ATP has multiple functions, most notably aiding intracellular signaling by serving as a substrate for kinases and donating phosphate groups to other proteins, triggering downstream signaling cascades.2 Additionally, ATP is a precursor to DNA and RNA synthesis and is used as a coenzyme. Yet, there are many other roles ATP may play that extend outside of our remote college and medical school biology and biochemistry course coverage.
In the realm of cancer immunity, ATP may serve a positive effect by initiating pro-inflammatory responses.3 High levels of ATP may be released through tissue damage or immunogenic cell death into the extracellular environment. These high levels of ATP facilitate inflammation, acting as a chemoattractant for innate immune cells, which subsequently induce the adaptive immune response. However, this process is dynamic, as ATP does not remain an extracellular constant. ATP is eventually reduced to adenosine diphosphate (ADP), then adenosine monophosphate (AMP), and finally to adenosine. This hydrolysis of ATP leads to extracellular accumulation of adenosine, which subsequently has pro-tumorigenic potential, an opposite and undesired effect. Extracellular adenosine may result in many consequences, facilitating tumor immune escape, angiogenesis induction, and metastasis.4 Adenosine in tumors can also mediate immunosuppression by inhibiting CD3+ T cell and natural killer (NK) cell function.5
The process of reducing ATP in the tumor microenvironment to ADP and AMP, and further to adenosine, is dependent on the enzymatic activity of 2 distinct ectonucleotidases. Specifically, CD39 catalyzes the hydrolysis of ATP and ADP to AMP, while CD73 further hydrolyzes AMP to adenosine. Adenosine then inhibits activation and expansion of T cells by binding to G-protein coupled receptors. Although there are multiple receptors (e.g., A1, A2A, A2B and A3), the A2A receptor upregulates immune checkpoints like CTLA4 and PD-1,6 while stimulation of A2B receptor suppresses dendritic cells and macrophages. Preclinical evidence shows mice lacking A2A receptor have reduced tumor growth, implying tumor protection from T cells in the presence of the adenosine-A2A receptor interaction.7
Prostate cancer is a solid tumor that has FDA-approved cellular immunotherapy in sipuleucel-T.8 Yet, attempts with single-agent CTLA49, 10 and PD-(L)111, 12 checkpoint inhibition have not been very successful. This is likely due to the presence of an immune-exclusive tumor microenvironment. Relevant to the adenosine pathway, it has been shown that CD39 is strongly expressed in the stromal compartment of tumors. Prostatic acid phosphatase (PAP) is obviously upregulated in prostate cancer, and it also has ectonucleotidase activity which leads to conversion of AMP to adenosine.13, 14 Finally, A2B receptor is upregulated in prostate cancer,15-17 leading more support to the concept of adenosine-mediated immune exclusion.
Altogether, the above evidence offers potential for targeting the adenosine pathway to reduce the immune exclusive microenvironment in many solid tumors, including the prostate and other genitourinary malignancies. Manipulation of the microenvironment to retain ATP and avoid adenosine production and activation of specific adenosine receptors can be accomplished via multiple different mechanisms. This may include inhibiting the reduction of ATP through inhibition of CD39 and/or CD73, resulting in decreased adenosine accumulation. Additionally, inhibition of the adenosine receptors has the potential to minimize the impact of adenosine in the tumor microenvironment, by limiting immune checkpoint upregulation and suppression of innate immune system components. Hence, a tumor like prostate cancer, with an immune exclusive microenvironment, may be ideal for induction of anti-tumor inflammation, initiated by manipulation of the adenosine pathway. Clinical trials with novel therapeutics that manipulate the various components of the adenosine pathway are currently ongoing and in development. Below, I list relevant trials that are inclusive of