Adenosine signaling mediates hypoxic responses in the chronic lymphocytic leukemia microenvironment

Serra, Sara; Vaisitti, Tiziana; Audrito, Valentina; Bologna, Cinzia; Buonincontri, Roberta; Chen, Shih‐Shih; Arruga, Francesca; Brusa, Davide; Coscia, Marta; Jakšić, Ozren; Inghirami, Giorgio; Rossi, Davide; Furman, Richard R.; Robson, Simon C.; Gaïdano, Gianluca; Chiorazzi, Nicholas; Deaglio, Silvia

doi:10.1182/bloodadvances.2016000984

Cited by 50 publications

(62 citation statements)

References 75 publications

(76 reference statements)

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“…Similarly to other tumor environments, the lymphoid niche is highly hypoxic [118]. CLL cells and bystanders non-leukemic cells undergo metabolic adaptation upon oxygen deprivation, rapidly fostering energy production via glycolysis through HIF1-α-mediated transcriptional control and robustly upregulating glycolytic enzymes and glucose and lactate transporters [118,119]. Hypoxia-driven immunomodulation was described to occur in CLL microenvironment.…”

Section: Hypoxia and Metabolic Adaptationmentioning

confidence: 99%

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

Arruga

Gyau

Iannello

et al. 2020

IJMS

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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.

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Section: Hypoxia and Metabolic Adaptationmentioning

confidence: 99%

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

Arruga

Gyau

Iannello

et al. 2020

IJMS

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“…Alternative roles of the A2AR include reducing T cell motility through the modulation of potassium channels [147], regulation of metabolism, and modulation of memory differentiation through PI3K-AKT pathways [9,122,144,[148][149][150]. Although A2AR and A2BR are more highly expressed in effector memory cells their activation is associated with the preservation of a naïve/ central memory phenotype [35].…”

Section: Effect Of Adenosine On T Cell Responsesmentioning

confidence: 99%

“…Activation of A2AR or A2BR has also been shown to enhance the differentiation of alternatively activated macrophages, as shown by the upregulation of several M2 markers including TIMP-1 and arginase 1 [177]. A2AR signaling promotes ERK, pAKT and pSTAT3 in monocytes, leading to enhanced differentiation of M2 macrophages in the TME and increased release of pro-tumorigenic cytokines and factors [150]. Similarly, activation of the A2BR and potentially other ADO receptors on DCs was shown to impair DC maturation [178] and induce a tolerogenic phenotype with reduced CD8 + T cell priming capacity [179,180].…”

Section: Effect Of Adenosine On Myeloid Cellsmentioning

confidence: 99%

Targeting Adenosine Receptor Signaling in Cancer Immunotherapy

Sek¹,

Mølck²,

Stewart³

et al. 2018

Preprint

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The immune system plays a major role in the surveillance and control of malignant cells, with the presence of tumor infiltrating lymphocytes (TILs) correlating with better patient prognosis in multiple tumor types. The development of ‘checkpoint blockade’ and adoptive cellular therapy has revolutionized the landscape of cancer treatment and highlights the potential of utilizing the patient’s own immune system to eradicate cancer. One mechanism of tumor-mediated immunosuppression that has gained attention as a potential therapeutic target is the purinergic signaling axis, whereby the production of the purine nucleoside adenosine in the tumor microenvironment can potently suppress T and NK cell function. The production of extracellular adenosine is mediated by the cell surface ectoenzymes CD73, CD39 and CD38 and therapeutic agents have been developed to target these as well as the downstream adenosine receptors (A1R, A2AR, A2BR, A3R) to enhance anti-tumor immune responses. This review will discuss the role of adenosine and adenosine receptor signaling in tumor and immune cells with a focus on their cell-specific function and their potential as targets in cancer immunotherapy.

