CD8+ Immunosenescence Predicts Post-Transplant Cutaneous Squamous Cell Carcinoma in High-Risk Patients

Abstract

Most morbidity associated with malignancy in long-term renal transplant recipients is due to cutaneous squamous cell carcinoma (SCC). Previously identified measures to stratify SCC risk have limited use, however. We hypothesized that an increased proportion of senescent, terminally differentiated CD8 + T cells would identify renal transplant recipients at elevated SCC risk. Peripheral blood lymphocytes were isolated from 117 stable transplant recipients at high risk of SCC and analyzed phenotypically by flow cytometry. Participants were followed up prospectively for SCC development. The predictive value of variables was assessed using Cox regression. Age at transplant and enrollment, dialysis duration, and previous disease were predictive of SCC development during follow-up. Previously published clinical phenotype-based risk scores lost predictive value with the removal of age as a covariate. The percentage of CD57-expressing CD8 + T cells was the strongest immunologic predictor of future SCC and correlated with increasing CD8 + T cell differentiation. We dichotomized participants into those with a majority (CD57hi) and a minority (CD57lo) of CD8 + T cells expressing CD57; CD57hi participants were more likely to develop SCC during follow-up (hazard ratio, 2.9; 95% confidence interval, 1.0 to 8.0), independent of potential confounders, and tended to develop earlier recurrence. The CD57hi phenotype was stable with time and associated with increasing age and cytomegalovirus seropositivity. Our results show that the CD57hi phenotype is a strong predictor of SCC development and recurrence in this cohort of long-term, high-risk renal transplant recipients. This information may allow identification of recipients who may benefit from intensive dermatologic screening and immunosuppression reduction.

Cancer in ESRD: Clear on the Epidemiology, Hazy on the Mechanisms

“…9 Mechanistically, this study builds on earlier findings from this group of collaborators which suggest that an imbalance between immune regulation and competence underpin the development of SCC post-transplantation. 9,10 Consistent themes of an imbalance between an excess of regulatory T cells (resulting in potential inhibition of antitumor response), 10 reduction in the proportion or functional deficiency of tumor-surveillant cells that are known to conditionally promote antitumor responses (e.g., low number or functional impairment of dendritic cells, natural killer cells, and effector T cells), [9][10][11] in addition to an excess of CD57 hi immunosenescent CD8 1 T cells (associated with impaired protective immunity to viral or tumor antigens), 9 may help to build a theoretical construct in the pathogenesis of carcinogenesis after transplantation. The role of gd T cells in tumor immune surveillance remains unclear, with these cells exhibiting both antitumor and potential tumorigenic effects.…”

“…This is one of several issues requiring clarification, as indicated by the variability of associations between specific measures of immune phenotype and SCC development across different studies from this group. 9,10 The authors suggest patient stratification according CD8…”

“…9 While a measure of immune-competence for clinical use has been long awaited, much remains unknown as to the external validity of these findings in the prediction of SCC and other nonskin cancers before measurement of CD8…”

“…1,5 The same analyses demonstrate clear themes regarding carcinogenesis in this patient group, but at the same time indicates significant differences in the prevalence of specific cancers across the spectrum of ESRD and kidney transplantation. To better understand mechanism, further studies such as that by Bottomley et al 9 in this edition of the JASN are required to provide clarity and ultimately guide clinical practice.…”

“…1,5 A second related paper in this edition of the Journal of the American Society of Nephrology (JASN) by Bottomley et al explored the interesting hypothesis that a marker of T lymphocyte senescence, high-level cell surface expression of CD57 by CD81 T cells as detected by flow cytometry, would identify kidney transplant recipients at increased risk of future development of NMSC. 9 This is a key question both clinically and mechanistically as such cancers are very common (Figure 1), particularly among white recipients, and are a significant cause of morbidity and mortality. Early diagnosis requires frequent skin checks, which can potentially facilitate management and reduce tumor burden.…”