Early Reconstitution of NK and gamma delta T Cells and Its Implication for the Design of Post-Transplant Immunotherapy

Relapse is the most frequent cause of treatment failure after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Natural killer (NK) cells and gamma delta T cells reconstitute early after allo-HSCT, contribute to tumor immunosurveillance via major histocompatibility complex-independent mechanisms and do not induce graftversus-host disease. Here we performed a quantitative and qualitative analysis of the NK and gamma delta T cell repertoire in healthy individuals, recipients of HLA-matched sibling or unrelated donor allo-HSCT (MSD/MUD-HSCT) and umbilical cord blood-HSCT (UCB-HSCT). NK cells are present at high frequencies in all allo-HSCT recipients. Immune reconstitution (IR) of v delta 2(+) cells depended on stem cell source. In MSD/MUD-HSCT recipients, v delta 2(+) comprise up to 8% of the total lymphocyte pool, whereas v delta 2(+) T cells are barely detectable in UCB-HSCT recipients. v delta 2(+) IR was driven by CMV reactivation and was comparable between MSD/MUD-HSCT and UCB-HSCT. Strategies to augment NK cell mediated tumor responses, similar to IL-15 and antibodies, also induced v delta 2(+) T cell responses against a variety of different tumor targets. v delta 2(+) gamma delta T cells were induced less by these same stimuli. We also identified elevated expression of the checkpoint inhibitory molecule TIGIT (T cell Ig and ITIM domain), which is also observed on tumor-infiltrating lymphocytes and epidermal gamma delta T cells. Collectively, these data show multiple strategies that can result in a synergized NK and gamma delta T cell antitumor response. In the light of recent developments of low-toxicity allo-HSCT platforms, these interventions may contribute to the prevention of early relapse. (C) 2018 American Society for Blood and Marrow Transplantation.