Targeting adenosine-2 B receptor : a potential metabolic immune checkpoint
Adenosine is an anti-inflammatory and immunosuppressive metabolite that binds to the adenosine receptors (AR) - A1R, A2AR, A2BR and A3R. Adenosine immunosuppression is mediated via A2Rs, with A2BR only activated by high adenosine concentration such as within solid tumor microenvironments (TME). A...
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Format: | Final Year Project |
Language: | English |
Published: |
2019
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Online Access: | http://hdl.handle.net/10356/77108 |
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Institution: | Nanyang Technological University |
Language: | English |
Summary: | Adenosine is an anti-inflammatory and immunosuppressive metabolite that binds to
the adenosine receptors (AR) - A1R, A2AR, A2BR and A3R. Adenosine
immunosuppression is mediated via A2Rs, with A2BR only activated by high
adenosine concentration such as within solid tumor microenvironments (TME). A2BR
has been shown to be predominantly overexpressed and correlated to poor prognosis
in several cancers, hence inhibiting A2BR can specifically enhance anti-tumor immune
response. In this study, 5 A2BR inhibitors (A2BRi) were screened against a clinically
approved A2ARi. Functional readout assays were identified to show that cell viability
and proliferation of T and NK cells were rescued by A2BRi. Adenosine at 0.1mM was
concluded appropriate to study these effects in healthy peripheral-blood mononuclear
cells (PBMCs). Furthermore, to mimic pathophysiological adenosine production, a
TME model was developed and uncovered a previously undetectable A2BRi T-cell
proliferation response. An innovative adenosine production assay developed
confirmed the greater adenosine - 4-fold in tumor than normal tissue. A screening
workflow was thereupon established. With only one current A2BRi clinical trial, we
close the gap and collectively detected novel A2BRi with promising computational
medicinal chemistry data and dose-dependent immunomodulation. ISAM-140 and
Cmpd5 comparably improved T and NK cell proliferation with potential superiority than
A2ARi. |
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