The role of the immunosuppressive microenvironment in acute myeloid leukemia development and treatment

Abstract

Functional interplay between acute myeloid leukemia (AML) cells and the bone marrow microenvironment is a distinctive characteristic of this hematological cancer. Indeed, a large body of evidence suggests that proliferation, survival and drug resistance of AML are sustained and modulated by the bone marrow immunosuppressive microenvironment, where both innate and adaptive immune responses are profoundly deregulated. Furthermore, the presence of a number of different immunosuppressive mechanisms results in massive immune deregulation, which causes the eventual escape from natural immune control. Modulating the immune system, as documented by 40 years of stem cell transplantation, may improve survival of AML patients, as the immune system is clearly able to recognize and attack leukemic cells. The understanding of the factors responsible for the escape from immune destruction in AML, which becomes more prominent with disease progression, is necessary for the development of innovative immunotherapeutic treatment modalities in AML.

Keywords::

• acute myeloid leukemia
• immunotherapy
• microenvironment
• tolerogenic
• tumor immunity

Acknowledgements

The authors are supported in part by AIL Pesaro Onlus. They thank Musco N for editing the English version of the manuscript.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Key issues

• Acute myeloid leukemia (AML) is a clonal disease, which is developmentally related to normal hematopoiesis and, similar to that, arises from a population of highly immature progenitors known as leukemic stem cells.

• Treatment for AML is capable of inducing a high rate of complete remission, but long-term survivors constitute less than 30% overall.

• In the attempt to improve the clinical outcome of AML patients, the identification of disease-specific alleles harbored by the malignant clone has triggered the development of molecular-based targeted therapies.

• Nonetheless, the efficacy of such approaches has proven limited in the long term and they are far from being curative when employed as a single therapeutic agent.

• Similar to solid tumors, AML is capable of creating an immunosuppressive microenvironment, where both innate and adaptive immune responses are profoundly deregulated.

• The presence of a number of different immunosuppressive mechanisms results in massive immune dysregulation, which causes the eventual escape from natural immune control.

• Harnessing the immune system against cancer, including leukemia, has been exploited for a very long time, as the immune system is clearly able to recognize and attack leukemic cells.

• The understanding of the factors responsible for the escape from immune destruction in AML, which becomes more prominent with disease progression, is necessary for the development of innovative immunotherapeutic treatment modalities in AML.

• Novel and important pathways of immunological escape by tumors have been recently established. In particular, a better knowledge of the role of immunological checkpoint regulators, such as programmed death-1 and cytotoxic T-lymphocyte antigen 4, in the induction of immunological tolerance against tumors, represents an important step forward in the definition of critical pathways for the manipulation of antitumor immune response.

• The availability of chimeric antigen receptor T cells re-directed to tumor, as well as of bispecific T-cell engager harnessing polyclonal cytotoxic T cells to kill targeted tumor cells adds to the immunological treatment armamentarium to beat AML.

Notes