Abstract
Immunotherapy with immune checkpoint blockade (ICB) has shown limited benefits in hepatocellular carcinoma (HCC) and other cancers, mediated in part by the immunosuppressive tumor microenvironment (TME). As p53 loss of function may play a role in immunosuppression, we herein examine the effects of restoring p53 expression on the immune TME and ICB efficacy. We develop and optimize a CXCR4-targeted mRNA nanoparticle platform to effectively induce p53 expression in HCC models. Using p53-null orthotopic and ectopic models of murine HCC, we find that combining CXCR4-targeted p53 mRNA nanoparticles with anti-PD-1 therapy effectively induces global reprogramming of cellular and molecular components of the immune TME. This effect results in improved anti-tumor effects compared to anti-PD-1 therapy or therapeutic p53 expression alone. Thus, our findings demonstrate the reversal of immunosuppression in HCC by a p53 mRNA nanomedicine when combined with ICB and support the implementation of this strategy for cancer treatment.
Highlights
Immunotherapy with immune checkpoint blockade (ICB) has shown limited benefits in hepatocellular carcinoma (HCC) and other cancers, mediated in part by the immunosuppressive tumor microenvironment (TME)
We report a targeted mRNA nanoparticle (NP) platform designed to induce p53 expression and reprogram the TME, which we test in proof-ofconcept studies in combination with ICB in p53-null murine HCC models
To improve HCC targeting, we modified the NPs with the targeting peptide CTCE-9908 (KGVSLSYRCRYSLSVGK; referred to as CTCE), which is specific to CXCR4, a chemokine receptor that is upregulated in cancer cells and is a validated selective target in HCC29,30
Summary
Immunotherapy with immune checkpoint blockade (ICB) has shown limited benefits in hepatocellular carcinoma (HCC) and other cancers, mediated in part by the immunosuppressive tumor microenvironment (TME). Using p53-null orthotopic and ectopic models of murine HCC, we find that combining CXCR4-targeted p53 mRNA nanoparticles with anti-PD-1 therapy effectively induces global reprogramming of cellular and molecular components of the immune TME This effect results in improved antitumor effects compared to anti-PD-1 therapy or therapeutic p53 expression alone. Recent studies suggest that immunogenic cancer cell death induced by cytotoxic agents may be associated with activation of the p53 pathway[18,19] Despite these advances in understanding the role of p53, developing therapeutic approaches that directly and effectively address the loss of p53 function and its role in immunosuppression and immunotherapy resistance in HCC remains an elusive goal. Combining p53 mRNA nanotherapy with ICB immunotherapy could become a transformative approach for the treatment of HCC and potentially other cancers involving p53 deficiency
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