Targeting Adenosine Receptor Signaling in Cancer Immunotherapy

Sek, Kevin; Mølck, Christina; Stewart, Gregory D.; Kats, Lev; Darcy, Phillip K.; Beavis, Paul A.

doi:10.3390/ijms19123837

Cited by 146 publications

(113 citation statements)

References 211 publications

(272 reference statements)

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“…The expression of CD73 in the tumor TME has been described in various types of cancer and is at least partly driven by hypoxia and activation of hypoxia-inducible (HIF) transcription factors [30]. Hypoxia drives expression of the well-defined transcription factor HIF1α, which promotes the expression of ectoenzymes CD39 and CD73 on tumor cells, stromal cells, and tumor-infiltrating immunosuppressive cell subsets, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) [31]. CD39 catalyzes the conversion of ATP and ADP into AMP, while CD73 catalyzes the irreversible conversion of AMP into adenosine [31].…”

Section: Discussionmentioning

confidence: 99%

“…Hypoxia drives expression of the well-defined transcription factor HIF1α, which promotes the expression of ectoenzymes CD39 and CD73 on tumor cells, stromal cells, and tumor-infiltrating immunosuppressive cell subsets, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) [31]. CD39 catalyzes the conversion of ATP and ADP into AMP, while CD73 catalyzes the irreversible conversion of AMP into adenosine [31]. CD73-derived adenosine accumulates in the TME and exerts multiple immunosuppressive actions to dampen antitumor immunity, leading to worse clinical outcomes [30].…”

Section: Discussionmentioning

confidence: 99%

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Immunomodulatory Molecules On Lung Cancer Stem Cells From Lymph Nodes Aspirates

Raniszewska

Kwiecień

Sokołowski

et al. 2020

Cancers

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Over the past decade, immune checkpoint inhibitors have revolutionized the treatment of non-small cell lung cancer (NSCLC). Unfortunately, not all patients benefit from PD-(L)1 blockade, yet, the PD-L1 tumor cell expression is the only approved biomarker, and other biomarkers have been investigated. In the present study, we analyzed the presence of immunomodulatory molecules: PD-L1, CD47, CD73, Fas, and FasL on mature tumor cells (MTCs) and cancer stem cells (CSCs) in lymph nodes (LNs) aspirates and refer it to the lymphocyte subpopulation in peripheral blood (PB). PB samples and LNs aspirates obtained during the endobronchial ultrasound-guided transbronchial needle aspiration (EBUS/TBNA) procedure of 20 patients at different stages of NSCLC. The cells were analyzed by multiparameter flow cytometry. We reported the higher frequency of MTCs and CSCs expressing the investigated immunomodulating molecules in metastatic LNs than in nonmetastatic. The expression of CD47 and PD-L1 was significantly higher on CSCs than on MTCs. Among the lymphocyte subpopulation in PB, we observed a higher frequency of PD-1+ CD8 T cells and Fas+ CD8 T cells in patients with confirmed metastases than in nonmetastatic. Next, we found that the percentage of FasL+ MTCs correlated with the frequency of Fas+ CD3 T cells in LNs aspirates and Fas+ CD8 T cells in PB. Finally, we found that patients with metastatic disease had a significantly higher FasL+/Fas+ MTCs ratio than patients with nonmetastatic disease. Both MTCs and CSCs express different immunomodulatory molecules on their surface. The frequency of FasL+ MTCs associates with altered distribution of Fas+ lymphocyte subpopulations in LNs and PB.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Immunomodulatory Molecules On Lung Cancer Stem Cells From Lymph Nodes Aspirates

Raniszewska

Kwiecień

Sokołowski

et al. 2020

Cancers

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“…Interestingly, shIF1 cells reveal significant increased expression of the CXC chemokine receptor 4 (CXCR4), which is involved in the inhibition of the activation and proliferation of NK cells by tumor cells [48,49] (Figure 7E). Moreover, shIF1 cells significantly increased the expression of the transcription factor SMAD3 and of the ecto-5'nucleotidase CD73/NT5E, which is under the control of SMAD3, an enzyme that generates adenosine in the tumor microenvironment leading to the suppression of multiple immune subsets including NK cells [50,51] ( Figure 7E). In addition, the mRNA of LDHA (two fold, false discovery rate (FDR) < 0.007) was also significantly increased in shIF1 cells, suggesting that they produce more lactate which might be released to the tumor microenvironment acting also as an immune metabolite that hampers immune surveillance and activation of NK cells [52] ( Figure 7E).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Mitochondrial IF1 Prevents Metastatic Disease of Colorectal Cancer by Enhancing Anoikis and Tumor Infiltration of NK Cells

