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

Cancer Immunol Res. 2018 Sep;6(9):1110-1119. doi: 10.1158/2326-6066.CIR-17-0711. Epub 2018 Jul 6.


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. Cancer Immunol Res; 6(9); 1110-9. ©2018 AACR.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antibodies, Viral / blood*
  • Cytomegalovirus
  • Cytomegalovirus Infections / immunology*
  • Female
  • HLA Antigens / genetics
  • Histamine / therapeutic use
  • Humans
  • Immunotherapy
  • Interleukin-2 / therapeutic use*
  • Killer Cells, Natural / immunology*
  • Leukemia, Myeloid, Acute / immunology*
  • Leukemia, Myeloid, Acute / therapy*
  • Male
  • Middle Aged
  • Receptors, KIR / genetics
  • Young Adult


  • Antibodies, Viral
  • HLA Antigens
  • Interleukin-2
  • Receptors, KIR
  • Histamine