Next Article in Journal
A Meta-Analysis of Multiple Whole Blood Gene Expression Data Unveils a Diagnostic Host-Response Transcript Signature for Respiratory Syncytial Virus
Next Article in Special Issue
VLA-4 Expression and Activation in B Cell Malignancies: Functional and Clinical Aspects
Previous Article in Journal
Bisphenol S Impaired Human Granulosa Cell Steroidogenesis in Vitro
Previous Article in Special Issue
Bone Marrow Stromal Cells Drive Key Hallmarks of B Cell Malignancies
Review

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

Department of Medical Sciences, University of Turin, via Nizza, 52, 10126 Torino, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(5), 1825; https://doi.org/10.3390/ijms21051825
Received: 1 January 2020 / Revised: 29 February 2020 / Accepted: 3 March 2020 / Published: 6 March 2020
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. View Full-Text
Keywords: immunosuppression; tolerance; immune checkpoints; microenvironment; hypoxia immunosuppression; tolerance; immune checkpoints; microenvironment; hypoxia
Show Figures

Figure 1

MDPI and ACS Style

Arruga, F.; Gyau, B.B.; Iannello, A.; Vitale, N.; Vaisitti, T.; Deaglio, S. Immune Response Dysfunction in Chronic Lymphocytic Leukemia: Dissecting Molecular Mechanisms and Microenvironmental Conditions. Int. J. Mol. Sci. 2020, 21, 1825. https://doi.org/10.3390/ijms21051825

AMA Style

Arruga F, Gyau BB, Iannello A, Vitale N, Vaisitti T, Deaglio S. Immune Response Dysfunction in Chronic Lymphocytic Leukemia: Dissecting Molecular Mechanisms and Microenvironmental Conditions. International Journal of Molecular Sciences. 2020; 21(5):1825. https://doi.org/10.3390/ijms21051825

Chicago/Turabian Style

Arruga, Francesca, Benjamin B. Gyau, Andrea Iannello, Nicoletta Vitale, Tiziana Vaisitti, and Silvia Deaglio. 2020. "Immune Response Dysfunction in Chronic Lymphocytic Leukemia: Dissecting Molecular Mechanisms and Microenvironmental Conditions" International Journal of Molecular Sciences 21, no. 5: 1825. https://doi.org/10.3390/ijms21051825

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop