Abstract
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.
Highlights
Chronic lymphocytic leukemia (CLL) is a blood malignancy of mature B cells, which clonally expand and accumulate in the peripheral blood, bone marrow, lymph nodes and spleen [1]
A broad range of defects of the innate and adaptive immune response is found in chronic lymphocytic leukemia (CLL) patients since early disease stage
Several approaches aimed at evoking the immune response against leukemia have been developed, none of them so far appeared to be as revolutionary and successful in CLL as some of them are in other tumor models, including lymphomas [135,136]
Summary
Chronic lymphocytic leukemia (CLL) is a blood malignancy of mature B cells, which clonally expand and accumulate in the peripheral blood, bone marrow, lymph nodes and spleen [1]. One of the most characteristic features of CLL innate immune response is the presence of a macrophage population with pro-tumoral (M2-like) phenotype, termed nurse-like cells (NLCs) These cells were originally described as spontaneously differentiating in vitro from circulating monocytes [10]. These cells were identified as a major component of the microenvironment in various malignancies including CLL and can inhibit T-cell responses limiting immune therapeutic approaches These cells are defined as a CD14+HLA-DRlo population and it was observed that an increased frequency of this cell subset is associated with poor prognosis, higher leukemic burden and decreased time to progression in CLL patients [20]. Reduced levels of complement proteins, including some of the C1-C4 components, were described in a significant proportion of CLL patients, likely contributing to increased risk of infection as a consequence of impaired pathogens coating [25]
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