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Abstract: Chronic lymphocytic leukemia (CLL) cells display features consistent with a defect in apoptosis and exhibit prolonged survival in vivo. Survival of these malignant cells is influenced by interactions with non-leukemic cells located in permissive niches in lymphoid organs. Leukemic cells subvert the normal architecture of the lymphoid organs, recruiting stromal cells, dendritic cells and T lymphocytes, all reported as playing active roles in the survival and proliferation of CLL. The same survival-promoting environment also rescues/protects leukemic cells from cytotoxic therapies, giving way to disease relapse. This review summarizes and discusses current knowledge about the intricate network of soluble and cell-bound signals regulating the life and death of CLL cells in different districts. At the same time, it seeks to hone in on which discrete molecular elements are best suited as targets for treating this still incurable disease. [Copyright &y& Elsevier]

Abstract: CLL is characterized by a dynamic balance between cells proliferating in the lymphoid organs and circulating cells resisting programmed cell death. Regulating this equilibrium entails complex interactions between tumor and host, modulated by a set of surface molecules expressed by the CLL cell according to environmental conditions. The result is a constantly shifting pattern of resistance, apoptosis and proliferation. The CD38 surface molecule is an independent negative prognostic factor expressed by approximately one-third of CLL patients. Our view is that CD38 is crucial to tumor–host communication and that its signals are detrimental to clinical outcome. CD38+ CLL cells can proliferate in vitro in the presence of anti-CD38 mAbs and IL-2 and are more sensitive to the effects of the CXCL12 chemokine. Blockage of CD38 signals impairs CLL cell movement from blood to lymphoid organs, as confirmed using animal models. One model to be explored considers CD38 a key component of the CLL invadosome, a still hypothetical membrane domain containing adhesion molecules, chemokine receptors and matrix metalloproteases. Some components of the invadosome are genetically polymorphic, explaining heterogeneity in functional response. The CD38 gene shows genetic differences in the promoter region, some of which represent an independent risk for Richter transformation. In addition to driving the clinical outcome of the disease, CD38 is thus an excellent candidate therapeutic target for a significant subset of CLL patients. [ABSTRACT FROM AUTHOR]

Representing the major cause of morbidity and mortality for chronic lymphocytic leukemia (CLL) patients, immunosuppression is a common feature of the disease. Effectors of the innate and the adaptive immune response show marked dysfunction and skewing towards the generation of a tolerant environment that favors disease expansion. Major deregulations are found in the T lymphocyte compartment, with inhibition of CD8+ cytotoxic and CD4+ activated effector T cells, replaced by exhausted and more tolerogenic subsets. Likewise, differentiation of monocytes towards a suppressive M2-like phenotype is induced at the expense of pro-inflammatory sub-populations. Thanks to their B-regulatory phenotype, leukemic cells play a central role in driving immunosuppression, progressively inhibiting immune responses. A number of signaling cascades triggered by soluble mediators and cell–cell contacts contribute to immunomodulation in CLL, fostered also by local environmental conditions, such as hypoxia and derived metabolic acidosis. Specifically, molecular pathways modulating T-cell activity in CLL, spanning from the best known cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death 1 (PD-1) to the emerging T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT)/CD155 axes, are attracting increasing research interest and therapeutic relevance also in the CLL field. On the other hand, in the microenvironment, the B cell receptor (BCR), which is undoubtedly the master regulator of leukemic cell behavior, plays an important role in orchestrating immune responses, as well. Lastly, local conditions of hypoxia, typical of the lymphoid niche, have major effects both on CLL cells and on non-leukemic immune cells, partly mediated through adenosine signaling, for which novel specific inhibitors are currently under development. In summary, this review will provide an overview of the molecular and microenvironmental mechanisms that modify innate and adaptive immune responses of CLL patients, focusing attention on those that may have therapeutic implications. [ABSTRACT FROM AUTHOR]