Colorectal cancer, a strategy to increase response to immunotherapy
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Finding a way to make colorectal cancers susceptible to immunotherapy. This is the objective of a new study conducted by researchers from Ifom in Milan and the University of Turin, whose first results published in Cancer cell they are promising. So much so that the magazine has chosen to dedicate the cover to this study.
Few colorectal cancers are sensitive to immunotherapy
The arrival of immunotherapy – which works by taking the brakes off the immune system so that it can recognize cancer cells as foreign and attack them – has changed the natural history of many cancers, but not all. There are, in fact, neoplasms that doctors define as “immunologically cold”, which are invisible to our immune system even in the presence of immunotherapies. Among these are colorectal cancers: in fact, only in a small minority of advanced stage patients (about 5%), immunotherapy is effective.
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The reason? According to scholars it is to be found in the DNA repair mechanisms. Paradoxically, a malfunction of these mechanisms plays to our advantage, because it produces altered proteins that “alert” the immune system and make the tumor immunologically “hot”. “But in about 95% of patients with metastatic colorectal cancer, this repair mechanism is intact and functioning,” he says. Alberto BardelliDirector of the Ifom research program Tumor genomics and targeted anticancer therapies, Professor at the University of Turin and coordinator of the study together with John Germano.
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Heterogeneous tumors
However, there are also heterogeneous tumors, in which some tumor cells show defects in DNA repair and others do not. Hence the intuition: is it possible to increase the percentage of malfunctioning cells within a tumor, in order to transform it from “cold” to “hot”? From this question, thanks to the support of the Airc Foundation, the study started two years ago: “We discovered that in the small group of heterogeneous tumors potentially cold and warm tumor areas coexist from an immunological point of view – he explains Vito Amodiofirst author of the article and holder of an Airc scholarship – and we wondered if there were already available therapies capable of increasing the efficacy of immunotherapy for colorectal cancers that do not currently benefit from it”.
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The study on cells and animal models
In this first phase, the research group conducted experiments on cells and laboratory mice, in which the efficacy of 6-Thioguanine was evaluated, a drug already used in the treatment of some leukemias, toxic only for the cells in which the DNA repair mechanisms are functioning. In this way, by selectively targeting “cold” cancer cells, they managed to increase the percentage of “warm” ones. It has also been discovered that the immune response activated by the “hot cells” also extends to the “cold” counterpart.
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The next steps
The percentage of cases of heterogeneous colorectal cancer is not known but, according to another study conducted by the same team, it seems to be on the increase: a possible consequence of the effects of pharmacological therapies. “Although encouraging – the scientists conclude – the results were obtained in laboratory animals and we are currently verifying whether they can be transferred to the clinic shortly. However, the study underlines the importance of fully understanding the ecosystem of each individual tumor in order to understand which are the best therapeutic options that can be used”.
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