Efflux capacity and aldehyde dehydrogenase both contribute to CD8+ T-cell resistance to posttransplant cyclophosphamide

Abstract

Mechanisms of T-cell survival after cytotoxic chemotherapy, including post-transplantation cyclophosphamide (PTCy), are not well understood. Here, we explored the impact of PTCy on human CD8+ T-cell survival and reconstitution, including what cellular pathways drive PTCy resistance. In MHC-mismatched mixed lymphocyte culture (MLC), treatment with mafosfamide, an in vitro active cyclophosphamide analog, preserved a relatively normal distribution of naïve and memory CD8+ T cells, while the percentages of mucosal-associated-invariant-T (MAIT) and phenotypic stem-cell-memory (Tscm) T-cell subsets were increased. Activated (CD25+) and proliferating CD8+ T cells derived from both naïve and memory subsets and were reduced but still present after mafosfamide. By contrast, cyclosporine-A or rapamycin treatment preferentially maintained non-proliferating CD25- naïve cells. Drug efflux capacity and aldehyde dehydrogenase-1A1 expression were increased in CD8+ T cells in allogeneic reactions in vitro and in patients, were modulated by common γ-chain cytokines and the cell's proliferative state, and contributed to CD8+ T-cell survival after mafosfamide. The CD8+ T-cell composition early after hematopoietic cell transplantation (HCT) in PTCy-treated patients was dominated by CD25+ and phenotypic memory, including Tscm and MAIT, cells, consistent with MLC. Yet, MHC-mismatched murine HCT studies revealed that peripherally expanded, phenotypically memory T cells 1-3 months post-transplant originated largely from naïve-derived rather than memory-derived T cells surviving PTCy, suggesting that initial resistance and subsequent immune reconstitution are distinct. These studies provide insight into the complex immune mechanisms active in CD8+ T-cell survival, differentiation, and reconstitution after cyclophosphamide, with relevance for post-HCT immune recovery, chemotherapy use in autologous settings, and adoptive cellular therapies.

Graft-versus-tumor effect of post-transplant cyclophosphamide-based allogeneic hematopoietic cell transplantation

“…In addition, aldehyde dehydrogenase-1A1 expression in CD8+ T cells is increased in allogeneic reactions in patients; CD8+ T also rely in part on aldehyde dehydrogenase for protection against PTCy, and their recovery is more robust than conventional CD4+ T cells. They can therefore help prevent relapses after allo-HCT ( 10 ). In contrast, Ritacco et al.…”