Scientists at the Karolinska Institutet in Sweden published a paper (“Pharmacological activation of p53 triggers viral mimicry response thereby abolishing tumor immune evasion and promoting anti-tumor immunity”) in Cancer Discovery showing how pharmacological activation of the protein p53 boosts the immune response against tumors. The results can be of significance to the development of new combination therapies that will give more cancer patients access to immunotherapy, according to the research team.
“The repression of repetitive elements is an important facet of p53’s function as a guardian of the genome. Paradoxically, we found that p53 activated by MDM2 inhibitors induced the expression of endogenous retroviruses (ERVs) via increased occupancy on ERV promoters and inhibition of two major ERV repressors, histone demethylase LSD1 and DNA methyltransferase DNMT1,” write the investigators.
“Double-stranded RNA stress caused by ERVs triggered type I/III interferons expression and antigen processing and presentation. Pharmacological activation of p53 in vivo unleashed the interferon program, promoted T cell infiltration and significantly enhanced the efficacy of checkpoint therapy in a xenograft tumor model. Furthermore, MDM2 inhibitor ALRN-6924 induced a viral mimicry pathway and tumor inflammation signature genes in melanoma patients.
“Our results identify ERV expression as the central mechanism whereby p53 induction overcomes tumor immune evasion and transforms tumor microenvironment to a favorable phenotype, providing a rationale for the synergy of MDM2 inhibitors and immunotherapy.”
Given its ability to react to damage to cellular DNA and the key part it is thought to play in preventing tumor growth, p53 has been dubbed the “guardian of the genome.” Half of all tumors have mutations in the gene that codes for the protein, and in many other tumors, p53 is disabled by another protein, MDM2.
It has long been known that p53 is able to silence endogenous retroviruses in our genome, thus preventing genome instability. The researchers now show that the protein can also activate these sequences in cancer cells, leading to anti-tumor immune response.
“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 lead investigator Galina Selivanova, PhD, professor in the department of microbiology, tumor and cell biology.
Worked with mouse models
The results were obtained when the researchers blocked MDM2 in mouse models using a substance coded as ALRN-6924 from a U.S. company, Aileron Therapeutics. An increase in the interferon response was also seen in tumor samples from two patients taking part in the company’s clinical trials of ALRN-6924.
“This shows that there are synergies that should be exploited between substances that block MDM2 and modern immunotherapies,” continues Selivanova. “A combination of these can be particularly important for patients who don’t respond to immunotherapy.”
Immunotherapy does not work with all patients, and the presence of interferons could be a biomarker for whether or not immunotherapy will prove efficacious.
“If we can increase the level of interferons, we can therefore increase the chances that the immunotherapy will succeed,” adds Selivanova, who has studied how mutated p53 can be re-activated using special molecules, one of which, APR-246, is undergoing clinical studies under the name Eprenetapopt at Aprea Therapeutics, a company that she co-founded.
“We now want to examine if Eprenetapopt produces the same interferon boost and can have the same potential to increase access to immunotherapy for patients with severe forms of cancer,” she says.