Targeting adenosine for cancer immunotherapy

Abstract

Immune checkpoint antagonists (CTLA-4 and PD-1/PD-L1) and CAR T-cell therapies generate unparalleled durable responses in several cancers and have firmly established immunotherapy as a new pillar of cancer therapy. To extend the impact of immunotherapy to more patients and a broader range of cancers, targeting additional mechanisms of tumor immune evasion will be critical. Adenosine signaling has emerged as a key metabolic pathway that regulates tumor immunity. Adenosine is an immunosuppressive metabolite produced at high levels within the tumor microenvironment. Hypoxia, high cell turnover, and expression of CD39 and CD73 are important factors in adenosine production. Adenosine signaling through the A2a receptor expressed on immune cells potently dampens immune responses in inflamed tissues. In this article, we will describe the role of adenosine signaling in regulating tumor immunity, highlighting potential therapeutic targets in the pathway. We will also review preclinical data for each target and provide an update of current clinical activity within the field. Together, current data suggest that rational combination immunotherapy strategies that incorporate inhibitors of the hypoxia-CD39-CD73-A2aR pathway have great promise for further improving clinical outcomes in cancer patients.

Transcriptional mediators of treatment resistance in lethal prostate cancer

“…The presence of this cell population may explain why some patients with advanced prostate cancer respond to immune checkpoint inhibition in combination with androgen-targeting therapies 47 . ENTPD1 (CD39) expression in this population suggests that targeting immunosuppressive adenosine signalling may provide benefit in addition to targeting the PD-1 axis 48 . This population was uncommon in bone biopsies, which instead contained clonally expanded CD8 + T cells with high effector molecule, low exhaustion marker, and CX3CR1 expression.…”

Lactate secreted by cervical cancer cells modulates macrophage phenotype

“…Soluble factors secreted by tumor cells, including cytokines, lipid mediators and metabolites can modulate Mϕ phenotype. The later includes adenosine, produced from ATP through the activity of CD39 and CD73 expressed by either tumor or stroma cells, and tryptophan metabolites, as kynurenine, generated through the activity of enzymes as indoleamine‐ 2,3 dioxygenase . Lactate, a by‐product of tumor cell metabolism, secreted to the extracellular environment, exerts an immunomodulatory role in several immune cells .…”

Immune checkpoint inhibitors: The linchpins of modern immunotherapy

“…A third master regulator of the immunosuppressive TME is the adenosine signaling pathway. As recently reviewed, extracellular ATP is released in response to inflammation or early cancer growth, acting as a DAMP to promote innate and adaptive immune responses. Over time ATP is dephosphorylated by the ectonucleotidases CD39 and CD73, leading to formation of adenosine.…”

“…A third master regulator of the immunosuppressive TME is the adenosine signaling pathway. As recently reviewed, 101 Based on the multidimensional impact of the adenosine pathway, inhibitors of this pathway are in various stages of clinical development. 101 Monoclonal antibodies to CD73 are currently in phase 1/2 trials in combination with anti-PD-L1 therapy in advanced solid tumors.…”

“…As recently reviewed, 101 Based on the multidimensional impact of the adenosine pathway, inhibitors of this pathway are in various stages of clinical development. 101 Monoclonal antibodies to CD73 are currently in phase 1/2 trials in combination with anti-PD-L1 therapy in advanced solid tumors. Additionally, a large phase 2 study is testing anti-CD73 in various combinations with anti-PD-L1, anti-CTLA-4, and anti-OX40 for ovarian carcinoma.…”