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Theranostics 2020; 10(7):3049-3063. doi:10.7150/thno.42385 This issue Cite

Research Paper

Targeting CAMKII to reprogram tumor-associated macrophages and inhibit tumor cells for cancer immunotherapy with an injectable hybrid peptide hydrogel

Xiaomeng Dai1*, Jingshu Meng1*, Suke Deng1*, Lingling Zhang1, Chao Wan1, Lisen Lu1, Jing Huang1, Yan Hu1, Zhanjie Zhang1, Yan Li1, Jonathan F. Lovell2, Gang Wu1, Kunyu Yang1✉, Honglin Jin1✉

1. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
2. Department of Chemical and Biological Engineering, University at Buffalo, State University of New York. Buffalo, New York 14260, USA
* These authors contributed equally to this work.

✉ Corresponding authors: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Fax: +86-27-65650733; Tel: +86-27-85873100. Email: Kunyu Yang, yangkunyucom.cn; Honglin Jin, j More

Citation:
Dai X, Meng J, Deng S, Zhang L, Wan C, Lu L, Huang J, Hu Y, Zhang Z, Li Y, Lovell JF, Wu G, Yang K, Jin H. Targeting CAMKII to reprogram tumor-associated macrophages and inhibit tumor cells for cancer immunotherapy with an injectable hybrid peptide hydrogel. Theranostics 2020; 10(7):3049-3063. doi:10.7150/thno.42385. https://www.thno.org/v10p3049.htm
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Abstract

Graphic abstract

Simultaneously targeted treatment of tumor cells and their surrounding growth-supporting immune cells is a promising strategy to reshape immunosuppressive tumor microenvironment (TME) and potentiate host innate and adaptive antitumor immune responses.

Methods: We designed a series of melittin-(RADA)n hybrid peptide sequences with varying self-assembling motifs of RADA and screened out a melittin-(RADA)6 peptide that has an optimal gel-formation ability and in vitro antitumor activity.

Results: The formed melittin-(RADA)6 (MR52) hydrogel scaffold could be loaded with a specific Ca2+/calmodulin-dependent protein kinase II (CAMKII) inhibitor, KN93, originally found to have both direct tumoricidal activity and macrophages-reprogramming ability, for potent immunotherapy against melanoma and hepatoma ascites in mice models. Our MR52 hydrogel has an interweaving nanofiber-like structure, possesses direct antitumor and controlled drug release properties, and promotes the enhanced intracellular uptake of loaded cargo. Compared to free KN93, the MR52-KN93 hydrogel (MRK) improved the killing effects and levels of immunogenic cell death (ICD) on tumor cells significantly. Due to the dual role of KN93, the injection of the MRK hydrogel retarded the growth of subcutaneous melanoma tumors dramatically and resulted in a high number of mature dendritic cells of draining lymph nodes, significantly enhancing the portion of cytotoxic T cells and reduced number of M2-like tumor-associated macrophages (TAMs) in tumors. Using a mouse model of malignant ascites (MAs), where traditional therapy was ineffective, we demonstrated that the MRK hydrogel treatment offered a significantly prolonged survival compared to controls. Following treatment with the MRK hydrogel, macrophages had elevated programmed cell death protein ligand-1 (PD-L1) expression, promising follow-up combined anti-PD-1 therapy that confers a cure rate of approximately 30% against MAs in mice models.

Conclusion: Thus, the MRK hydrogel may serve as a prospective platform for antitumor applications.

Keywords: Hydrogel, cancer immunotherapy, tumor-associated macrophages, anti-PD-1, CAMKII

Citation styles

APA
Dai, X., Meng, J., Deng, S., Zhang, L., Wan, C., Lu, L., Huang, J., Hu, Y., Zhang, Z., Li, Y., Lovell, J.F., Wu, G., Yang, K., Jin, H. (2020). Targeting CAMKII to reprogram tumor-associated macrophages and inhibit tumor cells for cancer immunotherapy with an injectable hybrid peptide hydrogel. Theranostics, 10(7), 3049-3063. https://doi.org/10.7150/thno.42385.

ACS
Dai, X.; Meng, J.; Deng, S.; Zhang, L.; Wan, C.; Lu, L.; Huang, J.; Hu, Y.; Zhang, Z.; Li, Y.; Lovell, J.F.; Wu, G.; Yang, K.; Jin, H. Targeting CAMKII to reprogram tumor-associated macrophages and inhibit tumor cells for cancer immunotherapy with an injectable hybrid peptide hydrogel. Theranostics 2020, 10 (7), 3049-3063. DOI: 10.7150/thno.42385.

NLM
Dai X, Meng J, Deng S, Zhang L, Wan C, Lu L, Huang J, Hu Y, Zhang Z, Li Y, Lovell JF, Wu G, Yang K, Jin H. Targeting CAMKII to reprogram tumor-associated macrophages and inhibit tumor cells for cancer immunotherapy with an injectable hybrid peptide hydrogel. Theranostics 2020; 10(7):3049-3063. doi:10.7150/thno.42385. https://www.thno.org/v10p3049.htm

CSE
Dai X, Meng J, Deng S, Zhang L, Wan C, Lu L, Huang J, Hu Y, Zhang Z, Li Y, Lovell JF, Wu G, Yang K, Jin H. 2020. Targeting CAMKII to reprogram tumor-associated macrophages and inhibit tumor cells for cancer immunotherapy with an injectable hybrid peptide hydrogel. Theranostics. 10(7):3049-3063.

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