Adolescents and young adults successfully restore lymphocyte homeostasis after intensive T‐cell depleting therapy for cancer

Abstract

Long-term impairment of T-cell regeneration has been widely recognized in humans rendered lymphopenic by disease or therapy (Hakim & Gress, 2005). Successful restoration of T-cell homeostasis following lymphodepletion requires residual thymic function, and age-associated declines in thymic function prevent full immune reconstitution in a substantial percentage of adolescents and adults following the induction of lymphopenia. These observations raise the possibility that only young children are capable of full restoration of T-cell homeostasis following lymphocyte depletion. However, most studies demonstrating incomplete restoration of lymphocyte homeostasis are either limited by relatively short follow-up periods (<2 years) (Hakim et al, 2005) or are confounded by ongoing thymotoxic diseases, such as graft-versus-host disease (Weinberg et al, 2001) or human immunodeficiency virus infection (Douek et al, 2000). In one study, persistent depletion of naïve subsets was observed as long as 30 years following treatment for Hodgkin lymphoma (Watanabe et al, 1997), but an important effect of thymic irradiation in this population could not be ruled out. In order to address whether populations rendered lymphopenic during late childhood, adolescence and young adulthood are capable of full immune reconstitution, we analysed peripheral lymphocyte subsets as part of a cross-sectional study examining late effects of treatment for paediatric sarcomas. Thirty-two patients, described previously (Mansky et al, 2006), treated for the Ewing sarcoma family of tumours (ESFT), rhabdomyosarcoma (RMS) and non-rhabdomyosarcoma soft tissue sarcomas (NR-STS) at the Pediatric Oncology Branch of National Cancer Institute (1965–1998), were studied. All patients received multimodality therapy known to induce profound lymphopenia, which included high dose ciclophosphamide (mean 16·7 gm/m2, range 5·8–18·4 gm/m2). Peripheral blood CD4, naïve CD4 (CD4+CD62L+CD45RA+), total CD8, naïve CD8 (CD8+CD62L+CD45RA+), B (CD20), and natural killer (NK; CD16+CD56+CD3+) subsets were enumerated using standard techniques and compared with 53 healthy controls studied in the same laboratory. Comparisons were made using two-tailed t-tests, with P ≤ 0·01 considered significant. Median age at treatment was 15·4 years (range 7·1–34·2 years), median age at time of analysis was 37·4 years (range 17·5–55·4 years) and median time elapsed from completion of therapy to analysis was 17·3 years (2·9–32·6 years). Median age of controls was 38·6 years (range 25·2–62·8 years). Sarcoma survivors demonstrated normal levels of total circulating CD4 and CD8 T cells, and NK cells and a modest increase in total B cells (Fig 1). Furthermore, they all demonstrated recovery of normal naïve CD4 subsets and there was a statistically significant increase in naïve CD8+ cells, indicative of thymic-dependent immune reconstitution. No patient presented clinical evidence for immune deficiency or autoimmunity following completion of therapy. Thus, in the absence of intercurrent disease and high-dose mediastinal irradiation, humans that were rendered lymphopenic during adolescence and early adulthood successfully restored lymphocyte homeostasis when followed for prolonged periods. Whether populations of older individuals also reliably restore lymphocyte homeostasis with prolonged follow-up will require long-term studies. Adolescents and young adults restore normal T-cell homeostasis following lymphodepleting chemotherapy. Patients, treated with intensive chemotherapy a median of 17 years earlier for sarcoma, showed no evidence for depletion of any lymphocyte subset. Treated patients demonstrated slightly higher median levels of CD8+ naïve T cells and B cells compared with controls.