Impact of killer-immunoglobulin-like receptor and human leukocyte antigen genotypes on the efficacy of immunotherapy in acute myeloid leukemia

Interactions between killer-immunoglobulin-like receptors (KIRs) and their HLA class I ligands are instrumental in natural killer (NK) cell regulation and protect normal tissue from NK cell attack. Human KIR haplotypes comprise genes encoding mainly inhibitory receptors (KIR A) or activating and inhibitory receptors (KIR B). A substantial fraction of humans lack ligands for inhibitory KIRs (iKIRs), that is, a 'missing ligand' genotype. KIR B/x and missing ligand genotypes may thus give rise to potentially autoreactive, unlicensed NK cells. Little is known regarding the impact of such genotypes in untransplanted acute myeloid leukemia (AML). For this study, NK cell phenotypes and KIR/HLA genotypes were determined in 81 AML patients who received immunotherapy with histamine dihydrochloride and low-dose IL-2 for relapse prevention (NCT01347996). We observed that presence of unlicensed NK cells impacted favorably on clinical outcome, in particular among patients harboring functional NK cells reflected by high expression of the natural cytotoxicity receptor (NCR) NKp46. Genotype analyses suggested that the clinical benefit of high NCR expression was restricted to patients with a missing ligand genotype and/or a KIR B/x genotype. These data imply that functional NK cells are significant anti-leukemic effector cells in patients with KIR/HLA genotypes that favor NK cell autoreactivity

Downregulation of HLA Class I Renders Inflammatory Neutrophils More Susceptible to NK Cell-Induced Apoptosis

Neutrophils are potent effector cells and contain a battery of harmful substances and degrading enzymes. A silent neutrophil death, i.e., apoptosis, is therefore of importance to avoid damage to the surrounding tissue and to enable termination of the acute inflammatory process. There is a pile of evidence supporting the role for pro-inflammatory cytokines in extending the life-span of neutrophils, but relatively few studies have been devoted to mechanisms actively driving apoptosis induction in neutrophils. We have previously demonstrated that natural killer (NK) cells can promote apoptosis in healthy neutrophils. In this study, we set out to investigate how neutrophil sensitivity to NK cell-mediated cytotoxicity is regulated under inflammatory conditions. Using in vitro-activated neutrophils and a human skin chamber model that allowed collection of in vivo-transmigrated neutrophils, we performed a comprehensive characterization of neutrophil expression of ligands to NK cell receptors. These studies revealed a dramatic downregulation of HLA class I molecules in inflammatory neutrophils, which was associated with an enhanced susceptibility to NK cell cytotoxicity. Collectively, our data shed light on the complex regulation of interactions between NK cells and neutrophils during an inflammatory response and provide further support for a role of NK cells in the resolution phase of inflammation

Role of regulatory T cells in acute myeloid leukemia patients undergoing relapse-preventive immunotherapy

Regulatory T cells (Tregs) have been proposed to dampen functions of anti-neoplastic immune cells and thus promote cancer progression. In a phase IV trial (Re:Mission Trial, NCT01347996, http://www.clinicaltrials.gov ) 84 patients (age 18-79) with acute myeloid leukemia (AML) in first complete remission (CR) received ten consecutive 3-week cycles of immunotherapy with histamine dihydrochloride (HDC) and low-dose interleukin-2 (IL-2) to prevent relapse of leukemia in the post-consolidation phase. This study aimed at defining the features, function and dynamics of Foxp3+CD25highCD4+ Tregs during immunotherapy and to determine the potential impact of Tregs on relapse risk and survival. We observed a pronounced increase in Treg counts in peripheral blood during initial cycles of HDC/IL-2. The accumulating Tregs resembled thymic-derived natural Tregs (nTregs), showed augmented expression of CTLA-4 and suppressed the cell cycle proliferation of conventional T cells ex vivo. Relapse of AML was not prognosticated by Treg counts at onset of treatment or after the first cycle of immunotherapy. However, the magnitude of Treg induction was diminished in subsequent treatment cycles. Exploratory analyses implied that a reduced expansion of Tregs in later treatment cycles and a short Treg telomere length were significantly associated with a favorable clinical outcome. Our results suggest that immunotherapy with HDC/IL-2 in AML entails induction of immunosuppressive Tregs that may be targeted for improved anti-leukemic efficiency

