Immunotherapies are a promising anticancer arsenal and work by mobilizing the immune system to recognize and destroy cancer cells. Currently, however, only a third of patients respond to immunotherapies, in part because the tumour environment can be hostile to immune cells, depriving them of their source of energy, which diminishes treatment efficacy.
The energy status of the various types of immune cells is a marker of their activity, and particularly of their pro- or anti-tumour action. To personalize and boost the effectiveness of immunotherapies, it is thus essential to have a simple method for profiling the energy profiles of immune cells found in patient tumour samples.
In a new study published Dec. 1, 2020, in Cell Metabolism, an international team of scientists working in Marseille and San Francisco describe just such a method.
The patented new technique - called SCENITH2 (Single Cell ENergetIc metabolism by profilIng Translation inhibition. Patent: PCT/EP2020/060486) - identifies the energy sources on which different cells in a tumour sample are dependant and, most importantly, the specific needs of immune cells in this hostile environment. It uses the level of protein synthesis, a process responsible for half of cellular energy consumption, as an indicator of a cell's energy status.
In the technique, a tumor biopsy sample is separated into parts that are each treated with an inhibitor of one of several metabolic pathways through which cells produce energy. Levels of protein synthesis are then measured using a flow cytometer, which also makes it possible to differentiate types of cells in the sample and identify cell surface markers targeted by therapies. The SCENITH method thus identifies the energy status of each immune or cancer cell within the tumour, its energy sources, and the metabolic pathways it relies upon.
"SCENITH can be applied to study the metabolism of virtually any type of cell - bacteria, yeast, protozoa, plants and animals, including humans - and any context - diet, cancer, infection, metabolic disease, aging, cardiovascular disease, autoimmunity, and more," said study co-lead author Rafael Argüello, PhD, a researcher with the French National Centre for Scientific Research (CNRS) at Centre d'Immunologie de Marseille-Luminy (CIML). "However, from a diagnostic point of view, our priority is use SCENITH to study cancer and immune cells in the blood of patients. The technique can provide information on the strengths and metabolic weaknesses of each patient's tumor cells and their immune response. We believe that this will help identify which patients will respond to which therapy, something that represents one of the greatest challenges of modern medicine."
The scientists behind SCENITH have begun working with clinical research teams to better understand how it might be used to predict patient treatment response. They seek further collaborations of this kind to determine profiles associated with different responses to immuno- and chemotherapy. SCENITH seeks to enable personalised treatment for each patient that exploits the strengths of the immune response and the weaknesses of the tumour.
"We embarked upon this project to address unanswered questions about how cells live communally, sharing resources like sugar and fats to stay alive," said study co-senior author Max Krummel, PhD, Robert E. Smith Endowed Chair in Experimental Pathology and chair of UCSF Bakar ImmunoX Initiative. "This technology can be used to readout how cells 'match' one another's needs and provide energy to each other. Our goal in applying this to cancer is to use this knowledge to find ways to stop host cells from feeding the tumor by reversing this cellular cooperation."
A Scientific Labor of Love
The concept behind SCENITH came from discussions between Arguello and Krummel about the need for a tool to better understand cellular energy sources during Krummel's 2016 sabbatical at the CIML. The two envisioned a technology that could enhance cancer therapy, whether by cutting tumor cells off from their fuel sources or boosting the vigor of the immune cells increasingly being used to target cancers through immunotherapies.
Arguello continued pursuing the idea, ultimately developing the SCENITH technique, as part of his post-doctoral research with study co-senior author Philippe Pierre, PhD, a CNRS team leader at CIML in Marseille. In 2018, he brought the technique with him on his own sabbatical to Krummel's lab at UCSF, where he was able to to test the technique on samples of tumor tissue, working closely with Alexis Combes, PhD, who had also moved from CIML to UCSF as a postdoc with Krummel's group and has since been hired to lead the Disease2Biology CoLab within the UCSF ImmunoX Initiative.
"The main driving forces of this project has been curiosity, friendship and support. Max and Alexis and I spent many long nights discussing science at the flow cytometer and had a lot of fun making this happen," said Arguello, who shares lead-authorship of the new paper with Combes.
"This whole project has been a scientific labor of love," Krummel agreed. "Scientific answers do not always come from just one place. Tools and ideas that exist in France may not have seeped into our world and visa versa, so this cultural and scientific exchange emphasizes the value of collaboration across borders in moving our knowledge and understanding forward."
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