Adenosinergic Axis Provides an Anchor in Multiple Anti-tumor Combination Strategies
Becker, A, Piovesan, D, Soriano, F, Leleti M, Jeffrey J, Miles D, Powers JP, Schindler, U, Walters MJ, Tan J Arcus Biosciences, Hayward, CA, USA Tumor cell death induced by hypoxia or chemotherapy releases large amounts of ATP (adenosine triphosphate). ATP is rapidly converted to AMP (adenosine monophosphate) which, in turn, is converted by hypoxia-induced CD73 into adenosine (ADO). ADO suppresses immune responses, including those of T cells, NK cells and dendritic cells through activation of adenosine receptors A2aR and A2bR. Exhausted T cells and NK cells express high levels of several immune checkpoint (IC) proteins, including PD-1 and TIGIT. Combined expression of IC proteins with CD73 or A2aR/A2bR in multiple tumor types presents an opportunity for novel combinatorial therapies. We present here in vitro and in vivo data on the utility of combining adenosinergic pathway inhibition with multiple therapeutic modalities, including antagonistic antibodies targeted against PD-1 and TIGIT, as well as platinum-based chemotherapeutics. Mechanistically, AMP abrogated the enhanced T cell activation and IFN-γ production mediated by blocking PD-1/PD-L1 and TIGIT, an effect that was reversed by CD73 inhibitors (CD73i). Global gene changes measured by Nanostring include down-regulation of activation markers, co-stimulatory molecules (CD28, ICOS, 4-1BB), and IC proteins (PD-1, TIM-3, LAG3), changes that were confirmed by flow cytometry. Thus, activation of the adenosinergic pathway may limit the efficacy of IC inhibitors and agonistic antibodies. In vivo proof of concept studies combining chemotherapy or anti-PD-1 antagonistic antibody with CD73i or a dual A2aR/A2bR antagonist result in strong suppression of tumor growth as well as measurable changes in the immune compartment. These data provide a rationale for strategically combining adenosinergic pathway inhibitors with a range of clinical interventions affecting a broad array of different immune cell types.
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