Invariant NKT Cell Reconstitution in Pediatric Leukemia Patients Given HLA-Haploidentical Stem Cell Transplantation Defines Distinct CD4+ and CD4− Subset Dynamics and Correlates with Remission State

Abstract

Immune reconstitution plays a crucial role on the outcome of patients given T cell-depleted HLA-haploidentical hematopoietic stem cell transplantation (hHSCT) for hematological malignancies. CD1d-restricted invariant NKT (iNKT) cells are innate-like, lipid-reactive T lymphocytes controlling infections, cancer, and autoimmunity. Adult mature iNKT cells are divided in two functionally distinct CD4+ and CD4− subsets that express the NK receptor CD161 and derive from thymic CD4+CD161− precursors. We investigated iNKT cell reconstitution dynamics in 33 pediatric patients given hHSCT for hematological malignancies, with a follow-up reaching 6 y posttransplantation, and correlated their emergence with disease relapse. iNKT cells fully reconstitute and rapidly convert into IFN-γ–expressing effectors in the 25 patients maintaining remission. CD4+ cells emerge earlier than the CD4− ones, both displaying CD161− immature phenotypes. CD4− cells expand more slowly than CD4+ cells, though they mature with significantly faster kinetics, reaching full maturation by 18 mo post-hHSCT. Between 4 and 6 y post-hHSCT, mature CD4− iNKT cells undergo a substantial expansion burst, resulting in a CD4+<CD4− NKT cell ratio similar to that found in healthy adults. In contrast with patients maintaining remission, iNKT cells failed to reconstitute in all eight patients experiencing disease relapse. These findings define the peripheral dynamics of human iNKT cells and suggest a contribution of these cells to maintain remission, possibly via early IFN-γ provision. Adoptive transfer of donor-derived iNKT cells into HLA-haploidentical patients failing to reconstitute these cells might represent a novel therapeutic option to prevent leukemia recurrence.

Invariant NKT cells with chimeric antigen receptor provide a novel platform for safe and effective cancer immunotherapy

“…48,49 Consistent with these findings, a recent report demonstrated that reconstitution of NKT cells in peripheral blood is associated with long-term remission of pediatric leukemia patients receiving haploidentical transplantation. 50,51 Overall, our results provide the rationale for the development of an NKT-cell-based platform for CAR-directed cancer immunotherapy that could be applied to a broad range of malignancies and used in either autologous or allogeneic settings.…”

Larger number of invariant natural killer T cells in PBSC allografts correlates with improved GVHD-free and progression-free survival

“…32 In the setting of allo-SCT, de Lalla et al reported that after ex vivo T cell-depleted pediatric haploidentical allo-SCT, iNKT reconstitution was associated with sustained disease remission. 37 Finally, in the study of Rubio et al, patients with a higher iNKT/T-cell ratio showed a trend toward a lower risk of relapse. 21 Together with the current study, these data suggest an antitumor effect of donor-derived iNKTs after allo-SCT.…”

Rapamycin Combined with TGF-β Converts Human Invariant NKT Cells into Suppressive Foxp3+ Regulatory Cells

“…As reported in this study, Foxp3 + iNKT cells can suppress both autologous and heterologous CD4 + T cells, suggesting that these cells could contribute to controlling exacerbated inflammatory responses and to autoimmunity, but also to the expansion of heterologous cells as in the case of graft-versus-host disease. In support of this notion, several studies have provided evidence for a role of iNKT cells in promoting or maintaining tolerance in a variety of experimental graft-versus-host disease or autoimmune disorders (18,19,(48)(49)(50)(51)(52). The mechanisms accounting for their tolerogenic effects are still unclear but they were shown to be independent from IL-4 and IL-10 in autoimmune diabetes (53).…”