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

International Journal of Molecular Sciences
Francesca ArrugaSilvia Deaglio

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 i...Continue Reading

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Citations

Sep 25, 2020·International Journal of Molecular Sciences·Silvia Deaglio, Tanja Nicole Hartmann
Nov 6, 2020·Cells·Ewelina GrywalskaPaulina Niedźwiedzka-Rystwej
Dec 15, 2020·Frontiers in Immunology·Valentina GriggioMarta Coscia
Mar 7, 2021·Pharmaceuticals·Marcello Francesco LinguaAlessandro Morotti
Apr 13, 2021·Frontiers in Oncology·Benedetta ApollonioAlan G Ramsay
May 2, 2021·Journal for Immunotherapy of Cancer·Najmeh BozorgmehrShokrollah Elahi
May 4, 2021·Frontiers in Oncology·Maria Cristina PuzzoloRobin Foà
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Jul 3, 2021·Cancers·Elisavet VlachonikolaAnastasia Chatzidimitriou
Jul 3, 2021·International Journal of Molecular Sciences·Paolo SportolettiEmanuela Rosati
Mar 31, 2021·Ophthalmic Plastic and Reconstructive Surgery·Matthew HabibTal J Rubinstein
Sep 4, 2021·Hematological Oncology·Silvia Sánchez-RamónCharlotte Cunningham-Rundles

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Methods Mentioned

BETA
xenograft

Clinical Trials Mentioned

NCT01822509
NCT00089076
NCT03514017
NCT02332980
NCT03884998
NCT04047862
NCT03563716
NCT03628677
NCT02913313

Software Mentioned

TIGIT

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