There is one oncological weapon that has shaken up the game against cancer in the last decade: immunotherapy, a therapeutic approach that consists of stimulating the patient’s own immune system so that it can better fight malignant cells. These treatments have achieved unthinkable victories, even turning around the devastating prognosis of some tumors, and although they are increasingly promising, they are not infallible recipes. For example, immune checkpoint inhibitors, which are a type of immunotherapy that lift the brakes that the tumor puts on the immune system to prevent it from killing it, have already saved thousands of lives, but they barely reach 25% or 30% of patients: they are not valid for all patients or for all tumors. This means that cancer continues to put obstacles that not even these new drugs can overcome.
The scientific community is trying to find out why these therapies, capable of destroying aggressive tumors in some patients, barely scratch malignant cells in other cases. And along these lines, a group of researchers from the Institute for Research in Biomedicine of Barcelona (IRB) have described, in an article published this Thursday in the magazine Nature Geneticsthe main clinical and tumor characteristics that trip up these checkpoint inhibitors: the number of mutations, a particular tumor environment or having undergone other previous treatments influence the response to this type of immunotherapy and the final survival of patients.
Although there had already been previous research pointing to various molecular signals (biomarkers) that could help predict response to immunotherapy, the new study, in which researchers from the Vall d’Hebron Institute of Oncology (VHIO) also participated, aimed to identify exactly which aspects of the tumor were determining factors in the response to checkpoint inhibitors. “It is not clear at present how many latent factors of response [a este tipo de inmunoterapia] and survival exist, what aspects of the tumor, its microenvironment or the host they represent and whether they are universally relevant in different types of tumors,” the authors stated at the beginning of the article.
To address these questions, the researchers analyzed genomic and clinical data from a cohort of 479 patients with metastasis and discovered five key features that they then validated across six independent cohorts of nearly 1,500 patients. “We wanted to do an analysis from scratch, looking at everything and giving everything a chance to see what is important and what is not to better predict response to treatment. There are so many partial and disparate studies that some things that had been identified [como potenciales biomarcadores] We see that they end up converging on the same aspect,” explains Núria López-Bigas, ICREA researcher at the IRB and author of the study.
The research concludes that one of the characteristics that influences the response to this type of immunotherapy is the mutational load of the tumor: the more mutations in the genes of the cancer cells, the better the response to these drugs. And this is explained because a cancer with many mutations tends to generate more neoantigens, which are like a kind of molecular marks on malignant cells that serve the immune system to identify and eliminate them. The more neoantigens the tumor has, the easier it will be for the body’s defensive army to detect these abnormal cells and destroy them.
The authors also discovered that having received previous treatments is associated with a poorer response to this type of immunotherapy. The scientists consider that this may be due to a deterioration in the patient’s baseline condition, since they have already undergone other treatments that have weakened their immune system and are faced with immunotherapy in worse conditions. Another hypothesis they propose is the aggressiveness of the tumor itself: if the patient has undergone other treatments and they have not worked, this may indicate that the tumor, due to its complexity and natural violence, has managed to escape those first lines of treatment and is more difficult to treat.
Another key feature is the effective infiltration of T cells into the tumor. The fact that these types of immune system cells are able to penetrate the tumor environment with confidence and in considerable numbers is essential for patients to respond to this type of immunotherapy. “This is a very active field of research: if there are no T cells or those that exist are not effective or are exhausted, immunotherapy does not work,” López-Bigas emphasizes.
Researchers have also found that activity in the tumor microenvironment, which is the entire environment that surrounds and feeds tumor cells, also plays an important role in the response to immunotherapy. Specifically, the activity of a protein, the growth factor TGF-β, is related to the behavior of some cells in this microenvironment: high TGF-β activity can suppress the immune response, leading to poorer patient survival after immunotherapy.
The fifth essential characteristic in the response to immunotherapy is the proliferative potential of the tumor: the greater the growth capacity, the more aggressive the tumor tends to be and the worse the survival rate after treatment. López-Bigas also points out that this is not only an aspect relevant to the response to immunotherapy, but also to other treatments.
Improving personalized medicine
The authors state that no factor other than these five reported was associated with the response to checkpoint inhibitors or with survival after this treatment. “Virtually all significant characteristics are grouped within one of them,” they insist in the article. However, they also do not rule out that there may be more key aspects that mediate the response to this immunotherapy and that have not yet been identified: “Some relevant characteristics may still be below the statistical power of the cohort.” [estudiada] or appear significantly associated with response or survival in a single tumor type,” they admit.
The five factors, in any case, are independent of each other, says López-Bigas, and the importance of each of them changes depending on the type of tumor. For example, in lung cancer, the mutational load is more decisive; in melanoma, however, the most relevant factor is the effective infiltration of T cells into the tumor.
Josep Tabernero, director of VHIO and also a signatory of this research, highlights that the five factors described “are predictive of the effectiveness of all the types of tumors that have been studied” and argues that this research represents a step forward “in trying to understand why only 25% or 30% of patients treated respond to immunotherapy.”
The IRB researcher, for her part, assures that her findings will serve as a framework to improve personalized medicine and better define which patients will benefit most from this type of treatment. In research contexts, in fact, it is already possible to measure the five key characteristics and, although there are still no clinically approved tools to routinely analyze all these fundamental aspects, it is feasible to think that it will be possible to “develop and clinically validate a predictor that takes all these factors into account,” predicts the IRB scientist.
Martín Lázaro, an oncologist at the Complexo Hospitalario Universitario de Vigo, also points out that this research, in which he has not participated, “provides knowledge” to learn how to better select patients who will respond best. The doctor points out that at present they barely have biomarkers —such as the overexpression of the PD-L1 protein or alterations in DNA repair proteins— to predict the response to immunotherapy and they need more tools to better fine-tune treatments: “The ideal would be that, in the future, these factors would be incorporated for the stratification of patients and that we could confirm these results in prospective studies.”
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