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“…In contrast to the previously published papers they showed that T cell proliferation is essentially required for CLL cell proliferation and that depletion of T cells completely blocked CLL engraftment in vivo [27]. Therefore, they further refined this protocol by activating CD3+ cells from CLL patients for 3-14 days with CD3/CD28 Dynabeads and IL-2 and transferred them with CLL-PBMCs into NSG mice via the retro-orbital vein [28][29][30]. Although they could engraft even good prognostic CLLs [27], major drawbacks of these models are the use of conditioning regimens, such as chemotherapy or irradiation, which irreversibly alter the microenvironment and the leukemic niche, and their reliance on allogeneic settings triggering immunological processes with unforeseeable implications on CLL biology.…”

mentioning

confidence: 98%

Optimized Xenograft Protocol for Chronic Lymphocytic Leukemia Results in High Engraftment Efficiency for All CLL Subgroups

Decker

Zwick

Saleem

et al. 2019

IJMS

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Preclinical drug development for human chronic lymphocytic leukemia (CLL) requires robust xenograft models recapitulating the entire spectrum of the disease, including all prognostic subgroups. Current CLL xenograft models are hampered by inefficient engraftment of good prognostic CLLs, overgrowth with co-transplanted T cells, and the need for allogeneic humanization or irradiation. Therefore, we aimed to establish an effective and reproducible xenograft protocol which allows engraftment of all CLL subtypes without the need of humanization or irradiation. Unmanipulated NOD.Cg-Prkdc scid Il2rg tm1Sug / JicTac (NOG) mice in contrast to C.Cg-Rag2 tm1Fwa-/-Il2rg tm1Sug / JicTac (BRG) mice allowed engraftment of all tested CLL subgroups with 100% success rate, if CLL cells were fresh, injected simultaneously intra-peritoneally and intravenously, and co-transferred with low fractions of autologous T cells (2%-4%). CLL transplanted NOG mice (24 different patients) developed CLL pseudofollicles in the spleen, which increased over 4-6 weeks, and were then limited by the expanding autologous T cells. Ibrutinib treatment studies were performed to validate our model, and recapitulated treatment responses seen in patients. In conclusion, we developed an easy-to-use CLL xenograft protocol which allows reliable engraftment for all CLL subgroups without humanization or irradiation of mice. This protocol can be widely used to study CLL biology and to explore novel drug candidates. others live for 20 years or more even without treatment [5]. Several prognostic markers such as Rai and Binet staging systems, immunoglobulin V H gene mutational status [6], ζ-associated protein 70 (ZAP70) expression [7,8], cytogenetic abnormalities [9], and gene mutations can be used to predict the survival outcome and the need for treatment of patients with CLL [10,11]. While del 17p or del 11q CLL samples are highly aggressive and resistant to many chemotherapeutic agents, del 13q14 or a normal karyotype are associated with a good prognosis. In vitro monocultures of CLL cells are limited, and can only be used for drug screens based on short term readouts [12]. Co-culture of CLL cells with nurse-like cells or BM-stroma derived cell lines can maintain CLL survival for several days [13,14], but none of the available in vitro culture systems allow long-term culture or proliferation of CLL cells, which limits the relevance of such models for testing novel drugs [15].Transgenic mouse models which show key features of human CLL have been developed by several groups to study the disease. The Eµ-TCL1 tg mouse model recapitulates many features of an aggressive CLL with increasing numbers of CD5+ CD19+ lymphocytes expanding in spleen, PB and BM leading to death of the mice within 1-1.5 years [16]. The double transgenic BCL-2:Traf2DN mouse model mimics refractory CLL and mice develop increased B cell counts with severe splenomegaly and lymphadenopathy by 6 months of age [17]. The cluster-deleted DLEU2/miR15a/16-1 replicates the deletion of the chromosomal region...

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Adenosine signaling mediates hypoxic responses in the chronic lymphocytic leukemia microenvironment

Cited by 50 publications

References 75 publications

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

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

Targeting Adenosine Receptor Signaling in Cancer Immunotherapy

Optimized Xenograft Protocol for Chronic Lymphocytic Leukemia Results in High Engraftment Efficiency for All CLL Subgroups

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