A group of researchers from Massachusetts General Hospital and Brigham and Women’s Hospital in the USA have reported the efficacy of combining immune checkpoint blockade with p53 mRNA induction via nanoparticle approach in hepatocellular carcinoma (HCC) laboratory models. The findings of this work were recently published in the journal Nature Communications.
HCC are one of the most common forms of liver cancers with poorer clinical outcomes in affected individuals. Currently, immune checkpoint blockers (ICB) are at the forefront of cancer treatment and have shown high efficacy in treating many cancers. However, limited benefits with immunotherapy are seen in patients with HCCs, plausibly due to the immunosuppressive tumour microenvironment (TME). Therefore, multiple strategies are under development to improve the efficiency of ICBs. However, no such combination showing high efficacy has been reported so far for HCCs.
In the current study, the researchers have used induction of p53, a well-known tumour suppressor gene, to potentiate the response with ICBs. The p53 gene, well-known for its cell-autonomous tumour-suppressive effects, is mutated in more than one-third of cases of HCCs. Interestingly, it is also reported to regulate the immune TME by modulating the interaction between tumour and immune cells.
To investigate the impact of p53 restoration on TME, the researchers developed and optimised an mRNA nanoparticle strategy to induce p53 function in complex animal models of HCCs. A combination of p53 mRNA nanoparticles with anti-PD-1 therapy effectively induced the cellular and molecular components of the immune TME in p53-null orthotopic and ectopic models of murine HCC. Thus, the combination showed anti-tumour effects not seen in either anti-PD-1 therapy or therapeutic p53 expression alone.
In conclusion, the study demonstrates a potential therapeutic strategy for reversing immunosuppression in HCC by adding a p53mRNA nanomedicine to ICBs.
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