Targeting Adenosine Receptor Signaling in Cancer Immunotherapy

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

doi:10.20944/preprints201810.0707.v1

Cited by 47 publications

(39 citation statements)

References 182 publications

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“…Targeting components of adenosinergic pathway including ectonucleotidases (CD73, CD39) and adenosine receptors has been investigated in cancer-immunotherapy [14][15][16]. Blocking the effects of adenosine on T cells has been achieved by pharmacological agents, antibodies and molecular methods [17][18][19][20][21][22]. In the current study, the effects of A2aR gene knockdown and pharmacologic inhibition on MSLN-specific CAR T cells were investigated.…”

Section: Discussionmentioning

confidence: 99%

Genetic and pharmacological targeting of A2a receptor improves function of anti-mesothelin CAR T cells

Masoumi

Jafarzadeh

Mirzaei

et al. 2020

J Exp Clin Cancer Res

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Background: CAR T cell-based therapies have shown promising results in hematological malignancies. Results of CAR T cell projects in solid tumors have been less impressive, and factors including lack of targetable antigens and immunosuppressive tumor microenvironment (TME) have been suggested as culprits. Adenosine, a metabolite which is highly produced in TME, is known to mediate the suppression of anti-tumor T cell responses via binding and signaling through adenosine 2a receptor (A2aR). Methods: In this study, the expression of A2aR and the effects of its activation on the function of fully human anti-mesothelin CAR T cells (MSLN-CAR T), were analyzed. Afterwards, the molecular and pharmacological means to overcome the inhibitory effects of A2aR signaling on CAR T cell function were used. This was performed by targeting A2aR expression in MSLN-CAR T cells using various anti-A2aR shRNA sequences embedded in the CAR vector and an A2aR pharmacological antagonist, SCH-58261. Statistical analyses were performed Prism 7 software. Results: Our experiments showed significant A2aR upregulation on T cells during the CAR T cell production procedure (cell activation and transduction). Activation of adenosine signaling using adenosine analog led to the suppression of all major anti-tumor functions in MSLN-CAR T cells. Interestingly, CAR T cells that carried the anti-A2aR shRNA sequences were resistant to the inhibitory effects of adenosine signaling. Pharmacological inhibition of A2aR reversed the reduction in CAR T cell proliferation and cytokine response caused by the adenosine analog; however, it failed to rescue the cytotoxic function of the cells. Conclusion: Altogether, our results indicate that mitigating A2aR signaling by genetic targeting of the receptor might be a promising approach in improving CAR T cell function in an unreceptive microenvironment and could potentially improve the outcome of treatment in clinical settings.

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Section: Discussionmentioning

confidence: 99%

Genetic and pharmacological targeting of A2a receptor improves function of anti-mesothelin CAR T cells

Masoumi

Jafarzadeh

Mirzaei

et al. 2020

J Exp Clin Cancer Res

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“…Binding of adenosine to tumorexpressed A2aR promotes tumor cell proliferation and metastasis, whereas ligation of immune cell-expressed A2aR suppresses immune function (see Fig. 1) (Sek et al 2018). Together with increased extracellular adenosine levels caused by inefficient ATP production by tumor cells, a wide range of tumors exploit this pro tumorigenic and immune suppressive mechanism by expressing extracellular adenosine level increasing enzymes (CD39 and CD73) (Gao et al 2014).…”

Section: A2ar Imagingmentioning

confidence: 99%

Tracers for non-invasive radionuclide imaging of immune checkpoint expression in cancer

Wierstra

Sandker

Aarntzen

et al. 2019

EJNMMI radiopharm. chem.

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Immunotherapy with checkpoint inhibitors demonstrates impressive improvements in the treatment of several types of cancer. Unfortunately, not all patients respond to therapy while severe immune-related adverse effects are prevalent. Currently, patient stratification is based on immunotherapy marker expression through immunohistochemical analysis on biopsied material. However, expression can be heterogeneous within and between tumor lesions, amplifying the sampling limitations of biopsies. Analysis of immunotherapy target expression by noninvasive quantitative molecular imaging with PET or SPECT may overcome this issue. In this review, an overview of tracers that have been developed for preclinical and clinical imaging of key immunotherapy targets, such as programmed cell death-1, programmed cell death ligand-1, IDO1 and cytotoxic T lymphocyteassociated antigen-4 is presented. We discuss important aspects to consider when developing such tracers and outline the future perspectives of molecular imaging of immunotherapy markers.

