Natural killer cells adopt an activated and decidual-like phenotype after autologous hematopoietic stem cell transplantation in children with cancer

Introduction

Autologous hematopoietic stem cell transplantation (autoHSCT) is a widespread procedure used to treat many different types of cancer, including hematological tumors in adults and solid tumors in children. It is a relatively common therapeutic tool to combat not only hematological malignancies, such as multiple myeloma (MM) or non-Hodgkin lymphoma (NHL), but also for some pediatric solid tumors, such as neuroblastoma, and might be a salvage option for other tumors like lymphomas and sarcomas^{1, 2–3}. Early immune reconstitution following autoHSCT is associated with a better outcome in a variety of cancers^{4, 5–6}. Day 15 absolute lymphocyte count (ALC-15) of ≥500 cells/µl after autoHSCT is an independent prognostic indicator in MM and NHL patients. Natural killer (NK) cells are a relevant lymphocyte subset in ALC-15 that affects the outcome following autoHSCT, as they are the first lymphocyte subset reaching normal circulating levels after HSCT^5,7,8.

NK cells can directly kill target cells through different mechanisms, and they have a central role in the defense against virus-infected and cancer cells⁹. Human circulating NK cells have been classified into two major subsets with different functionalities, depending on the expression of CD56 and CD16: CD56^brightCD16^low/− (CD56^bright) and CD56^dimCD16+ (CD56^dim). CD56^bright NK cells produce large amounts of immunomodulatory cytokines and chemokines but have low cytotoxicity unless they are activated by cytokines. On the other hand, CD56^dim NK cells are more cytotoxic but produce lower amounts of cytokines^10,11. NK cells express activating and inhibitory receptors whose integrated signals will determine their response¹². In this manner, they do not get activated when they recognize autologous determinants such as class I human leukocyte antigens (HLA-I) through inhibitory killer immunoglobulin-like receptors (KIRs) and CD94/NKG2A receptor. On the other hand, NK cells are activated when they interact with virus-infected or cancer cells, either by the direct detection of upregulated stress-induced self-molecules or via antibody-dependent cell-mediated cytotoxicity^13,14. Given the potent anti-tumor effect of NK cells and their early recovery after autoHSCT, studying their biology and reconstitution in this setting is of utmost interest. Studies are scarce, and they are mostly focused on adult patients. They show that following autoHSCT, and shortly after leukocyte...