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Inhibition of Gastric Cancer by a New Controlled Releasing Compound of TLR-7/8 Agonist via Immune Activation in a Gastric Cancer Xenograft Mouse Model

Authors
Hyun Myong Kim1, Kyoungyun Jeong1, Jaeun Yoo1, Yie-Ri Yoo1, Ji-Yeon Shin1, Juhee Jeong5, Sandra Ryeom7, Sam Yoon7, Do Joong Park1,2, Hyuk-Joon Lee1,2, Han-Kwang Yang1,2, Do-Youn Oh1,3, Hye Seung Lee1,4, Keehoon Jung5, Yong Taik Lim6, Seong-Ho Kong1,2,*

Affiliations

  1. Cancer Research Institute, Seoul National University, Seoul, Korea
  2. Department of Surgery, Seoul National University Hospital, Seoul, Korea
  3. Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
  4. Departments of Pathology, Seoul National University College of Medicine, Seoul, Korea.
  5. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
  6. SKKU Advanced Institute of Nanotechnology (SAINT), Department of Nano Engineering, Department of Chemical Engineering, Sungkyunkwan University, Suwon, Korea
  7. Department of Surgery, Columbia University Irving Medical Center, New York, USA

Purpose
TLR-7/8 agonist has been suggested to be an effective immunotherapeutic agent, possible systemic side effect has forbidden its clinical usage. A new controlled-releasing compound of TLR-7/8 agonist was developed to overcome the limitations, and this study aimed to evaluate efficacy and safety of this new compound in xenograft mouse model using cell lines derived from triple conditional (Tcon) mouse which develop gastric cancer spontaneously.

Methods
A cell line was established by tumor tissue in Tcon mouse which was developed by activation of Kras and suppression of E-cadherin and P53. Cell line was evaluated its growth rate, drug sensitivity and in vivo tumorigenicity. Cell line was subcutaneously injected to flank of syngeneic mice, and 5-FU and/or TLR-7/8 agonist were administered into 4 groups of mice. 5-FU was administered i.p in once a week and TLR-7/8 agonist was injected i.t 3 times a week. Tumor size and mouse weight were measured for drug efficacy and safety. Immune profile was analyzed by FACS.

Results
Tumors in 5-FU alone group showed slight decrease in size compared with that in control group, However, TLR-7/8 agonist alone and combination significantly inhibited tumor growth. In immune profiling, TLR-7/8 mono or combination group showed increased levels of NK cell as well as significantly increase M1/M2 ratio of macrophages.

Conclusion
A new controlled releasing system of TLR-7/8 agonist with or without 5-FU showed a excellent tumor inhibition with low toxicity in gastric cancer mouse model. The effect seemed to be through multiple immune activations including cell-mediated immune response.A new controlled releasing system of TLR-7/8 agonist with or without 5-FU showed a excellent tumor inhibition with low toxicity in gastric cancer mouse model. The effect seemed to be through multiple immune activations including cell-mediated immune response.