The researcher Pilar Baldominos, who is currently pursuing her Universitat Politècnica de València PhD at Harvard University's Dana-Farber Cancer Institute, has completed a study on the defence mechanisms used by some tumour cells to defeat both the immune system and immunotherapy. Her work, published in the journal Cell, reports the results that she obtained thanks to the pioneering PADMEseq technology, which was developed by Baldominos during her PhD studies, thanks to a grant from the “la Caixa” Foundation.
PADMEseq (Photoconversion of Areas to Determine Micro-Environments) is a technique that is used in combination with JEDI (Just eGFP Death Inducer) mice, which are developed at the same Dana-Farber Cancer Institute laboratory, directed by Judith Agudo Cantero, who is also from Spain. Both PADME and JEDI are names inspired by Star Wars. “In our laboratory, cancer is the dark side, and science is the force”, says Baldominos, referring to the popular saga conceived by film-maker George Lucas. By combining PADME and JEDI, regions with cells that the immune system is unable to kill can be marked under the microscope for comparison with other tumour regions.
“We have identified a population of cells in tumours that is able to withstand immunotherapy, and which, despite appearing ‘dormant’ initially, is able to generate a new tumour. Thanks to our technique, we now know that these resistant cells are grouped together in a kind of hostile neighbourhood that is practically impenetrable to the cells of the immune system, which are supposed to kill them. In fact, the few immune system cells that manage to get in are highly dysfunctional, and even act in favour of the tumour rather than against it”, explains Baldominos.
The work by the team at the Dana Farber Cancer Institute demonstrates that there are small regions within a tumour where tumour cells with very specific characteristics live. These cells are characterised by barely dividing and by generating a hostile environment around them for the immune system, allowing them to survive and ensure therapy continues to fail despite efforts to revive immunity.
“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 tumour cells still have it (this is known as immunoediting). Thanks to the JEDI mouse (Just eGFP Death Inducer), we have now been able to observe this phenomenon for the first time, as its lymphocytes have been modified to recognise a green fluorescent protein that can be introduced in tumour cells. This model not only allows us to fully control the interaction between the lymphocyte and the tumour cell, but also to unequivocally isolate those cells that still have this protein and yet have not been eliminated by the immune system”, explains Baldominos.
Once these therapy-resistant tumour micro-neighbourhoods had been identified, the next step for the research team was to study which cells they contain and their condition (immune system cells can act for or against the tumour). The PADMEseq technology was developed for this purpose.
“With a mouse whose cells can change from fluorescent green to red, we can use a microscope to mark the regions where those cells that the immune system is unable to kill are found, and compare them to other tumour regions. This has allowed us to achieve an extremely accurate resolution. In this way, we have found out that resistant micro-regions are characterized by a lower density of immune system cells, and that those cells that do enter them are pro-tumour in character, thereby preventing the immune system from working properly, which explains resistance to therapy”, adds Baldominos.
These findings could help doctors to better select which patients respond best to immunotherapy, and facilitate improving current therapies. “Understanding who these cells’ neighbours are helps us understand why therapy fails, and opens new avenues to study how to reverse the situation”, concludes Baldominos.
Immunotherapy consists of reviving the immune system so it will attack and eliminate a tumour. This treatment marked a revolution for certain tumours. It was named Discovery of the Year by Science magazine in 2013, and awarded the Nobel Prize for Medicine in 2018. It has recently been approved as a first line of treatment for triple negative breast tumours, increasing life expectancy. However, only 20% of patients respond to treatment on a permanent basis.
“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”, says Pilar Baldominos.
About Pilar Baldominos
Pilar Baldominos Flores was born in Alcalá de Henares in 1993 and has lived most of her life in València. After graduating from Universitat Politècnica de València (UPV) in 2015, she completed her bachelor’s thesis at the Hospital Universitari i Politècnic La Fe’s haematology service. She also took part in a range of projects, completed an Erasmus+ stay at Cambridge University (UK), and was a member of the UPV’s iGEM 2015 team, winning a gold medal. She subsequently completed a master’s degree in Advanced Immunology at the Universitat de Barcelona (UB). After her studies, she went on to join Fyodor Kondrashov’s laboratory, first at the Centre for Genomic Regulation (CRG) in Barcelona and later at the Institute of Science and Technology (IST) in Austria.
She is currently pursuing her Universitat Politècnica de València PhD at Judith Agudo’s laboratory at Harvard University’s Dana-Farber Cancer Institute in Boston, researching the escape mechanisms used by tumours to survive the immune system, which may lead to new therapeutic targets.
Pilar Baldominos, Alex Barbera-Mourelle, Olga Barreiro, Yu Huang, Andrew Wight, Jae-Won Cho, Xi Zhao, Guillem Estivill, Isam Adam, Xavier Sanchez, Shannon McCarthy, Julien Schaller, Zara Khan, Albert Ruzo, Ricardo Pastorello, Edward T. Richardson, Deborah Dillon, Paula Montero-Llopis, Romualdo Barroso-Sousa, Juliet Forman, Sachet A. Shukla, Sara M. Tolaney, Elizabeth A. Mittendorf, Ulrich H. von Andrian, Kai W. Wucherpfennig, Martin Hemberg, Judith Agudo, Quiescent cancer cells resist T cell attack by forming an immunosuppressive niche. Cell, 2022, ISSN 0092-8674, https://doi.org/10.1016/j.cell.2022.03.033