Targeting MDSC-HTR2B to Improve Immune Checkpoint Inhibitors in Breast to Brain Metastasis

Area of Science:

• Oncology
• Immunology
• Neuroscience

Background:

• Myeloid-derived suppressor cells (MDSCs) are known to promote tumor growth and immune evasion in breast cancer.
• Breast cancer brain metastasis remains a significant clinical challenge with limited understanding of the underlying mechanisms.
• The role of MDSCs within the specific microenvironment of breast-to-brain metastasis is not well-defined.

Purpose of the Study:

• To investigate the contribution of MDSCs to the breast-to-brain metastatic microenvironment.
• To identify molecular mechanisms by which MDSCs promote brain metastasis.
• To explore novel therapeutic strategies targeting MDSC-mediated immune suppression in metastatic breast cancer.

Main Methods:

• Co-culture models simulating a tumor-neuron-immune microenvironment.
• Analysis of patient tissue arrays.
• In vivo murine models of metastatic and intracranial breast tumors.
• Treatment with clozapine (HTR2B antagonist) and anti-PD-1 immunotherapy.

Main Results:

• Identified the serotonergic receptor HTR2B on MDSCs.
• HTR2B signaling upregulates pNF-κB, leading to suppressed T cell proliferation and enhanced tumor growth.
• Combination therapy with clozapine and anti-PD-1 significantly increased survival and T cell infiltration in murine models.

Conclusions:

• MDSC-HTR2B signaling plays a critical role in breast-to-brain metastasis.
• Targeting HTR2B on MDSCs represents a novel therapeutic strategy.
• Repurposing neurological drugs like clozapine offers a potential immediate treatment approach for patients with metastatic breast cancer.