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The targeting of immunosuppressive mechanisms in hematological malignancies

Abstract

The adaptive immune system has the capacity to recognize and kill leukemic cells. However, immune tolerance mechanisms that normally protect healthy tissues from autoimmune effects prevent the development of effective antitumor immunity. Tumors use several different immunosuppressive mechanisms to evade otherwise effective T-cell responses. A growing number of immune evasion mechanisms have been characterized mainly in solid tumors. In hematological malignancies, less is known about how different immune escape mechanisms influence tumor immune evasion and the extent of their impact on ongoing immune responses. The present review highlights the potential role of three well-defined immunosuppressive mechanisms in hematological malignancies: (i) inhibitory T-cell pathways (especially programmed death ligand 1/programmed death 1 (PD-L1/PD-1)), (ii) regulatory immune cells, and (iii) metabolic enzymes such as indoeamine-2,3-dioxygenase (IDO). The possible therapeutic targeting of these pathways is also discussed. Exciting new strategies that might affect future antileukemia immunotherapy include monoclonal antibodies that block inhibitory T-cell pathways (PD-1/PD-L1) and the prevention of tryptophan depletion by IDO inhibitors. Furthermore, the clinical effect of several chemotherapeutic drugs may arise from the targeting of immunosuppressive cells. Evidence for a new feedback mechanism to suppress the function of regulatory immune cells was recently provided by the identification and characterization of spontaneous cytotoxic T lymphocyte (CTL) responses against regulatory immune cells. Such specific CTLs may be immensely useful in anticancer immunotherapy (for example, by anticancer vaccination). The targeting of one or more immunosuppressive pathways may be especially interesting in combination with antileukemic immunotherapy in cases in which immunosuppressive mechanisms antagonize the desired effects of the therapy.

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Acknowledgements

I would like to thank Charlotte Hald Andersen for her assistance with the preparation of the figures. This work was supported by the Danish Cancer Society, the Danish Council for Independent Research and Herlev Hospital.

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It should be noted, however, that MHA is an author and co-author of two filed patent applications based on the use of PD-L1 or IDO for vaccination. The rights of the patent applications have been transferred to Copenhagen University Hospital, Herlev according to Danish Law of Public Inventions at Public Research Institutions.

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Andersen, M. The targeting of immunosuppressive mechanisms in hematological malignancies. Leukemia 28, 1784–1792 (2014). https://doi.org/10.1038/leu.2014.108

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