Maternal and infant characteristics associated with maternal opioid overdose in the year following delivery

Background and aimsOpioid-related overdose is increasingly linked to pregnancy-associated deaths, but factors associated with postpartum overdose are unknown. We aimed to estimate the strength of the association between maternal and infant characteristics and postpartum opioid-related overdose.DesignRetrospective cohort study using a linked, population-level data set.SettingMassachusetts, United States.ConclusionAmong women who delivered live infants in Massachusetts, USA between 2012 and 2014, maternal diagnosis of OUD, prior non-fatal overdose, infant diagnosis of NAS and high unscheduled health-care utilization appeared to be positively associated with postpartum opioid overdose. However, more than half of postpartum overdoses in that period were to women without a diagnosis of OUD. Engagement in methadone or buprenorphine treatment in the month prior to delivery was not sufficient to reduce the odds of postpartum overdose.ParticipantsWomen who delivered one or more live births from 2012 to 2014 (n = 174 517).MeasurementsThe primary outcome was opioid-related overdose in the postpartum year. We used multivariable logistic regression to explore the independent associations of maternal (demographics, substance use, pregnancy) and infant [gestational age, birthweight, neonatal abstinence syndrome (NAS)] characteristics with postpartum opioid overdose. Findings were stratified by maternal opioid use disorder (OUD) diagnosis.FindingsThere were 189 deliveries to women who experienced ≥ 1 opioid overdose in the first year postpartum (11 of 10 000 deliveries). Among women with postpartum opioid overdose, 46.6% had an OUD diagnosis within 12 months before delivery. In our adjusted model, maternal diagnosis of OUD [adjusted odds ratio (aOR) = 3.61, 95% confidence interval (CI) = 1.73-7.51] and prior non-fatal overdose (aOR = 2.40, 95% CI = 1.11-5.17) were most strongly associated with postpartum overdose. After stratifying by OUD status, infant diagnosis of NAS (OUD+ aOR = 2.03, 95% CI = 1.26-3.27; OUD- aOR = 2.79, 95% CI = 1.12-6.93) and high unscheduled health-care utilization (OUD+ aOR = 2.27, 95% CI = 1.38-3.73; OUD- aOR = 2.11, 95% CI = 1.24-3.58) were positively associated with postpartum overdose in both groups

Cytomegalovirus serostatus affects autoreactive NK cells and outcomes of IL2-based immunotherapy in acute myeloid leukemia

Human cytomegalovirus (CMV) infection is reported to promote NK cell differentiation and education. The CMV-induced generation of highly differentiated adaptive-like NK cells has been proposed to affect favorably on the maintenance of remission in patients with acute myeloid leukemia (AML) after allogeneic stem cell transplantation (allo-SCT). The impact of CMV infection and adaptive-like NK cells on relapse and survival of patients with AML not receiving allo-SCT remains unknown. We assayed CMV IgG serostatus to determine past CMV infection in 81 nontransplanted AML patients who were receiving relapse-prevention immunotherapy comprising histamine dihydrochloride and low-dose interleukin-2 (HDC/IL2; NCT01347996). CMV seropositivity correlated negatively with leukemia-free and overall survival of patients receiving HDC/IL2, but did not correlate with outcomes in a contemporary control cohort. Analysis of outcome after stratification of patients based on concordant or discordant killer immunoglobulin-like receptor (KIR) and HLA genotypes implied that the negative impact of CMV seropositivity was restricted to patients lacking a ligand to inhibitory KIRs (iKIR). Previous CMV infection was also associated with fewer NK cells expressing only nonself iKIRs (NS-iKIR). We propose that CMV-driven NK cell education depletes the population of NS-iKIR NK cells, which in turn reduces the clinical benefit of relapse-preventive immunotherapy in AML

