Immunotherapy has represented a true revolution in cancer treatment. The development of therapies such as checkpoint inhibitors, which allow the immune system to 'wake up' to locate and destroy tumor cells, is already making it possible for many patients to overcome the disease.. Unfortunately, this approach is not effective in a high percentage of cases.. And we still don't know the reasons.
New research this week sheds light on this question and understands why some patients do not respond to therapy with immune checkpoint inhibitors.. The work, which is published in Nature Genetics, provides a tool to better identify the patients most likely to benefit from treatment.
One of the cases where higher response rates to treatment have been observed is in tumors with a large number of mutations, such as tumors called MMRd, in which the cancer 'takes advantage' of a 'fault' in the error repair system. that cells have.
Despite this characteristic, this type of tumors, very common in the colon or stomach, still do not respond long-term in a high percentage of cases to therapy with immune checkpoint inhibitors, a paradox that a collaboration wanted to study. international group of researchers from the European Bioinformatics Institute of the European Molecular Biology Institute (EMBL-EBI), the Cold Spring Harbor Laboratory and the Massachusetts Institute of Technology, of which the Spanish researcher Isidro Cortés-Ciriano, group leader at the EMBL, is a member. -EBI.
“Checkpoint inhibitors are antibodies that block a signal in cells called a checkpoint and whose function is to prevent indiscriminate attack by the immune system. Cancer cells use this mechanism as a disguise to protect themselves from the immune system.. However, when this immunotherapy is applied, this signal is blocked, which 'removes the disguise' of the cancer cells and stimulates the immune system,” explains Cortés-Ciriano.
“Patients with MMRd tumors present many aberrant proteins that, once this disguise is removed from the cancer cells, should stimulate the immune system to attack the cancer cells and kill them.”. However, in approximately 50% of patients this does not happen and we wanted to find out why.”
The Spanish researcher Isidro Cortés-Ciriano EMBL-EBI
For the analysis, the researchers used both mouse cancer models and cell lines and DNA sequencing data from tumors from immunotherapy clinical trials.
Research has brought to light that intratumoral heterogeneity plays a fundamental role in predicting response to treatment.
“The fundamental finding of this study is that in MMRd tumors, for a response to immunotherapy to occur, it is necessary that a large portion of the tumor cells have the same aberrant proteins, and that these aberrant proteins are shared by many cells. tumor cells, so they are capable of stimulating the immune system,” explains the researcher, who uses an analogy to explain it more clearly:
“One way to visualize this phenomenon is to imagine a crowd where each person holds a yellow flashlight.. If everyone turns on their flashlight, the yellow beam of light can be seen from afar. Similarly, the more cells with the same mutations there are in a tumor, the stronger the signal and the more likely it is to trigger an immune response.. However, if each person in the crowd has a different colored flashlight, the light emanating from the crowd is less clear and the signal becomes confused,” he notes.
The findings of the study provide a tool to identify which patients are most likely to benefit from therapy with immune checkpoint inhibitors, highlights the researcher from Zaragoza, who graduated in Biology and Biochemistry at the University of Navarra, did his doctorate in the Pasteur Institute in Paris and the post-doc at the Harvard Medical School in Boston (USA). Since 2019 it has its laboratory at the European Institute of Molecular Biology (United Kingdom).
The researcher highlights that the study has been possible by combining tests on animals and cell lines with human data, which highlights “the importance for research of being able to access data from clinical trials through secure mechanisms.”
Using clinical data, the researchers verified that colon and stomach tumors with intratumoral heterogeneity presented a diluted mutational signal and, therefore, showed a reduced signal to treatment with immunotherapy.
Studies in mouse models also showed that inactivation of MMR is not sufficient to improve responsiveness to inhibitors.
For Luis Álvarez Vallina, head of the H12O-CNIO Cancer Immunotherapy Clinical Research Unit, this is a “pioneering and very interesting” work that “begins to make it possible to understand the dynamism that occurs in the relationship of the immune system with the tumor.” and the role of intratumoral heterogeneity”.
In clinical practice, having response biomarkers that allow us to indicate whether a certain compound is going to be beneficial for the patient is essential, and this work points out very interesting data, continues the researcher, who highlights the use in the work of a system of very relevant in vivo animal studies that allow “studying mutations continuously from the beginning of the process to advanced disease”.
“In addition, they have validated it with a sample obtained in clinical trials, although it is a small sample that should be extended in prospective studies,” concludes Álvarez Vallina..