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Review
. 2020 Mar 6;21(5):1825.
doi: 10.3390/ijms21051825.

Immune Response Dysfunction in Chronic Lymphocytic Leukemia: Dissecting Molecular Mechanisms and Microenvironmental Conditions

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Free PMC article
Review

Immune Response Dysfunction in Chronic Lymphocytic Leukemia: Dissecting Molecular Mechanisms and Microenvironmental Conditions

Francesca Arruga et al. Int J Mol Sci. .
Free PMC article

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.

Keywords: hypoxia; immune checkpoints; immunosuppression; microenvironment; tolerance.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Defects of the innate and the adaptive immune response in chronic lymphocytic leukemia (CLL). B-CLL cells harbor B-regulatory properties and play a central role in driving immunosuppression through cell-cell contacts and cytokines release. Deregulation of the immune system includes wide phenotypical changes and functional defects across different elements of the immune surveillance, ultimately promoting tolerance and favoring tumor expansion.
Figure 2
Figure 2
Surface molecules and extracellular mediators contribute to the downregulation of immune cell functions. The CLL niche is an hypoxic environment where leukemic cells interact with non-tumor cells and shape their phenotype and function towards tolerance. Upregulation of cytotoxic T lymphocyte antigen-4 (CTLA-4), T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT) and programmed cell death 1 (PD-1) on the cell surface of T lymphocytes downmodulates T cell receptor (TCR)-mediated signaling and limits T cell activation. This effect is fostered also by the upregulation of the respective partner proteins on macrophages, dendritic cells and leukemic cells themselves. Moreover, CLL cells secrete pro-tolerant cytokines such as IL-10 and IL-6 and release nicotinamide phosphorybosyltransferase (NAMPT) in the extracellular space, which promote skewing of macrophages towards an M2-like phenotype. Upregulation of the adenosine-generating and -sensing molecules further boosts immunomodulation in CLL.

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