Activating the ‘cancer guardian’ protein p53 using drugs helps the immune system of people with cancer to fight against their tumors, shows research from the Karolinska Institute in Sweden.
The researchers think this finding, published in the journal Cancer Discovery, could help give more cancer patients access to immunotherapy.
When properly functioning, p53 acts as a cancer guardian in humans and other species. However, it is fairly susceptible to mutation and these genetic variants are commonly implicated in various types of cancer.
Around 50% of all tumors have mutations in the TP53 gene, which encodes p53, and in a lot of other tumors variants in another gene called MDM2 that can indirectly stop p53 from working properly.
One of the mechanisms of action of p53 is silencing sections of our genome that derive from viruses in the distant past known as endogenous retroviruses.
However, Galina Selivanova, a professor in the Department of Microbiology, Tumor and Cell Biology at the Karolinska Institutet, and colleagues have now discovered that p53 can also ‘turn on’ these sections of the DNA in the presence of cancer and by doing so improve anti-tumor immune activity.
“This was an astonishing discovery. When we blocked the suppressor MDM2, p53 activated endogenous retroviruses which induced antiviral response and boosted the production of immune-activating interferons,” says Selivanova in a press statement.
The researchers used a mouse model to trial the use of a new drug compound developed by Aileron Therapeutics, a Boston-based biotech aiming to reduce chemotherapy-induced side effects in cancer patients. They also assessed results from two patients taking part in a clinical trial being run by the company.
The activation of p53 boosted interferons, promoted T-cell infiltration into tumors and improved checkpoint inhibitor therapy, a commonly used cancer immunotherapy, in the mouse model. The researchers also found inflammatory biomarkers in the two melanoma patients treated with the drug candidate that suggested their immune systems were better targeting their tumors than before they had the treatment.
“This shows that there are synergies that should be exploited between substances that block MDM2 and modern immunotherapies. A combination of these can be particularly important for patients who don’t respond to immunotherapy,” emphasizes Selivanova.
“If we can increase the level of interferons, we can therefore increase the chances that the immunotherapy will succeed.”
Many cancers seem to be able to avoid the immune system by inducing mutations such as those that block p53 directly or via MDM2.
“Restoring interferon signaling by pharmacological reinstatement of p53 function has potential to release the ‘brake’ that cancer uses to evade the immune system,” conclude the authors.
“The encouraging anti-tumor results shown reinforce the MDM2 inhibitor/immune checkpoint inhibitor combination results from Novartis, Boehringer Ingelheim, Ascentage Pharma who initiated human clinical trials to test these combinations in cancer patients.”
