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A Chemoimmunotherapy Nanogel Enables Efficient Delivery of Interleukin-2 and Induction of Immunogenic Cell Death for Effective Cancer Therapy |
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| Authors: | Hsuan-Yu Mu Yen-Nhi Ngoc Ta Max Jing Rui Tham Fu-Fei Hsu Yu-Chieh Lin Hsi-Chien Huang Yun-Chieh Sung Chih-I Huang Ching-Ling Wu Chao-Hung Chang Sheng Yang Tsung-Ying Lee Dehui Wan Jane Wang Dan G Duda Yves Boucher Jen-Huang Huang Wee Han Ang Yunching Chen |
| Affiliation: | 1. Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, 30013 Taiwan
Department of Chemical Engineering, National Tsing Hua University, Hsinchu, 30013 Taiwan;2. Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, 30013 Taiwan International Intercollegiate Ph.D. Program, National Tsing Hua University, Hsinchu, 30013 Taiwan;3. Department of Chemistry, National University of Singapore, Singapore, 117544 Singapore NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, 119077 Singapore;4. Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529 Taiwan;5. Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, 30013 Taiwan;6. Department of Chemical Engineering, National Tsing Hua University, Hsinchu, 30013 Taiwan;7. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114 USA;8. Department of Chemistry, National University of Singapore, Singapore, 117544 Singapore |
| Abstract: | Interleukin-2 (IL-2) is one of the first FDA-approved immunotherapeutics, but its use is limited by toxicity and low efficacy. In addition, all immunotherapies are limited by the immunosuppressive and desmoplastic microenvironment of “immunologically cold” tumors, such as pancreatic ductal adenocarcinoma (PDAC) or hepatocellular carcinoma (HCC) with advanced liver fibrosis. Here, a new chemoimmunotherapy nanogel (IL2-Pt@Nanogel) for dual delivery of IL-2 and the type II immunogenic cell death inducer Pt-NHC that reduces the immunosuppressive phenotype of tumor-associated macrophages and diminishes regulatory T cell infiltration by inducing the production of type I interferon (IFN) by cancer cells is reported. Combining the angiotensin II receptor blocker losartan with IL2-Pt@Nanogel treatment reduces desmoplasia and reprogrammes the microenvironment of PDAC and HCC toward an immunostimulatory one. These effects result in potent anti-tumor efficacy in models of primary and metastatic PDAC and HCC with underlying liver fibrosis. This study presents a strategy for IL-2-based chemoimmunotherapy with the potential for clinical translation to treat solid tumors. |
| Keywords: | HCC immunogenic cell death interleukin-2 losartan PDAC silk fibroin |