Combinational delivery of TLR4 and TLR7/8 agonist enhanced the therapeutic efficacy of immune checkpoint inhibitors to colon tumor

Author:

Wang, Mengjiao

Wan, Quan

Wang, Chenglv

Jing, Qianyu

Nie, Yujie

Zhang, Xiangyan

Chen, Xin

Yang,De

Pan, Runsang

Li, Linzhao

Zhu, Lan

Gui, Huan

Chen, Shuanghui

Deng, Yuezhen

Chen, Tao

Nie, Yingjie
Author Address

GuiZhou University Medical College, Guiyang, 550025, China., School of Preclinical Medicine of Zunyi Medical University, Zunyi, 563000, China., NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People 39;s Hospital, Guiyang, 550002, China., State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, 999078, SAR, China., Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute at Frederick, NIH, Frederick, MD, USA., Department of Pathophysiology, School of Basic Medicine, Guizhou Medical University, Guiyang, 550025, China., Department of Thoracic Surgery, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China., State Key Laboratory of Respiratory Disease at People 39;s Hospital of Yangjiang, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China. taochen@gird.cn., Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China. nienyj@hotmail.com.,

Abstract:

Immunotherapy is regarded as a potent cancer treatment, with DC vaccines playing a crucial role. Although clinical trials have demonstrated the safety and efficacy of DC vaccines, loading antigens in vitro is challenging, and their therapeutic effects remain unpredictable. Moreover, the diverse subtypes and maturity states of DCs in the body could induce both immune responses and immune tolerance, potentially affecting the vaccine's efficacy. Hence, the optimization of DC vaccines remains imperative. Our study discovered a new therapeutic strategy by using CT26 and MC38 mouse colon cancer models, as well as LLC mouse lung cancer models. The strategy involved the synergistic activation of DCs through intertumoral administration of TLR4 agonist high-mobility group nucleosome binding protein 1 (HMGN1) and TLR7/8 agonist (R848/resiquimod), combined with intraperitoneal administration of TNFR2 immunosuppressant antibody. The experimental results indicated that the combined use of HMGN1, R848, and a-TNFR2 had no effect on LLC cold tumors. However, it was effective in eradicating CT26 and MC38 colon cancer and inducing long-term immune memory. The combination of these three drugs altered the TME and promoted an increase in anti-tumor immune components. This may provide a promising new treatment strategy for colon cancer. © 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

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