Improved Overall Survival, Relapse-Free-Survival, and Less Graft-vs.-Host-Disease in Patients With High Immune Reconstitution of TCR Gamma Delta Cells 2 Months After Allogeneic Stem Cell Transplantation

Front Immunol. 2019 Aug 22;10:1997. doi: 10.3389/fimmu.2019.01997. eCollection 2019.

Abstract

T-cell receptor (TCR) γδ cells are perceived as innate-like effector cells with the possibility of mediating graft-vs. -tumor (GVT) without causing graft-vs.-host disease (GVHD) in the setting of hematopoietic allogeneic stem cell transplantation (HSCT). We conducted a prospective study to assess the clinical impact of TCR γδ cell immune reconstitution on overall survival, relapse-free-survival, relapse and GVHD. The impact of CD3, CD4, and CD8 T cells together with NK cells including subtypes were analyzed in parallel. A total of 108 patients with hematological malignancies transplanted with HLA-matched, T cell replete stem cell grafts were included for analyses of absolute concentrations of CD3, CD4, and CD8 positive T cells and NK cells together with a multi-color flow cytometry panel with staining for TCRαβ, TCRγδ, Vδ1, Vδ2, CD3, CD4, CD8, HLA-DR, CD196, CD45RO, CD45RA, CD16, CD56, CD337, and CD314 at 28, 56, 91, 180, and 365 days after transplantation. Immune reconstitution data including subsets and differentiation markers of T and NK cells during the first year after transplantation was provided. Patients with TCR γδ cell concentrations above the median value of 21 (0-416) × 106 cells/L 56 days after transplantation had significantly improved overall survival (p = 0.001) and relapse-free survival (p = 0.007) compared to patients with concentrations below this value. When day 56 cell subset concentrations were included as continuous variables, TCR γδ cells were the only T cell subsets with a significant impact on OS and RFS; the impact of TCR γδ cells remained statistically significant in multivariate analyses adjusted for pre-transplant risk factors. The risk of death from relapse was significantly decreased in patients with high concentrations of TCR γδ cells 56 days after transplantation (p = 0.003). Also, the risk of acute GVHD was significantly lower in patients with day 28 TCR γδ cell concentrations above the median of 18 × 106 cells/L compared to patients with low concentrations (p = 0.01). These results suggest a protective role of TCR γδ cells in relapse and GVHD and encourage further research in developing adaptive TCR γδ cell therapy for improving outcomes after HSCT.

Keywords: allogeneic stem cell transplantation; cell therapy; gamma delta (γδ) T cells; innate immunology; transplant immunology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Female
  • Graft vs Host Disease / diagnosis
  • Graft vs Host Disease / etiology*
  • Graft vs Host Disease / metabolism*
  • Graft vs Host Disease / mortality
  • Hematopoietic Stem Cell Transplantation / adverse effects*
  • Hematopoietic Stem Cell Transplantation / methods
  • Humans
  • Immune Reconstitution*
  • Immunity, Innate
  • Immunophenotyping
  • Male
  • Middle Aged
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism*
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism*
  • Transplantation Conditioning
  • Transplantation Immunology
  • Transplantation, Homologous
  • Young Adult

Substances

  • Receptors, Antigen, T-Cell, gamma-delta