Interleukin-15 and innate effector cells as predictors of outcome in allogeneic hematopoietic cell transplantation

Marie Warny^1*Sisse Rye Ostrowski¹Søren Lykke Petersen¹Lone Smidstrup Friis¹Brian Thomas Kornblit¹Niels Smedegaard Andersen¹Ida Schjoedt¹Margit Hørup Larsen²Janne Amstrup Møller¹Eva Kannik Haastrup¹Henrik Sengeløv¹Lia Minculescu¹

• ¹Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
• ²Translational Research, Novo Nordisk A/S, Måløv, Denmark

Introduction: Immune reconstitution is a critical parameter in successful hematopoietic cell transplantation (HCT) and involves different cell types and a microenvironment including cytokines. NK cells and γδ T cells are known to repopulate early after HCT and are proposed to have the intriguing capacity of mediating GVL effects without accompanying GVHD. IL-15 and IL-7 are key homeostatic cytokines, with effects on both T and NK cells, making these cytokines especially interesting in a HCT setting. Methods: In this prospective study we investigated associations between IL-15 and IL-7, NK cells and γδ T cells, including activated subtypes, and clinical outcomes. We included 105 patients undergoing allogeneic HCT at a single center institution. IL-15, IL-7, and extended T and NK cell phenotyping were measured longitudinally at fixed time points following HCT. Results: We found high IL-15 concentrations early post-transplant to be significantly associated with reduced overall survival, reduced relapse-free survival, and excess acute GVHD. Furthermore, IL-15 showed significant inverse correlations with NK cells and γδ T cells, including activated subtypes early after HCT, and with conventional T cells at later time points. IL-7 was significantly inverse correlated with conventional T cells, but also with γδ T cells early after HCT. Discussion: These findings may suggest that early immune reconstitution of NK cells and γδ T cells is influenced by the bioavailability of IL-15 after HCT, and that IL-15 could have a mechanistic effect in the activity of these innate effector cells. NK cells and γδ T cells are currently being investigated in several promising treatment settings, and IL-15 may here offer a potential benefit.