LAUSR

In this issue, M€ uller-Thomas et al. explored the predictive value of indoleamine 2,3 dioxygenase (IDO) expression in 96 patients with high-risk myelodysplastic syndromes (MDS) and secondary AML (sAML) treated with azacitidine. MDS are clonal haematopoietic stem cell (HSC) disorders characterised by progressive bone marrow (BM) failure resulting in cytopenias, with approximately one-third of patients progressing to sAML, a process during which the increased ratio of apoptosis to proliferation is inversed and replaced by a differentiation block. The pathophysiology of early-stage MDS is a much-debated topic, and it remains unclear whether (i) the MDS clone emerged first (e.g. via mutations), followed by CD8 cytotoxic T cell (CTL) attack against aberrantly expressed tumour-associated antigens (‘T against the clone scenario’); (ii) the immune defect came first, with expansion of autoreactive or cross-reactive polyclonal CTLs targeting normal HSCs (‘autoimmune attack’); or (iii) microenvironmental defects came first, with (ii) and (iii) resulting in selection pressure for MDS clones. What is clear, however, is that both the microenvironment and the immune system are severely disturbed in MDS and AML (hereafter referred to as MDS/AML), and that disease progression is paralleled by a progression from immunosurveillance to immunoselection and ultimately immuno-subversion, resulting in tumour immune escape. MDS/AML are characterised by a plethora of numerical and functional changes in virtually all cellular components of the immune system and microenvironment. Much of the immune suppression and evasion results from intense crosstalk between the MDS/AML clone with mesenchymal stem and progenitor cells (MSPCs). Under inflammatory licensing conditions, which prevail in the BM of MDS/AML patients, tumour-educated Type-2 MSPCs exert their strongly immunosuppressive function, that is, via secretion of high levels of IDO. IDO is expressed by different cells throughout the body, including macrophages and dendritic cells, but is also found in tumour cells and the tumour microenvironment. IDO has been linked to the development of several cancer types, including MDS/AML, via suppression of the immune system, propagation of cancer cell growth, migration and invasion. IDO is an endocellular monomeric enzyme that degrades the essential amino acid L-tryptophan to L-kynurenine. Tryptophan starvation results in T-cell cycle arrest, and kynurenine and its metabolites are also directly toxic for many Tand natural killer cells (NKCs). IDO also induces a plethora of regulatory cells and the switch from M0to M2-macrophages, which, together with the induction of T-cell anergy, results in a tolerogenic microenvironment, strong immunosuppression, tumour immune escape and disease progression (Fig 1). Furthermore, the enzyme inhibits the production of erythropoietin and may also be mutagenic, thus contributing to genetic instability. Thus far, only a few groups have studied IDO in the context of MDS/AML. Constitutive overexpression of the strongly-immunosuppressive enzyme has been detected in primary human AML blasts and patient sera. It has been correlated with increased levels of circulating T regulatory cells (T-regs) at initial diagnosis and linked with decreased relapse-free and overall survival. In MDS, elevated IDO metabolites were detected in patient sera and correlated with the degree of cytopenia. Primary MSPCs from MDS patients have been shown to secrete IDO. The fact that IDO has emerged as a key target in cancer immunotherapy, and the paucity of data regarding this critical switch towards immune suppression and evasion in MDS/AML, highlight the relevance and need of the current report by M€ uller-Thomas et al. Immunohistochemistry staining for IDO in BM sections revealed that 37% of their cohort showed moderate to high expression of IDO, with cytoplasmic positivity being observed mainly in CD11c myelomonocytic cells and in a few mature CD68 macrophages, while BM blasts remained negative. In line with the reported immunosuppressive function of IDO, the group observed a significantly lower CD8/ CD3 ratio (P < 0 0001) and a trend for lower FOXP3 Correspondence: Lisa Pleyer, Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute – Laboratory of Immunological and Molecular Cancer Research (SCRI-LIMCR), Salzburg, Austria. E-mail: [email protected] commentary