eISSN: 2299-0046
ISSN: 1642-395X
Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii
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SCImago Journal & Country Rank
5/2018
vol. 35
 
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abstract:
Original paper

Evaluation of quantitative changes in regulatory T cells in peripheral blood of kidney transplant recipients with skin cancer after conversion to mTOR inhibitors

Agnieszka Cegielska, Katarzyna Lisowska, Alicja Dębska-Ślizień, Beata Imko-Walczuk, Aleksandra Okuniewska, Bolesław Rutkowski

Adv Dermatol Allergol 2018; XXXV (5): 474-480
Online publish date: 2018/07/19
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Introduction
Immunosuppressive therapy, necessary for graft survival, has its clinical consequences with an increased risk of developing malignancies being one of them. It seems that the maintenance of a proper balance between cytotoxic and regulatory activity of the immune system may prevent graft rejection, and with a lower risk of cancer.

Aim
To assess the quantitative changes in regulatory T cells (Tregs) in peripheral blood of kidney transplant recipients with post-transplantation skin neoplasm after conversion to mTOR inhibitors (mTORi) and to assess the incidence of secondary skin cancer in that group of patients.

Material and Methods
Fourteen patients with post-transplant cutaneous malignancies converted to mTORi were included into the study. The control group consisted of eighteen patients maintained on immunosuppressive regimens without mTORi. The level of Tregs with a phenotype defined as CD4lowCD25high was measured before, and 6 months after, mTORi introduction.

Results
In all cases, 6 months after conversion, a significant decrease in the ratio of CD4+CD25+ to CD4lowCD25high from 6.52 to 4.29 was detected (p = 0.035). One patient converted to mTORi developed subsequent skin cancer, while in the control group, subsequent skin cancer was recognized in eight patients. Moreover, introducing mTORi significantly improved progression-free survival in this group of patients (p = 0.016).

Conclusions
Introducing mTORi to the immunosuppressive regimen resulted in an increase in the number of regulatory cells without increasing the incidence of secondary skin cancer in the investigated group of patients.

keywords:

