Combining TIGIT Blockade with MDSC Inhibition Hinders Breast Cancer Bone Metastasis by Activating Antitumor Immunity

Area of Science:

• Oncology
• Immunology
• Cancer Metastasis

Background:

• Bone metastasis is a frequent and incurable complication of breast cancer, leading to significant patient morbidity.
• The immune microenvironment in bone metastases plays a critical role in disease progression and therapeutic resistance.

Purpose of the Study:

• To investigate the dynamic immune changes during breast cancer bone metastasis using a mouse model.
• To identify key cellular and molecular players driving immunosuppression in the bone metastatic niche.
• To evaluate the therapeutic potential of targeting identified pathways in breast cancer bone metastasis.

Main Methods:

• Utilized an immunocompetent mouse model of spontaneous breast cancer bone metastasis.
• Performed immune transcriptome profiling of bone metastatic lesions and bone marrow at various stages.
• Analyzed immune cell interactions, focusing on granulocytes and T cells.
• Targeted specific signaling pathways (PD-1, TIGIT) and cytokines (IL1β) in vivo.
• Validated findings in human bone metastasis patient samples.

Main Results:

• Revealed dynamic immune transcriptome changes throughout the bone metastatic process.
• Identified significant cross-talk between granulocytes and T cells, creating an immunosuppressive microenvironment.
• Demonstrated that targeting TIGIT and IL1β pathways attenuated bone metastasis and improved survival by reactivating antitumor immunity.
• Confirmed the prominence of TIGIT and IL1β in human bone metastasis samples.

Conclusions:

• The interaction between granulocytes and T cells is crucial in shaping the immunosuppressive bone metastatic microenvironment.
• Cotargeting TIGIT and IL1β represents a promising therapeutic strategy to inhibit breast cancer bone metastasis.
• This approach holds potential for treating human bone metastasis by modulating the immune response.