%

Section: The Use Of Immunosuppressant Agentsmentioning

confidence: 99%

Section: T a B L E 2 Demographic And Clinical Characteristics Of Mtmentioning

confidence: 99%

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Effect of mechanistic target of rapamycin inhibitors on postrenal transplantation malignancy: A nationwide cohort study

et al. 2018

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“…Most cSCCs are surrounded by immune cell infiltrates; however, these cells are incapable of mounting an effective immune response directed against the cSCC . The role and phenotype of T cells surrounding an cSCC lesion has been studied extensively ; high numbers of forkhead box protein 3 (FoxP3) + regulatory T cells are associated with higher metastasis of cSCCs , whereas increased activity of effector and cytotoxic T cells often associates with better prognostic outcomes .…”

Section: Introductionmentioning

confidence: 99%

“…The role and phenotype of T cells surrounding an cSCC lesion has been studied extensively [8][9][10]; high numbers of forkhead box protein 3 (FoxP3) + regulatory T cells are associated with higher metastasis of cSCCs [11,12], whereas increased activity of effector and cytotoxic T cells often associates with better prognostic outcomes [13,14].…”

Section: Introductionmentioning

confidence: 99%

Disrupted regulation of serpinB9 in circulating T cells is associated with an increased risk for post-transplant skin cancer

Peters

Peeters

Bosch

et al. 2019

Clinical and Experimental Immunology

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Summary Cutaneous squamous cell carcinoma (cSCC) is a serious complication after organ transplantation and patients benefit from an early risk assessment. We hypothesized that functional differences in circulating T cells may represent risk factors for post‐transplant cSCC development. Here, we analysed genome‐wide DNA methylation of circulating T cells of kidney transplant recipients before the clinical onset of cSCC, to identify differences associated with post‐transplant cSCC development. This analysis identified higher DNA methylation of SERPINB9 , which is an intracellular inhibitor of granzyme B, a protein that induces apoptosis in target cells. High DNA methylation of SERPINB9 in circulating T cells was confirmed in a second patient cohort during recurrent cSCC, indicating that high SERPINB9 methylation represents a persistent risk factor for cSCC development. At the functional level, the inverse correlation between DNA methylation and messenger RNA expression present in non‐cSCC patients was absent in the cSCC patients. Also, a significant difference in serpinB9 protein expression between cSCC patients and non‐cSCC patients was observed. It was concluded that disturbed regulation of serpinB9 in circulating T cells represents a novel risk factor for post‐transplant cSCC in kidney transplant recipients.

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T-lymphocyte profiles differ between keratoacanthomas and invasive squamous cell carcinomas of the human skin

Bauer

Pari

Umansky

et al. 2018

Cancer Immunol Immunother

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Effector Antitumor and Regulatory T Cell Responses Influence the Development of Nonmelanoma Skin Cancer in Kidney Transplant Patients

Abstract: Tumor-specific T cell responses are strongly impaired in CNI-treated patients but recover after mTOR-i conversion, reducing SCC relapses.

Cited by 19 publications

References 49 publications

Effect of mechanistic target of rapamycin inhibitors on postrenal transplantation malignancy: A nationwide cohort study

Effect of mechanistic target of rapamycin inhibitors on postrenal transplantation malignancy: A nationwide cohort study

Disrupted regulation of serpinB9 in circulating T cells is associated with an increased risk for post-transplant skin cancer

T-lymphocyte profiles differ between keratoacanthomas and invasive squamous cell carcinomas of the human skin

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