Cytomegalovirus Serostatus Affects Autoreactive NK Cells and Outcomes of IL2-Based Immunotherapy in Acute Myeloid Leukemia

Abstract

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. .

Cytomegalovirus infection may be oncoprotective against neoplasms of B-lymphocyte lineage: single-institution experience and survey of global evidence

“…Virus prevalence in our patient cohort (90.4%) places the Republic of Serbia among the most CMV-permeated populations in the world [ 37 – 44 ]. Much lower seroprevalence (70%) of anti-CMV IgG was reported in a multicenter cohort of Swedish patients (Re: Mission, NCT01347996, www.clinicaltrials.gov [ 45 ]. The lowest CMV infestation was reported in landmark studies from the US [ 46 , 47 ], a highly developed country with one of the largest incidence rates of B-cell disorders.…”

“…2010 [ 92 ] Sweden & Italy, Gothenburg, Rome AML 81 (70%) 0.74 0.71 Chemoradio therapy Bernson et al . [ 45 ] Sweden, Germany, The Netherlands, Italy, France ALL (B- &T- cell types) 3 539 (55%) 0.62 (ave.) 0.58 (ave.) Allo-BMT & HCT Ljungman et al . 2003 [ 2 ] EBMT member centers (whole registry cohort) ALL, AML, HD, NHL 40 306 (53.9%) 0.62 (ave.) 0.58 (ave.) Allo- & auto-HCT Ljungman & Brand 2007 [ 3 ] Sweden, Spain, UK, France, Italy, The Netherlands, Poland, Germany ALL, LY 31 669 (59.8%) 0.62 (ave.) 0.58 (ave.) Allo-HCT Ljungman et al .…”

Impact of IL-1β and the IL-1R antagonist on relapse risk and survival in AML patients undergoing immunotherapy for remission maintenance

“…6,7,34,35 Administration of HDC/IL-2 activates NK cell-and T cellmediated immunity in AML patients and correlative analyses support that these aspects of immune regulation are critical for the reduction of relapse risk. 27,28,29,30,36,37 Further understanding of the immunomodulatory effects of HDC/IL-2 may translate into alternative or supplementary strategies for improved immunotherapy in AML. Histamine, which is the endogenous counterpart to HDC, has been ascribed multiple effects on the production of cytokines from immune and inflammatory cells (reviewed in [ 38]).…”

The HLA-B −21 dimorphism impacts on NK cell education and clinical outcome of immunotherapy in acute myeloid leukemia

“…Univariable analyses were performed for classical prognosis markers, such as age, risk group classification, number of induction courses required to achieve CR (1 or .1), number of consolidation courses (0-2 or .2), and previously reported NK cell-related biomarkers (NKp46 expression, cytomegalovirus serostatus, KIR/HLA discordance). 17,28,30 Covariates with values of P , .1 (age, induction courses, cytomegalovirus, NKp46) were included in the multivariable analysis.…”