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PlexinB1 Inactivation Reprograms Immune Cells in the Tumor Microenvironment, Inhibiting Breast Cancer Growth and
Giulia Franzolin1,2, Serena Brundu1,2, Carina F Cojocaru1,2
1Laboratory of Tumor Microenvironment, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
Cancer Immunology Research
|June 14, 2024
Summary
Targeting Plexin-B1 (PLXNB1) in the tumor microenvironment significantly reduced breast cancer growth and metastasis. This approach enhanced anti-PD-1 immunotherapy efficacy, suggesting PLXNB1 as a promising therapeutic target for metastatic breast cancer.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Semaphorin-plexin signaling is crucial in the tumor microenvironment (TME).
- Semaphorin 4D (SEMA4D) promotes tumor progression, but its receptor Plexin-B1 (PLXNB1) role in the TME is unclear.
Purpose of the Study:
- To investigate the role of Plexin-B1 (PLXNB1) in triple-negative breast cancer progression.
- To determine if targeting PLXNB1 can enhance anti-cancer immunity and immunotherapy response.
Main Methods:
- Utilized PLXNB1-deficient murine models of triple-negative breast carcinoma.
- Analyzed immune cell infiltration and polarization within the tumor microenvironment.
- Assessed the impact of PLXNB1 deficiency on anti-PD-1 immunotherapy efficacy.
- Evaluated a pharmacological PLXNB1 inhibitor in a preclinical breast cancer model.
Main Results:
- PLXNB1 deficiency significantly reduced primary tumor growth and metastasis, improving survival.
- Loss of PLXNB1 promoted M1 macrophage polarization and increased CD8+ T cell infiltration.
- PLXNB1 inactivation shifted T-cell balance towards Th1 and induced an antitumor gene signature.
- Combined PLXNB1 blockade with anti-PD-1 immunotherapy markedly enhanced antitumor effects.
Conclusions:
- PLXNB1 signaling negatively regulates antitumor immune responses within the TME.
- Inactivating PLXNB1 reprograms the TME to be more permissive to immune attack.
- PLXNB1 represents a promising therapeutic target for enhancing immunotherapy in metastatic breast cancer.
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