skin cancer, kidney transplant recipients, immunosuppression, regulatory T cells

references:
Jensen P, Hansen S, Moller B. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol 1999; 40: 177-86.
Danpanich E, Kasiske BL. Risk factors for cancer in renal transplant recipients. Transplantation 1999; 68: 1859-64.
Wood KJ, Sakaguchi S. Regulatory T cells in transplantation tolerance. Nat Rev Immunol 2003; 3: 199-210.
Hickman SP, Turka LA. Homeostatic T cell proliferation as a barrier to T cell tolerance. Philos Trans R Soc Lond B Biol Sci 2005; 360: 1713-21.
Battaglia M. Potential T regulatory cell therapy in transplantation: how far have we come and how far can we go? Transpl Int 2010; 23: 761-70.
Marcen R. Immunosuppressive drugs in kidney transplantation: impact on patient survival, and incidence of cardiovascular disease, malignancy and infection. Drugs 2009; 69: 2227-43.
Kauffman HM, Cherikh WS, Cheng Y, et al. Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies. Transplantation 2005; 80: 883-9.
Bryl E, Daca A, Jówik A, Witkowski JM. Human CD4lowCD25high regulatory T cells indiscriminately kill autologous activated T cells. Immunology 2009; 128: 287-95.
Bouves Bavinck JN, Hardie DR, Green A, et al. The risk of skin cancer in renal transplant recipients in Queensland, Australia. A follow-up study. Transplantation 1996; 61: 715-21.
Hartevelt MM, Bavinck JN, Kootte AM, et al. Incidence of skin cancer after renal transplantation in the Netherlands. Transplantation 1990; 49: 506-9.
Ramsay HM, Reece SM, Freyer AA, et al. Seven-year prospective study of non-melanoma skin cancer incidence in U.K. renal transplant recipients. Transplantation 2007; 84: 437-9.
Bunney MH, Benton EC, Barr BB, et al. The prevalence of skin disorders in renal allograft recipients receiving ciclosporin A compared to those receiving azathioprine. Nephrol Dial Transplant 1990; 5: 379-82.
Shuttelworth D, Marks R, Griffin PJ, Salaman JR. Epidermal dysplasia and ciclosporin therapy in renal transplant patients: a comparison with azathioprine. Br J Dermatol 1989; 120: 551-4.
Mathew T, Kreis H, Friend P. Two-year incidence of malignancy in sirolimus-treated renal transplant recipients: result from five multicenter studies. Clin Transplant 2004; 18: 446-9.
Geissler EK. Can immunosuppressive strategies be used to reduce cancer risk in renal transplant patients? Transplant Proc 2010; 42: S32-5.
Monaco A. The role of mTOR inhibitors in management of post-transplant malignancy. Transplantation 2009; 87: 157-63.
Mota A, Arias M, Taskinen EI, et al. Sirolimus-based therapy following early cyclosporine withdrawal provides significantly improved renal histology and function at 3 years. Am J Transplant 2004; 4: 953-61.
Guba M, von Breitenbuch P, Steinbauer M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangigenesis: involvement of vascular endothelial growth factor. Nat Med 2002; 8: 128-35.
Luan FL, Hojo M, Maluccio M, et al. Rapamycin blocks tumor progression: unlinking immunosuppression from antitumor efficacy. Transplantation 2002; 73: 1565-72.
Campistol JM, Eris J, Oberbauer R, et al. Sirolimus therapy after early cyclosporine withdrawal reduces the risk for cancer in adult renal transplantation. J Am Soc Nephrol 2005; 17: 581-9.
Diekman F, Campistol JM. Conversion from calcineurin inhibitors to sirolimus in chronic allograft nephropathy: benefits and risks. Nephrol Dial Transplant 2006; 21: 562-8.
Fernandez A, Marcen R, Pascual J, et al. Conversion from calcineurin inhibitors to everolimus in kidney transplant recipients with malignant neoplasia. Transplant Proc 2006; 38: 2453-5.
Caroti L, Zanazzi N, Paudice N, et al. Conversion from calcineurin inhibitors to everolimus with low-dose cyclosporine in renal transplant recipients with squamous cell carcinoma of the skin. Transplant Proc 2012; 44: 1926-7.
De Fijter JW. Use of proliferation signal inhibitors in non-melanoma skin cancer following renal transplantation. Nephrol Dial Transplant 2007; 22: i23-6.
Euvrard S, Morelon E, Rostaing L, et al. Sirolimus and secondary skin cancer prevention in kidney transplant. N Engl J Med 2012; 367: 329-39.
Sakaguchi S, Sakaguchi N, Asano M, et al. Immunologic self-tolerance maintained by activated T-cells expressing IL-2 receptor alpha – chains (CD25). Breakdown of a single mechanism of self-tolerance causes various auto-immune diseases. J Immunol 1995; 155: 1151-64.
Shevach EM. From vanilla to 28 flavors: multiple varieties of regulatory cells. Immunity 2006; 25: 195-201.
Belkaid Y, Rouse BT. Natural regulatory T cells in infectious disease. Nat Immunol 2005; 6: 353-60.
Smyth MJ, Teng MW, Swann J, et al. CD4+CD25+ T regulatory cells suppress NK-cell mediated immunotherapy of cancer. J Immunol 2006; 176: 1582-7.
Ghiringhelli F, Menard C, Terme M, et al. CD4+CD25+ T regulatory cells inhibit natural killer cell functions in a transforming growth factor-beta – dependent manner. J Exp Med 2005; 202: 1075-108.
Dummer CD, Carpio VN, Goncalves LF, et al. FOXP3+ regulatory T cells: from suppression off rejection to induction. Transpl Immunol 2012; 26: 1-10.
Sauer S, Bruno L, Hertweck A, et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci USA 2008; 105: 7797-802.
San Segundo D, Fernandez-Fresnedo G, Ruiz JC, et al. Calcineurin inhibitors, but not rapamycin, reduce percentages of CD4+CD25+FOXP3+ regulatory T cells in renal transplant recipients. Transplantation 2006; 82: 550-7.
San Segundo D, Fernandez-Fresendo G, Gago M, et al. Number of peripheral blood regulatory T cells and lymphocyte activation at 3 months after conversion to mTOR inhibitor therapy. Transplant Proc 2010; 42: 2871-3.
Carroll RP, Hester J, Wood KJ, Harden PN. Conversion to sirolimus in kidney transplant recipients with squamous cell cancer and changes in immune phenotype. Nephrol Dial Transplant 2013; 28: 462-5.
Hendrikx TK, Velthuis JHL, Klepper M, et al. Monotherapy rapamycin allows an increase of CD4+ CD25high FOXP3+ T cells in renal transplant recipients. Transpl Int 2009; 22: 884-991.
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