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Chronic Lymphocytic Leukemia
Targeting the A2A adenosine receptor counteracts immunosuppression in vivo in a mouse model of chronic lymphocytic leukemia
Ferrata Storti Foundation
Haematologica 2021 Volume 106(5):1343-1353
Francesca Arruga,1 Sara Serra,1 Nicoletta Vitale,1 Giulia Guerra,1
Andrea Papait,1 Benjamin Baffour Gyau,1 Francesco Tito,1 Dimitar Efremov,2 Tiziana Vaisitti1# and Silvia Deaglio1#
1Laboratory of Cancer Immunogenetics, Department of Medical Sciences, University of Turin, Turin and 2International Center for Genetic Engineering and Biotechnology, Trieste, Italy
#TV and SD contributed equally as co-senior authors.
ABSTRACT
Tumor immunosuppression is a major cause of treatment failure and disease relapse, both in solid tumors and leukemia. Local hypoxia is among the conditions that cause immunosuppression, acting at least in part through the upregulation of extracellular adenosine levels, which potently suppress T-cell responses and skew macrophages towards an M2 phenotype. Hence, there is intense investigation to identify drugs that target this axis. By using the TCL1 adoptive transfer chronic lymphocytic leukemia mouse model, we show that adenosine production and signaling are upreg- ulated in the hypoxic lymphoid niches, where intense colonization of leukemic cells occurs. This leads to a progressive remodeling of the immune system towards tolerance, with expansion of T regulatory cells (Treg), loss of CD8+ T-cell cytotoxicity and differentiation of murine macrophages towards the patrolling (M2-like) subset. In vivo administration of SCH58261, an inhibitor of the A2A adenosine receptor, re-awakens T-cell responses, while limiting Treg expansion, and re-polarizes monocytes towards the inflammatory (M1-like) phenotype. These results show for the first time the in vivo contribution of adenosine signaling to immune tolerance in chronic lymphocytic leukemia, and the translational implication of drugs interrupt- ing this pathway. Although the effects of SCH58261 on leukemic cells are limited, interfering with adenosine signaling may represent an appealing strategy for combination-based therapeutic approaches.
Introduction
Chronic lymphocytic leukemia (CLL) is a slowly progressive disease character- ized by complex interactions between leukemic cells and surrounding elements occurring mainly in privileged niches, such as lymphoid organs.1-3 Over the years, microenvironment-activated pathways, essential to sustain and protect leukemic cells, became a target for novel therapeutic approaches aimed at interrupting these interactions.4,5 However, despite their impressive clinical benefits, it is becoming clear that these drugs fail to produce a cure, underlining the need for combination strategies.6,7 We now know that the cross-talk between CLL cells and the microen- vironment is not a one-way relationship, in which leukemic cells “passively” receive positive stimuli. Several pieces of evidence showed that CLL cells play an active role in remodeling the phenotype and functions of cellular elements that inhabit the lymphoid niche.8 For example, nurse-like cells, an M2-like macrophage subset known to be a CLL-supporting population, can be differentiated only in the pres- ence of leukemic B cells, suggesting that CLL cells directly shape the microenviron- ment towards tumor-friendly immuno-tolerant conditions.9 Over the last two decades, many co-stimulatory signals and circuits have been identified, building the picture of a highly articulated space in which it may be difficult to understand hier- archical organization. It is therefore important to unravel unifying structural condi- tions of the microenvironment that may be more amenable to therapeutic targeting than single molecular circuits.
Correspondence:
SILVIA DEAGLIO
silvia.deaglio@unito.it
Received: November 18, 2019. Accepted: April 9, 2020. Pre-published: April 16, 2020.
https://doi.org/10.3324/haematol.2019.242016
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