González-Llorente

Santacatterina

Bocanegra

et al. 2019

Cancers

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Increasing evidences show that the ATPase Inhibitory Factor 1 (IF1), the physiological inhibitor of the ATP synthase, is overexpressed in a large number of carcinomas contributing to metabolic reprogramming and cancer progression. Herein, we show that in contrast to the findings in other carcinomas, the overexpression of IF1 in a cohort of colorectal carcinomas (CRC) predicts less chances of disease recurrence, IF1 being an independent predictor of survival. Bioinformatic and gene expression analyses of the transcriptome of colon cancer cells with differential expression of IF1 indicate that cells overexpressing IF1 display a less aggressive behavior than IF1 silenced (shIF1) cells. Proteomic and functional in vitro migration and invasion assays confirmed the higher tumorigenic potential of shIF1 cells. Moreover, shIF1 cells have increased in vivo metastatic potential. The higher metastatic potential of shIF1 cells relies on increased cFLIP-mediated resistance to undergo anoikis after cell detachment. Furthermore, tumor spheroids of shIF1 cells have an increased ability to escape from immune surveillance by NK cells. Altogether, the results reveal that the overexpression of IF1 acts as a tumor suppressor in CRC with an important anti-metastatic role, thus supporting IF1 as a potential therapeutic target in CRC.

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“…Adenosine signaling in the TME can reduce NK cell proliferation and activation, as well as its effector function (327)(328)(329). Blocking adenosine-catalyzing enzymes and purinergic signaling in the TME (such as antibodies against CD73, CD39, and CD38, which mediate the production of extracellular adenosine, and blockade of A 2A R) is therefore being investigated in multiple clinical trials in combination with immune checkpoint blockade (330) and may synergistically enhance tumor-resident NK cell activity (330)(331)(332)(333)(334)(335)(336)(337)(338).…”

Section: Modulating Tumor Metabolitesmentioning

confidence: 99%

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

2020

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The emergence of immunotherapy for cancer treatment bears considerable clinical promise. Nevertheless, many patients remain unresponsive, acquire resistance, or suffer dose-limiting toxicities. Immune-editing of tumors assists their escape from the immune system, and the tumor microenvironment (TME) induces immune suppression through multiple mechanisms. Immunotherapy aims to bolster the activity of immune cells against cancer by targeting these suppressive immunomodulatory processes. Natural Killer (NK) cells are a heterogeneous subset of immune cells, which express a diverse array of activating and inhibitory germline-encoded receptors, and are thus capable of directly targeting and killing cancer cells without the need for MHC specificity. Furthermore, they play a critical role in triggering the adaptive immune response. Enhancing the function of NK cells in the context of cancer is therefore a promising avenue for immunotherapy. Different NK-based therapies have been evaluated in clinical trials, and some have demonstrated clinical benefits, especially in the context of hematological malignancies. Solid tumors remain much more difficult to treat, and the time point and means of intervention of current NK-based treatments still require optimization to achieve long term effects. Here, we review recently described mechanisms of cancer evasion from NK cell immune surveillance, and the therapeutic approaches that aim to potentiate NK function. Specific focus is placed on the use of specialized monoclonal antibodies against moieties on the cancer cell, or on both the tumor and the NK cell. In addition, we highlight newly identified mechanisms that inhibit NK cell activity in the TME, and describe how biochemical modifications of the TME can synergize with current treatments and increase susceptibility to NK cell activity.

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Targeting Adenosine Receptor Signaling in Cancer Immunotherapy

Cited by 146 publications

References 211 publications

Immunomodulatory Molecules On Lung Cancer Stem Cells From Lymph Nodes Aspirates

Immunomodulatory Molecules On Lung Cancer Stem Cells From Lymph Nodes Aspirates

Overexpression of Mitochondrial IF1 Prevents Metastatic Disease of Colorectal Cancer by Enhancing Anoikis and Tumor Infiltration of NK Cells

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

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