Natural killer cells and acute myeloid leukaemia
Author(s)
Stringaris, Katherine
Type
Thesis
Abstract
Despite successful induction chemotherapy, most patients with acute myeloid leukemia (AML) will
relapse. Immune surveillance by T cells or natural killer (NK) cells may play a role in preventing
relapse. This thesis examines the potential of NK cells to control AML.
Study 1 explored in 248 patients with haematological malignancies from the US National Institutes
of Health, the genetic diversity of NK killer immunoglobulin receptor (KIR) genes in patients and
their stem cell donors and their impact on outcome after stem cell transplantation (SCT) for
haematological malignancy. Individuals with AML receiving SCT from donors inheriting 3
particular B-haplotype KIRs were 4 times less likely to relapse than those with donors without these
favourable KIRs.
Study 2 explored in samples obtained from 499 patients enrolled on UK MRC/NCRI AML trials,
whether KIR genotype affects the risk of developing AML or the outcome of remission induction
chemotherapy. While KIRs had no effect on the development or outcome of de novo AML,
individuals with more activatory KIRs, in particular 2DS2, developed significantly less secondary
AML, suggesting that activatory KIRs can protect against secondary AML. These studies support a
role for NK-mediated immune surveillance in AML.
Study 3 investigated the phenotype and function of AML NK cells. In 32 prospectively collected
samples from AML patients undergoing remission induction chemotherapy at the Hammersmith
Hospital, AML patients were found to have reduced NK activatory receptors, increased NK
inhibitory receptors, and reduced cytotoxic function towards leukaemia, compared to healthy donors.
These abnormalities corresponded with failure to achieve remission and can be induced in normal
NK incubated with AML blasts.
I conclude that KIR genetics have a limited influence on AML development and outcome but that
AML itself can impair NK function, reducing the chance of achieving remission. These findings
have implications for NK based immunotherapy for AML.
relapse. Immune surveillance by T cells or natural killer (NK) cells may play a role in preventing
relapse. This thesis examines the potential of NK cells to control AML.
Study 1 explored in 248 patients with haematological malignancies from the US National Institutes
of Health, the genetic diversity of NK killer immunoglobulin receptor (KIR) genes in patients and
their stem cell donors and their impact on outcome after stem cell transplantation (SCT) for
haematological malignancy. Individuals with AML receiving SCT from donors inheriting 3
particular B-haplotype KIRs were 4 times less likely to relapse than those with donors without these
favourable KIRs.
Study 2 explored in samples obtained from 499 patients enrolled on UK MRC/NCRI AML trials,
whether KIR genotype affects the risk of developing AML or the outcome of remission induction
chemotherapy. While KIRs had no effect on the development or outcome of de novo AML,
individuals with more activatory KIRs, in particular 2DS2, developed significantly less secondary
AML, suggesting that activatory KIRs can protect against secondary AML. These studies support a
role for NK-mediated immune surveillance in AML.
Study 3 investigated the phenotype and function of AML NK cells. In 32 prospectively collected
samples from AML patients undergoing remission induction chemotherapy at the Hammersmith
Hospital, AML patients were found to have reduced NK activatory receptors, increased NK
inhibitory receptors, and reduced cytotoxic function towards leukaemia, compared to healthy donors.
These abnormalities corresponded with failure to achieve remission and can be induced in normal
NK incubated with AML blasts.
I conclude that KIR genetics have a limited influence on AML development and outcome but that
AML itself can impair NK function, reducing the chance of achieving remission. These findings
have implications for NK based immunotherapy for AML.
Date Issued
2012-12
Date Awarded
2013-06
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Apperley, Jane
Sponsor
Leuka ; British Society for Haematology ; National Institutes of Health ; National Institute for Health Research (Great Britain)
Publisher Department
Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)