Harnessing the immune system in acute myeloid leukaemia
Introduction
The recent success of immune checkpoint inhibitors such as ipilimumab, anti-CTLA-4 and nivolumab and pembrolizumab, anti-PD-1, in improving survival of metastatic melanoma patients highlights that the immune system can be successfully harnessed to target and eliminate cancer cells more broadly for clinical benefit (Robert et al., 2015, Robert et al., 2014, Hamid et al., 2013, Hodi et al., 2010). An emerging paradigm for understanding cancer immunosurveillance and patient responses to immunotherapies is that genetic mutational quality directly correlates with tumour cell’s immunogenicity and is thus fundamental to driving patients’ clinical outcomes. Much of the evidence to support this paradigm has been generated from solid tumour patients such as melanoma, however less is known about the correlation of mutational quality and immune responses in haematological malignancies. This review will focus on acute myeloid leukaemia (AML) and discuss evidence for heterogeneous genetic abnormalities driving endogenous differential anti-leukemic immune responses. In particular, novel immunotherapeutic strategies will be discussed for treatment of AML patients.
The ability of the innate and adaptive immune cells to attack the tumour before it becomes clinically detectable is known as cancer immunosurveillance (Smyth et al., 2006, Swann and Smyth, 2007). However, cancers are able to avoid the immune response by a variety of mechanisms. Recently, “evasion of immune destruction” has been included as one of the emerging hallmarks of cancer (Hanahan and Weinberg, 2011). Thus, the important role of the immune response in cancer control and progression warrants a brief summary of the current theories. The term “cancer immunoediting” was coined to describe the phases of the immune response to cancer (Smyth et al., 2006, Schreiber et al., 2011, Dunn et al., 2004, Mittal et al., 2014). The elimination phase describes the initial recognition, targeting and killing of cancer by the innate and adaptive immune cells. The immune system and tumour cells may then enter an equilibrium phase where the immune system prevents the tumour from expanding. This phase is one of genetic instability in the tumour that eventually leads to the sculpting and escape of less immunogenic tumour cells from the immune system. The tumour cells facilitate escape either through employing mechanisms to suppress the immune response or by down-regulating (editing) immunogenic molecules. The next sections will discuss the evidence for the critical role of genetic mutations in cancer immunosurveillance.
Section snippets
Connecting oncogenesis and cancer immunosurveillance
The core feature of cancer cells that separates them from normal cells is the underlying genetic mutations that drive cancer progression (Vogelstein et al., 2013). Recently, a study identified 20 mutational signatures in 30 different types of cancer and found a varying prevalence of somatic mutations (Alexandrov et al., 2013). These mutational signatures may influence the ability of the immune system to recognise and attack the cancer. Proteins derived from mutated genes are known as
Genetic heterogeneity in AML
As genetic mutational quality is important for activation of the anti-cancer immune response, at least in melanoma, knowledge of the genetics of AML will be important in dissecting the immune responses in leukaemia patients. AML arises from genetic abnormalities in hematopoietic stem cells (HSCs) giving rise to leukaemia stem cell (LSC) populations (Bonnet and Dick, 1997, Passegué et al., 2003). Like HSCs, LSCs possess limitless self-renewal but have restricted differentiation capacity
AML antigen presentation
A critical step in the activation of the immune system is the recognition of neo-antigens presented at the surface of tumour cells. There are two main classes of antigen presentation machinery, MHC classes I and II. MHC Class I is encoded by a large group of polymorphoric genes known as human leukocyte antigen (HLA) and is expressed on the majority of cells and presents self-antigen that is derived from cytosolic proteins to cytotoxic T cells. In contrast, MHC Class II expression is usually
Defective anti-leukemic immune responses in AML patients and experimental models
The progression of AML in patients demonstrates that presentation of ASNAs and AAAs to the immune system is not sufficient to control AML expansion. AML cells employ many mechanisms to avoid immune destruction. The next sections will review defective cell-mediated cytotoxicity in AML patients and the immunosuppressive mechanisms employed to avoid the immune response. AML immune escape is caused by both intrinsic and extrinsic immunosuppressive mechanisms (Mittal et al., 2014, Teague and Kline,
Harnessing the immune response to target AML
Novel immunotherapies have shown promise in the treatment of some haematological malignancies providing encouragement for their use in the treatment of AML (Bachireddy et al., 2015, Armand, 2015). The evidence that patients can be cured through allo-HSCT (ie. positive responses in adoptive immunotherapy studies), and evidence of defective innate and adaptive immune responses in AML patients, all indicate that immunotherapies that boost immune responses against the leukemic cells could be
Challenges for immunotherapeutic treatment of AML
The relatively recent success of immune checkpoint blockade, such as anti-CTLA-4 and anti-PD-1, in solid tumours with high neo-antigen burden such as melanoma highlights the importance of cancer immunogenicity for the successful activation of the immune system and eradication of tumour cells. Thus, one of the main challenges facing the successful use of immunotherapies to treat AML patients will be the low neo-antigen burden and thus low immunogenicity of AML cells.
In solid tumours, the
Conflict of interest
MJS has a scientific research agreement with Bristol Myers Squibb. The other authors declare no conflict of interest.
Funding sources
Rebecca Austin is a PhD Scholar of the Leukaemia Foundation.
Steven Lane is a NH&MRC Career Development Fellow and has received research support from the Leukaemia Foundation, Cancer Australia, RBWH Foundation and Cure Cancer Australia Foundation.
Mark Smyth is a NH&MRC Senior Principal Research Fellow and thanks NH&MRC and CCQ for funding support.
Acknowledgments
Madeleine Flynn, illustrations, External Relations, QIMR Berghofer Medical Research Institute.
Rebecca Austin Rebecca Austin is a PhD candidate in the Translational Leukaemia Laboratory at QIMR Berghofer Medical Research Institute under the supervision of Assoc. Prof. Steven Lane and associate supervisor Prof. Mark Smyth. Rebecca obtained her Bachelors of Science/Arts at The University of Queensland in 2010 and her BSc (Honours) from University of Melbourne in 2011.
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Rebecca Austin Rebecca Austin is a PhD candidate in the Translational Leukaemia Laboratory at QIMR Berghofer Medical Research Institute under the supervision of Assoc. Prof. Steven Lane and associate supervisor Prof. Mark Smyth. Rebecca obtained her Bachelors of Science/Arts at The University of Queensland in 2010 and her BSc (Honours) from University of Melbourne in 2011.
Prof. Mark J. Smyth Professor Mark Smyth is a Senior Scientist and Immunology Coordinator at QIMR Berghofer Medical Research Institute. He completed his PhD in 1988 and trained at the NCI (1988–1992), before commencing his independent research career in Australia. Over the last 15 years he rekindled world-wide interest in cancer immune surveillance, defined immune-mediated dormancy of cancer, and the role of the host in chemotherapy responses in mice and humans. More recently, he has provided new means of classifying natural killer cell (NK) subtypes and two new targets for cancer immunotherapy.
Associate Prof. Steven W. Lane Assoc. Prof. Steven Lane is a clinical haematologist at the Royal Brisbane and Women’s Hospital, and team head at QIMR Berghofer Medical Research Institute. His research interests revolve around understanding the biology of leukaemia stem cell populations and leveraging their dependencies to find new treatments for patients with blood cancers. He is Associate Professor at the University of QLD Medical School.
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Contributed equally to this work.