Combining p53 mRNA nanotherapy with immune checkpoint blockade reprograms the immune microenvironment for effective cancer therapy

Yuling Xiao, Jiang Chen, Hui Zhou, Xiaodong Zeng, Zhiping Ruan, Zhangya Pu, Xingya Jiang, Aya Matsui, Lingling Zhu, Zohreh Amoozgar, Dean Shuailin Chen, Xiangfei Han, Dan G. Duda () and Jinjun Shi ()
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Yuling Xiao: Brigham and Women’s Hospital, Harvard Medical School
Jiang Chen: Massachusetts General Hospital and Harvard Medical School
Hui Zhou: Brigham and Women’s Hospital, Harvard Medical School
Xiaodong Zeng: Brigham and Women’s Hospital, Harvard Medical School
Zhiping Ruan: Massachusetts General Hospital and Harvard Medical School
Zhangya Pu: Massachusetts General Hospital and Harvard Medical School
Xingya Jiang: Brigham and Women’s Hospital, Harvard Medical School
Aya Matsui: Massachusetts General Hospital and Harvard Medical School
Lingling Zhu: Massachusetts General Hospital and Harvard Medical School
Zohreh Amoozgar: Massachusetts General Hospital and Harvard Medical School
Dean Shuailin Chen: Brigham and Women’s Hospital, Harvard Medical School
Xiangfei Han: Brigham and Women’s Hospital, Harvard Medical School
Dan G. Duda: Massachusetts General Hospital and Harvard Medical School
Jinjun Shi: Brigham and Women’s Hospital, Harvard Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28279-8

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