TLR Agonist Therapy of Metastatic Breast Cancer in Mice
Dennis M Klinman1, Emilie Goguet, Debra Tross
1National Cancer Institute, Frederick, MD.
Abstract:
Toll-like receptor (TLR) 7/8 and 9 agonists stimulate an innate immune response that supports the development of tumor-specific immunity. Previous studies showed that either agonist individually could cure mice of small tumors and that when used in combination, they could prevent the progression of larger tumors (>300 mm 3 ). To examine whether these agents combined could control metastatic disease, syngeneic mice were challenged with the highly aggressive 66cl4 triple-negative breast tumor cell line. Treatment was not initiated until pulmonary metastases were established, as verified by bioluminescent imaging of luciferase-tagged tumor cells. Results show that combined therapy with TLR7/8 and TLR9 agonists delivered to both primary and metastatic tumor sites significantly reduced tumor burden and extended survival. The inclusion of cyclophosphamide and anti-PD-L1 resulted in optimal tumor control, characterized by a 5-fold increase in the average duration of survival.
Insights
Combined Toll-like receptor (TLR) 7/8 and TLR9 agonists effectively reduced metastatic breast cancer burden in mice. This immunotherapy, with additional agents, significantly extended survival by enhancing anti-tumor immunity.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Toll-like receptor (TLR) agonists stimulate innate immunity, crucial for anti-tumor responses.
- Previous research demonstrated TLR7/8 and TLR9 agonists' efficacy against small and large tumors, respectively.
- The potential of combined TLR agonists in controlling metastatic disease remained unexplored.
Purpose of the Study:
- To investigate the efficacy of combined TLR7/8 and TLR9 agonists in controlling metastatic triple-negative breast cancer.
- To evaluate the impact of this combination therapy on tumor burden and survival in a syngeneic mouse model.
Main Methods:
- Syngeneic mice were implanted with luciferase-tagged 66cl4 triple-negative breast cancer cells.
- Pulmonary metastases were established before initiating treatment.
- Therapies included combined TLR7/8 and TLR9 agonists, cyclophosphamide, and anti-PD-L1, delivered to primary and metastatic sites.
Main Results:
- Combined TLR7/8 and TLR9 agonist therapy significantly reduced tumor burden in mice with established pulmonary metastases.
- The combination therapy notably extended survival compared to control groups.
- Optimal tumor control and a 5-fold increase in average survival duration were achieved with the addition of cyclophosphamide and anti-PD-L1.
Conclusions:
- Combined TLR7/8 and TLR9 agonists represent a promising strategy for managing metastatic breast cancer.
- The addition of cyclophosphamide and anti-PD-L1 enhances the therapeutic efficacy of TLR agonists, leading to superior tumor control.
- This immunotherapy approach holds potential for improving outcomes in patients with advanced triple-negative breast cancer.
