Abstract
Cutaneous squamous cell cancer (SCC) affects up to 30% of kidney transplant recipients (KTRs) within 10 years of transplantation. There are no reliable clinical tests that predict those who will develop multiple skin cancers. High numbers of regulatory T cells associate with poor prognosis for patients with cancer in the general population, suggesting their potential as a predictive marker of cutaneous SCC in KTRs. We matched KTRs with (n = 65) and without (n = 51) cutaneous SCC for gender, age, and duration of immunosuppression and assessed several risk factors for incident SCC during a median follow-up of 340 days. Greater than 35 peripheral FOXP3(+)CD4(+)CD127(low) regulatory T cells/microl, <100 natural killer cells/microl, and previous SCC each significantly associated with increased risk for new cutaneous SCC development (hazard ratio [HR] 2.48 [95% confidence interval (CI) 1.04 to 5.98], HR 5.6 [95% CI 1.31 to 24], and HR 1.33 [95% CI 1.15 to 1.53], respectively). In addition, the ratio of CD8/FOXP3 expression was significantly lower in cutaneous SCC excised from KTRs (n = 25) compared with matched SCC from non-KTRs (n = 25) and associated with development of new cutaneous SCCs. In summary, monitoring components of the immune system can predict development of cutaneous SCC among KTRs.
Highlights
Organ transplantation is the treatment of choice for individuals with organ failure
Univariate Cox regression for time to tumor and for immune phenotype of circulating peripheral blood lympho-. This is the largest study to analyze the immune phenotype of peripheral blood leukocytes present in long-term kidney transplant recipients (KTRs) (Ͼ5 years after transplantation) and is the first report that the immune phenotype of peripheral blood leukocytes is different between KTRs with and without squamous cell cancer (SCC)
KTRs with previous SCC have a higher number of FOXP3ϩCD4ϩCD127low and CD8ϩCD28Ϫ T cells present in the peripheral blood than KTRs without SCC
Summary
Immunosuppressive regimens have become more potent, resulting in transplant recipients experiencing fewer acute rejection episodes and improved 1-year graft survival.[1] Concurrently, there has been an increased incidence of malignancy.[2,3] Organ transplant recipients (OTRs) have a cancer prevalence four to six times higher than the general population.[4,5]. A low CD4 count predicted those at risk for any cancer after transplantation, including SCC.[17,18] These studies were performed within the first 10 years of transplantation, when skin cancer incidence is relatively low, and predictive, CD4 T cell count in this population had limited clinical utility. If a particular immune profile could accurately predict new SCC development in those at risk, it would be a valuable tool for posttransplantation clinical management and could allow targeted manipulations in immunosuppressive therapy and skin surveillance. The presence of increased numbers of regulatory T cells (Tregs; CD4ϩCD25highFOXP3ϩ and CD8ϩCD28Ϫ cells) within the tumor and peripheral circulation is associated with poor prognosis.[19,20,21,22] Under physiologic conditions, Tregs control immune responses, preventing excessive tissue damage and autoimmunity.[23,24] In the tumor microenvironment, Tregs may act by a variety of mechanisms, impairing antitumor functions of CD8ϩ T cells and natural killer (NK) cells.[25,26,27]
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