oa Editorial [Hot Topic: Targeting the Microenvironment in Hematological Malignancies: How to Condition both Stromal and Effector Cells to Overcome Cancer Spreading(Guest Editors: Maria Raffaella Zocchi and Alessandro Poggi)]

It is now accepted that cancer initiation, progression, and invasion occur in a dynamic microenvironment, where many cell types interact with tumor cells, including stromal cells, the intratumoral vasculature, macrophages and dendritic cells, the various types of lymphocytes such as NK cells, B and T cells, regulatory T-cells. The complex communications between all these cell populations involve interplay between soluble factors, such as cytochines and chemokines, surface receptors and adhesion molecules, and the balance between these events determines whether there is a tumour cell growth promotion or inhibition. As for haematological malignancies, accumulating evidence indicates that the cellular microenvironment plays an important role in the pathogenesis of multiple myeloma (MM), chronic lymphocytic and myeloid leukemias and follicular lymphomas. Accordingly, the survival, drug-resistance and proliferation of leukemic cells have been shown to be largely dependent on a supportive microenvironment. Among the different environment-associated parameters, those related to the status/activity of the immune system are particularly relevant. As such, all the players in the microenvironment represent a challenge to the development of therapeutic agents, requiring re-direction and inclusion of these non-neoplastic supportive cells into future treatment strategies. In this special issue, different aspects of this problem are presented focusing on possible therapeutic combined approaches aimed to direct the various components of the microenvironment towards an anti-tumor direction. Possible caveats of the different therapeutic approaches are also considered and discussed. The first review, by Krusch and Salih, addresses the “immunomodulatory” effects of BCR-ABL inhibitors, like imatinib, nilotinib and dasatinib. Multiple effects on different immune effector cell subsets and of these drugs have been reported, the latter being due to their particular and diverse potency and spectrum of target kinases. As multiple approaches presently aim to combine BCR-ABL inhibition with immunotherapeutic strategies to improve disease control in chronic myeloid leukemia, immunomodulatory effects of the available BCR-ABL inhibitors may be of direct clinical relevance. The authors review the available data regarding the effects of imatinib, nilotinib, and dasatinib on dendritic cells, T cells and natural killer cells as central effector cells of anti-tumor immunity. They also discuss the possible contribution of dasatinib to the elimination of chronic myeloid leukemia stem cells by enhancing anti-tumor immunity. The contribution by Ferrero and Ferrarini takes into consideration the microenvironment of multiple myeloma, discussing the effects of the proteasome inhibitor (PI) bortezomib and of some immunomodulatory drugs (IMiDs) on the interactions of myeloma cells, cells of the immune system and endothelial cells. Comparison with drugs acting on endothelium, and the potential additional impact on myeloma therapy, is also presented. Indeed, the patho-physiology of MM associated angiogenesis involves a plethora of soluble factors, cellular players and mechanisms. Moreover, the hypoxic microenvironment inside the bone marrow might significantly contribute to the induction and maintenance of a pro-angiogenic profile, given the well-known as hypoxia is involved in promoting angiogenesis in all its forms. In this article, an overview of the literature is presented focusing on the mechanisms implicated in the “angiogenic switch”, which corresponds to the transition from the avascular to the vascular phase of the disease. The anti-angiogenic effects of PI and IMiDs, which substantially contribute to their anti-MM activity, is also discussed, summarizing possible caveats and perspectives about anti-angiogenic strategies that could be addressed to improve the efficacy of treatments for MM patients. In the review by Alessandro Poggi and myself, the role of bone marrow mesenchymal stromal cells (BMSC) in modulating T lymphocyte function, promoting survival of normal and malignant B cells, is described. In this study, the effects of cholesterol synthesis inhibitors, such as statins, on the interaction between BMSC and T lymphocytes or on natural killer cell-mediated functions is analyzed and compared with other drugs known to act on BMSC, including thalidomide or lenalidomide. Besides lowering the plasma lipid levels, statins indeed show strong anti-inflammatory and immunomodulatory effects. On the other hand, these drugs can affect growth and survival of solid tumour and leukaemic cells, thus they have been proposed in the treatment of multiple myeloma, in association with drugs, as thalidomide, known to act on the cancer microenvironment.....