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Targeting A2A in CLL
Figure 6. Effects of adenosine signaling and A2A inhibition. Hypoxia upregulates CD39 and CD73 leading to increased adenosine generation. Adenosine in the extra- cellular space signals mainly through the A2A receptor, expressed on leukemic cells as well as immune cells in the microenvironment, and exerts autocrine and paracrine effects. Signaling via A2A activates protein kinase A (PKA) and CREB phosphorylation, which in turn inhibits nuclear factor (NF)-κB-driven inflammation. Depending on the cell population, A2A signaling may favor different outcomes each contributing to an immune-tolerant environment, such as interleukin (IL)-10 secretion by chronic lymphocytic leukemia (CLL) cells, regulatory T cell (Treg) differentiation and expansion, exhaustion of CD8+ T cells, and monocytes switching toward an M2 (patrolling) phenotype. Inhibition of A2A signaling with SCH58261 rescues CD8+ cytotoxicity and ability to secrete cytokines, such as IL-2 and interferon (IFN)-γ, while limiting Treg expansion and favoring monocyte differentiation towards a M1 (inflammatory) phenotype.
might be particularly relevant when interfering with paracrine circuits affecting immune cell functions, rather than having an impact on CLL cytoprotection. In addition, the observation that in SCH58261-treated mice no corre- lation was found between the variation of the tumor loads and the size of the effect of immune system repolarization (Online Supplementary Figure S4A-D) suggests that blocking A2A signaling might be sufficient to rescue immune cell dysfunctions, even without evidence of tumor regression. These findings prompt the way to future drug combina- tion studies aimed at dually targeting central pathways for the malignant behavior of leukemic cells while restoring immune competence, in order to achieve the best long- term responses.
Discussion
Dysfunction of the immune system is a major clinical issue in CLL since the early stages of the disease predispose patients to recurrent infections, which represent a major cause of morbidity and mortality.23 Qualitative and quanti- tative defects in the innate and adaptive immune responses
are frequently found in CLL patients and include T-cell exhaustion, expansion of Treg and skewing of macrophages towards a tumor-supportive M2 pheno- type.21,22,24,25 Growing evidence indicates that leukemic cells primarily drive immune cell dysregulation in an attempt to evade immune control. For example, CLL cells show fea- tures of regulatory B cells and they might exert a direct immunosuppressive effect by secreting interleukin-10.26 Regulatory activity is further enhanced within the lym- phoid niche, likely as a consequence of local B-cell activa- tion, highlighting the importance of microenvironmental conditions in bidirectional tumor-host remodeling.27
The TCL1 adoptive transfer model of CLL is based on injection of leukemic cells obtained from C57BL/6 animals that are transgenic for TCL1 into syngeneic hosts.28 Leukemic cells injected into the peritoneum engraft and leukemia develops over a period of a few weeks, during which it is possible to observe progressive adaptation of the immune system. Specifically, naïve CD4+ and CD8+ T lymphocytes are progressively substituted by memory cells that bear exhaustion markers and are poorly respon- sive to activation. In addition, the regulatory T-cell pool expands, while in the myeloid compartment the inflamma- tory subset is substituted by patrolling cells.29-32 As these
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