Researcher Pilar Baldominos’ findings could help determine better therapies for cancer patients. Through advanced techniques with names inspired by Star Wars — PADME and JEDI — Baldominos and her team managed to identify cell populations that are able to resist immunotherapy and produce a new tumor, despite initially appearing inactive.
“In our lab, cancer is the dark side and science is the force,” says Baldominos in reference to Star Wars. Her fondness for the saga has helped her to explain the defense of some tumors against immunotherapy.
The study, published in April 2022 in the magazine Cell, gathers the results of the technology developed by Baldominos during the doctorate she is doing through the Universitat Politècnica de València (UPV) at the Dana-Farber Cancer Institute of Harvard University.
To achieve the results — where the areas whose cells have not been eliminated by the immune system are marked under the microscope — the innovative technique combines the PADMEseq method (Photoconversion of Areas to Determine Micro Environments) and the use of mice JEDI (Just eGFP Death Inducer), which have also been developed at the Dana-Farber Cancer Institute laboratory.
Baldominos and her team have been able to identify populations of cells that are able to resist immunotherapy. The scientific breakthrough has helped identify that the resistant cells are clustered in hostile zones, which cannot be penetrated by immune system cells.
The comparison of tumor regions has also helped to see how the few immune system cells that manage to break through into the hostile region react dysfunctionally or in favor of the tumor. Meanwhile the tumor cells that cannot be penetrated are characterized by generating the hostile environment and barely dividing, this compartment allows these cells to continue to survive and therapies to fail.
“Understanding who these cells’ neighbors are helps us understand why therapy fails, and opens new avenues to study how to reverse the situation,” says Baldominos.
The complex study of cells that the immune system has been unable to kill was made possible thanks to the JEDI mouse; this method allows a green fluorescent protein to be recognized and has helped scientists to observe the phenomenon for the first time.
The model helps the interaction between the tumor cell and the lymphocyte to be controlled by the researchers, “and we will also be able to isolate unequivocally the cells that continue to have it and yet have not been eliminated by the immune system,” explains Baldominos.
“Our paper studies those cancer cells that can withstand being attacked by the immune system in order to see what they look like and how they behave. This would be the first step towards understanding why immunotherapy might fail in some patients, which would allow us to consider future alternatives that could improve it,” indicates Baldominos.
These types of discoveries are essential for understanding the immune response of patients. Through this work, it will be possible to follow a path where therapies could have a better response.
“Studying those cells that the immune system tries to kill, but is unable to, is very complex, as we need to know which target our lymphocytes are looking for and check that the surviving tumor cells still have it (this is known as immunoediting). Thanks to the JEDI mouse, we have now been able to observe this phenomenon for the first time, as its lymphocytes have been modified to recognize a green fluorescent protein that can be introduced in tumor cells. This model not only allows us to fully control the interaction between the lymphocyte and the tumor cell, but also to unequivocally isolate those cells that still have this protein and yet have not been eliminated by the immune system,” says Baldominos.
The findings associated with this technique are a key step for physicians to learn which immunotherapy works best for patients. The immunotherapy treatment was named Discovery of the Year by the journal Science in 2013 and awarded the Nobel Prize in Medicine in 2018, due to its great results in increasing life expectancy in patients with certain tumors.
The treatment involves reviving the immune system to get it to attack and kill the tumor. Only 20% of patients have had a positive response to treatment permanently, Baldominos’ results are key to understanding failure rates and devising new alternatives to improve their function.
Image: Original images by Louis Reed, Weweje and Suzy Rice and edited by Philippa Willitts