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“…In the tumor microenvironment, A2aR is overexpressed in all kinds of tumor cells and immune cell subsets, and is associated with many immunosuppressive factors. Most of A2aR highly expressed in immune cell subsets in tumor tissues reflects the promoting effect on tumor development and the inhibiting effect against tumor immunity 222 . The immunosuppressive effect of A2aR is usually achieved by inhibiting effector T‐cell proliferation, cytokine production and cytotoxicity, and reducing chemotaxis 223 ; provide immunosuppressive signals of NK cells and NKT cells; trigger activation of A2aR on Treg causes cell amplification and increases its immunomodulatory activity 224 .…”

Section: Pd‐1/pd‐l1 Resistance and Cell Metabolism And Metabolitesmentioning

confidence: 99%

Study and analysis of antitumor resistance mechanism of PD1/PD‐L1 immune checkpoint blocker

Wang

2020

Cancer Medicine

105

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Immunocheckpoint proteins of tumor infiltrating lymphocytes play an important role in tumor prognosis in the course of tumor clinicopathology. PD‐1 (Programmed cell death protein 1) is an important immunosuppressive molecule. By binding to PD‐L1 (programmed cell death‐ligand 1), it blocks TCR and its costimulus signal transduction, inhibits the activation and proliferation of T cells, depletes the function of effector T cells, and enables tumor cells to achieve immune escape. In recent years, immunocheckpoint blocking therapy targeting the PD‐1/PD‐L1 axis has achieved good results in a variety of malignant tumors, pushing tumor immunotherapy to a new milestone, such as anti‐PD‐1 monoclonal antibody Nivolumab, Pembrolizumab, and anti‐PD‐L1 monoclonal antibody Atezolizumab, which are considered as potential antitumor drugs. It was found in clinical use that some patients obtained long‐term efficacy, but most of them developed drug resistance recurrence in the later stage. The high incidence of drug resistance (including primary and acquired drug resistance) still cannot be ignored, which limited its clinical application and became a new problem in this field. Due to tumor heterogeneity, current limited research shows that PD‐1 or PD‐L1 monoclonal antibody drug resistance may be related to the following factors: mutation of tumor antigen and antigen presentation process, multiple immune checkpoint interactions, immune microenvironment changes dynamically, activation of oncogenic pathways, gene mutation and epigenetic changes of key proteins in tumors, tumor competitive metabolism, and accumulation of metabolites, etc, mechanisms of resistance are complex. Therefore, it is the most urgent task to further elucidate the mechanism of immune checkpoint inhibitor resistance, discover multitumor universal biomarkers, and develop new target agents to improve the response rate of immunotherapy in patients. In this study, the mechanism of anti‐PD‐1/PD‐L1 drug resistance in tumors, the potential biomarkers for predicting PD‐1 acquired resistance, and the recent development of combination therapy were reviewed one by one. It is believed that, based on the complex mechanism of drug resistance, it is of no clinical significance to simply search for and regulate drug resistance targets, and it may even produce drug resistance again soon. It is speculated that according to the possible tumor characteristics, three types of treatment methods should be combined to change the tumor microenvironment ecology and eliminate various heterogeneous tumor subsets, so as to reduce tumor drug resistance and improve long‐term clinical efficacy.

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Targeting Adenosine Receptor Signaling in Cancer Immunotherapy

Cited by 47 publications

References 182 publications

Genetic and pharmacological targeting of A2a receptor improves function of anti-mesothelin CAR T cells

Genetic and pharmacological targeting of A2a receptor improves function of anti-mesothelin CAR T cells

Tracers for non-invasive radionuclide imaging of immune checkpoint expression in cancer

Study and analysis of antitumor resistance mechanism of PD1/PD‐L1 immune checkpoint blocker

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