Maternal and infant characteristics associated with maternal opioid overdose in the year following delivery

Background and aimsOpioid-related overdose is increasingly linked to pregnancy-associated deaths, but factors associated with postpartum overdose are unknown. We aimed to estimate the strength of the association between maternal and infant characteristics and postpartum opioid-related overdose.DesignRetrospective cohort study using a linked, population-level data set.SettingMassachusetts, United States.ConclusionAmong women who delivered live infants in Massachusetts, USA between 2012 and 2014, maternal diagnosis of OUD, prior non-fatal overdose, infant diagnosis of NAS and high unscheduled health-care utilization appeared to be positively associated with postpartum opioid overdose. However, more than half of postpartum overdoses in that period were to women without a diagnosis of OUD. Engagement in methadone or buprenorphine treatment in the month prior to delivery was not sufficient to reduce the odds of postpartum overdose.ParticipantsWomen who delivered one or more live births from 2012 to 2014 (n = 174 517).MeasurementsThe primary outcome was opioid-related overdose in the postpartum year. We used multivariable logistic regression to explore the independent associations of maternal (demographics, substance use, pregnancy) and infant [gestational age, birthweight, neonatal abstinence syndrome (NAS)] characteristics with postpartum opioid overdose. Findings were stratified by maternal opioid use disorder (OUD) diagnosis.FindingsThere were 189 deliveries to women who experienced ≥ 1 opioid overdose in the first year postpartum (11 of 10 000 deliveries). Among women with postpartum opioid overdose, 46.6% had an OUD diagnosis within 12 months before delivery. In our adjusted model, maternal diagnosis of OUD [adjusted odds ratio (aOR) = 3.61, 95% confidence interval (CI) = 1.73-7.51] and prior non-fatal overdose (aOR = 2.40, 95% CI = 1.11-5.17) were most strongly associated with postpartum overdose. After stratifying by OUD status, infant diagnosis of NAS (OUD+ aOR = 2.03, 95% CI = 1.26-3.27; OUD- aOR = 2.79, 95% CI = 1.12-6.93) and high unscheduled health-care utilization (OUD+ aOR = 2.27, 95% CI = 1.38-3.73; OUD- aOR = 2.11, 95% CI = 1.24-3.58) were positively associated with postpartum overdose in both groups

TLR-Stimulated Neutrophils Instruct NK Cells To Trigger Dendritic Cell Maturation and Promote Adaptive T Cell Responses

Polymorphonuclear neutrophils (PMNs) are innate effector cells with pivotal roles in pathogen recognition, phagocytosis, and eradication. However, their role in the development of subsequent immune responses is incompletely understood. This study aimed to identify mechanisms of relevance to the cross talk between human neutrophils and NK cells and its potential role in promoting adaptive immunity. TLR-stimulated PMNs were found to release soluble mediators to attract and activate NK cells in vitro. PMN-conditioned NK cells displayed enhanced cytotoxicity and cytokine production, and responded vigorously to ensuing stimulation with exogenous and endogenous IL-12. The neutrophil-induced activation of NK cells was prevented by caspase-1 inhibitors and by natural antagonists to IL-1 and IL-18, suggesting a role for the NOD-like receptor family pyrin domain containing-3 inflammasome. In addition, PMN-conditioned NK cells triggered the maturation of monocyte-derived dendritic cells, which promoted T cell proliferation and IFN-gamma production. These data imply that neutrophils attract NK cells to sites of infection to convert these cells into an active state, which drives adaptive immune responses via maturation of dendritic cells. Our results add to a growing body of evidence that suggests a sophisticated role for neutrophils in orchestrating the immune response to pathogens