Blocking TLR2 activity attenuates pulmonary metastases of tumor
Hong-Zhen Yang1, Bing Cui, Han-Zhi Liu
1Molecular Immunology and Pharmacology Laboratory, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Background:
Metastasis is the most pivotal cause of mortality in cancer patients. Immune tolerance plays a crucial role in tumor progression and metastasis.
Methods And Findings:
In this study, we investigated the potential roles and mechanisms of TLR2 signaling on tumor metastasis in a mouse model of intravenously injected B16 melanoma cells. Multiple subtypes of TLRs were expressed on B16 cells and several human cancer cell lines; TLR2 mediated the invasive activity of these cells. High metastatic B16 cells released more heat shock protein 60 than poor metastatic B16-F1 cells. Importantly, heat shock protein 60 released by tumor cells caused a persistent activation of TLR2 and was critical in the constitutive activation of transcription factor Stat3, leading to the release of immunosuppressive cytokines and chemokines. Moreover, targeting TLR2 markedly reduced pulmonary metastases and increased the survival of B16-bearing mice by reversing B16 cells induced immunosuppressive microenvironment and restoring tumor-killing cells such as CD8(+) T cells and M1 macrophages. Combining an anti-TLR2 antibody and a cytotoxic agent, gemcitabine, provided a further improvement in the survival of tumor-bearing mice.
Conclusions And Significance:
Our results demonstrate that TLR2 is an attractive target against metastasis and that targeting immunosuppressive microenvironment using anti-TLR2 antibody is a novel therapeutic strategy for combating a life-threatening metastasis.
Insights
Targeting Toll-like receptor 2 (TLR2) effectively combats cancer metastasis. Blocking TLR2 reverses immune suppression, enhances anti-tumor immunity, and improves survival in preclinical models.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Cancer metastasis is a primary cause of cancer-related mortality.
- Immune tolerance is a key factor in tumor progression and metastasis.
Purpose of the Study:
- To investigate the role and mechanisms of Toll-like receptor 2 (TLR2) signaling in cancer metastasis.
- To explore TLR2 as a potential therapeutic target against metastasis.
Main Methods:
- Utilized a mouse model with intravenously injected B16 melanoma cells.
- Assessed TLR expression on cancer cells and measured heat shock protein 60 (HSP60) release.
- Investigated the activation of transcription factor Stat3 and cytokine/chemokine release.
- Evaluated the efficacy of targeting TLR2 using an anti-TLR2 antibody, alone and in combination with gemcitabine.
Main Results:
- TLR2 signaling mediated the invasive activity of B16 melanoma cells.
- Tumor-released HSP60 persistently activated TLR2, leading to Stat3 activation and immunosuppressive cytokine release.
- Targeting TLR2 significantly reduced pulmonary metastases and increased survival by restoring anti-tumor immune cells (CD8+ T cells, M1 macrophages).
- Combination therapy with anti-TLR2 antibody and gemcitabine further improved survival.
Conclusions:
- TLR2 is a promising therapeutic target for inhibiting cancer metastasis.
- Targeting the immunosuppressive tumor microenvironment via anti-TLR2 antibody represents a novel strategy against life-threatening metastasis.
More Related Videos
10:32Combined Use of Tail Vein Metastasis Assays and Real-Time In Vivo Imaging to Quantify Breast Cancer Metastatic Colonization and Burden in the Lungs
Published on: December 19, 2019
07:39The Establishment of a Lung Colonization Assay for Circulating Tumor Cell Visualization in Lung Tissues
Published on: June 16, 2018