mRNA Nanoparticles Restore p53 Function, Improve Immunotherapy Response
Researchers at Massachusetts General Hospital (MGH) and Brigham and Women’s Hospital (BWH) have used mRNA nanoparticles to reprogram the tumor microenvironment of liver cancer and restore the function of the p53 master regulator gene, a tumor suppressor that is mutated in different cancer types. The researchers demonstrated that when used in combination with immune checkpoint blockade (ICB), the p53 mRNA nanoparticle technology—which is similar to that used in COVID-19 vaccines—not only induced suppression of tumor growth but also significantly increased antitumor immune responses in hepatocellular carcinoma (HCC) laboratory models.
“The reprogramming of the cellular and molecular components of the tumor microenvironment could be a transformative approach for treating HCC and other cancers,” said co-senior author Jinjun Shi, PhD, at the Center for Nanomedicine at BWH, who developed the platform with MGH liver cancer biologist and co-senior author Dan G. Duda, DMD, PhD. “By using this new approach, we’re targeting specific pathways in tumor cells with mRNA nanoparticles. These tiny particles provide the cells with the instructions to build proteins, which, in the case of HCC, delayed tumor growth and rendered the tumor more responsive to treatment with immunotherapy.”
The team described its development in Nature Communications, in a paper titled, “Combining p53 mRNA nanotherapy with immune checkpoint blockade reprograms the immune microenvironment for effective cancer therapy,” in which they concluded, “If successfully translated, the mRNA nanotherapy-based p53 restoration strategy could be transformative and impactful in cancer immunotherapy.”
HCC is the most prevalent form of liver cancer, characterized by a high mortality rate and “dismal prognosis” for patients, the authors wrote. Immune checkpoint blockers, a new class of drugs that enable the body’s immune system to recognize and attack cancer cells, have shown efficacy in treating HCC, but still, most patients do not benefit. To overcome this resistance to treatment, multiple strategies are being developed to improve ICBs by combining them with other existing therapies, such as anti-VEGF drugs and radiotherapy. However, even these approaches are expected to benefit only a small number of patients, creating an urgent need for new combination treatments. “Such combinations have been shown to improve anti-tumor efficacy in animal models and increase the survival of patients in clinical trials,” the team commented. “However, an increasing majority of HCC patients show no responses, and thus, new combinatorial strategies are still desperately needed.”
The tumor suppressor p53 is one of the most frequently mutated genes in a wide range of cancers, and is linked with tumorigenesis, tumor progression, resistance to anticancer therapy, and poor prognosis, the scientists said. “Beyond cell autonomous tumor-suppressive effects, increasing evidence indicates that p53 protein can also regulate the immune tumor microenvironment (TME) by modulating interactions of tumor cells with immune cells,” they noted. “Compelling evidence suggests that p53 dysfunction leads to immunosuppression and immune evasion.” The ability to restore p53 function might thus offer opportunities to reverse immunosuppression of the TME and improve the antitumor efficacy of ICB therapy.
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