Hayward, CA, USA – August 14, 2020 – A multi-site research team headed by Dr. Ruoning Wang at the Nationwide Children’s Hospital has uncovered a metabolic pathway that can potentially be exploited to enhance the killing of anti-cancer T cells such as CAR-T cells. Immunotherapies using T cells have been shown to be effective in clinical treatment against B cell leukemias and checkpoint blockade therapies in melanoma, non-small-cell lung cancer, bladder cancer, and others. However, the success of the T cell therapy is limited to less than one-quarter of cancers. Hence, many cancer researchers are looking for novel ways to improve T cell based cancer therapies.
The approach of the research team was to study the metabolic fitness of T cells. Cancer cells are metabolically strong, and solid tumors create a tumor microenvironment which presents challenges and barriers to block the normal immune response spearheaded by T cells. Essentially, the cancer cells too often outcompete the immune cells called effector T cells. Human effector T cells were prepared and tested using Biolog’s Phenotype MicroArray™ set of 367 nutritional carbon sources. As expected, the effector T cells showed primarily metabolism of sugars, but surprisingly they also showed rather strong metabolism of the nucleoside inosine. Metabolism of inosine to produce energy was noted in a 2011 paper by Biolog scientists. More importantly, this new study showed that inosine could restore proliferation of human and mouse effector T cells by relieving starvation after exhaustion of glucose (i.e., blood sugar). Cancer cells are noted for their ability to consume glucose. Thus, utilization of inosine provides effector T cells with another nutritional option for surviving in the tumor microenvironment.
Dr. Wang’s team further showed that the ability of the effector T cells to consume inosine required the enzyme purine nucleoside phosphorylase (PNP). This enzyme converts inosine to hypoxanthine plus ribose-1-phosphate, an important metabolite that can be utilized by cells for growth and energy production. Some cancer cells also have PNP and can therefore still compete for inosine with the effector T cells. However for those cancer types with little or no PNP, the effector T cells can outcompete the cancer cells and significantly extend the life of mice with implanted tumors. Experiments showed that provision of inosine enhances the killing of PNP deficient cancer cells both with CAR-T cells and with T cells provided antibodies against checkpoint blockade inhibitors such as PDL-1.
The discovery of the inosine pathway was enabled by the Biolog assay technology which provides a comprehensive survey of 367 potential metabolic pathways in a single experiment taking only a day or two. Sophisticated and expensive mass spec based metabolic analysis would have missed the discovery of inosine because it gives a detailed but narrow view of cell metabolism. Biolog metabolic analysis is becoming increasingly used in cancer research to compare cancer cell types to understand and exploit metabolic properties in different subtypes of cancers and hence uncover their metabolic vulnerabilities. This new study beautifully demonstrates how PNP deficient cancers are vulnerable to inosine. Two other recent publications have used Biolog metabolic assays to uncover the unexpected importance of arginine metabolism in regulatory T cells and aggressive melanoma cells.
Although not obvious, it is becoming increasing clear that inosine and other nucleosides play an important role in immunometabolism. Wherever immune cells are targeting and killing other cells, there will be localized release of ATP and mono- and polynucleotides which can be converted to adenosine and inosine, if the enzyme adenosine deaminase (ADA) is present. Going back even to 1975, there are strong hints of the importance of these two nucleosides in cellular immunology. People with ADA deficiency exhibit combined T and B cell immunodeficiency, and those with PNP deficiency exhibit a T cell related immunosuppressed phenotype.
Also using Biolog technology, inosine (beneficial) and adenosine (harmful) have been shown to play a role in Lou Gehrig’s disease (ALS). This has been demonstrated recently in two publications from a scientific team led by Dr. Scott Allen at Sheffield University. According to Dr. Barry Bochner, Biolog’s CEO, “the Biolog cell analysis technology was developed with the intent of providing scientists with a new and broader approach for comparing normal versus disease cells to look for differences that could underlie the deficiencies. Credit goes to Dr. Wang and his colleagues for being one of the first to set up an excellent cell model and then employ the Biolog technology strategically.”