Why does immunotherapy only awaken certain types of cells in the immune system that later become narcotized by the tumor? What are the characteristics of T cells that are reactivated by these therapies? These questions are answered, for the first time, by a study whose results are published in the prestigious journal, “The Journal of Experimental Medicine”, the result of collaboration between the Laboratory of Translational Immunology of Humanitas, of which Dr. Enrico Lugli is Principal Investigator, and the Section of Robotic Thoracic Surgery of Humanitas led by Dr. Giulia Veronesi.
The first authors of the study were immunologist Jolanda Brummelman (supported by a three-year AIRC grant) and bioinformatics Emilia Mazza (supported by a postdoc grant from the Veronesi Foundation). The study was partly supported by AIRC.
Immunotherapy in lung cancer
Immunotherapy with antibodies that block immune checkpoints, such as anti-PD-1/PD-L1, has recently revolutionized the clinical history of several types of cancer, including some types of lung cancer, allowing patients to increase their survival.
The so-called checkpoints are natural brakes on our immune system: our defense apparatus is a bit like an extraordinary car capable of travelling at high speed. To function well and not go off the road it needs accelerators that make it start and run, but also brakes (the checkpoints, precisely) that allow it to slow down and, when appropriate, stop.
Immunotherapy acts by removing these brakes and awakening particular immune cells, the T lymphocytes, which within the tumor act like narcotics from the disease.
What did the study reveal?
“In the study, we examined 53 patients with non-small cell lung cancer (NSCLC), at an operable stage and then underwent surgery. Using a particularly innovative technology, 30-parameter flow cytometry – we were able to define with considerable precision the immune properties of T cells expressing the PD-1 checkpoint,” explains Dr. Lugli.
Cytometry, which in Humanitas is used with the most advanced technologies, allows individual cells to be counted, separated and recognized on the basis of specific markers. The analysis of several parameters, physical, phenotypic and functional, can take place simultaneously for tens of thousands of cells per second. Cytometry is also widely used for a more precise diagnosis of certain diseases, such as tumors. The particular cytofluorimeter present in Humanitas allows doing basic and translational research at very high levels, analyzing 30 parameters of each cell.
“We have demonstrated – continues Dr. Lugli – that these cells are not all the same, but are organized in a hierarchy: the youngest, identified by the membrane receptor CXCR5, remain functional and are potentially able to exert a powerful anti-tumor activity, while the most differentiated (the oldest) lose this ability. The hypothesis, therefore, is that with immunotherapy young cells in particular are awakened.
For the future, the challenge is to identify the molecular signals underlying the generation and maintenance of these cells, so as to use this information to generate armed T cells in the laboratory that can improve the response to tumors.
