Immunosenescence and cancer predisposition in pediatric transplant recipients: An emerging paradigm

Abstract

Pediatric solid organ and hematopoietic stem cell transplant recipients paradoxically experience accelerated immune aging despite chronological youth, establishing a paradigm with profound implications for cancer risk and long-term outcomes. This comprehensive review synthesizes current evidence demonstrating how transplantation-related factors, anti-thymocyte globulin-mediated T cell depletion, cytomegalovirus reactivation, chronic immunosuppression, and thymic dysfunction, induce premature immunosenescent phenotypes. These processes converge to generate T cell populations exhibiting CD28 loss, killer cell lectin-like receptor G1 positivity, telomere attrition, and functional exhaustion characteristic of elderly individuals. Concurrently, inflammaging pathways and senescence-associated secretory phenotypes establish pro-tumorigenic microenvironments. Consequently, pediatric recipients demonstrate 4- to 20-fold elevated cancer incidence, with standardized incidence ratios for post-transplant lymphoproliferative disease exceeding 200 in some cohorts. Beyond hematological malignancies, significant increases in solid tumors suggest fundamental immunosurveillance failure. Emerging biomarkers including flow cytometric senescence panels, telomere length measurement, and epigenetic clocks enable personalized risk stratification. Therapeutic horizons encompass senolytic agents, checkpoint inhibitor modulation, thymic regeneration strategies, and metabolic interventions targeting aging pathways. This paradigm shift necessitates reconceptualizing pediatric transplantation through the aging lens, integrating precision medicine approaches that balance graft survival, immune competence preservation, and cancer prevention in this vulnerable population.

Keywords: Immunosenescence; Pediatric transplantation; Cancer predisposition; T cell exhaustion; Post-transplant lymphoproliferative disease; Cytomegalovirus; Telomere dysfunction; Thymic involution; Inflammaging; Senescence-associated secretory phenotype

Core Tip: Children who undergo organ transplantation often experience premature aging of the immune system, largely due to factors such as anti-thymocyte globulin exposure, cytomegalovirus reactivation, thymic dysfunction, and long-term immunosuppressive therapy. This accelerated immune decline substantially increases their risk of developing cancer both early and later in life. Adopting a biomarker-driven clinical approach, including senescence-related flow cytometry panels, T cell receptor excision circle/telomere assessments, and epigenetic aging markers, along with tailored immunosuppression strategies, vigilant cytomegalovirus management, and emerging therapies targeting senescent, thymic, or metabolic pathways may help lessen cancer risk and improve long-term patient outcomes.