Antiangiogenesis immunotherapy induces epitope spreading to Her-2/neu resulting in breast tumor immunoediting

Area of Science:

• Immunology
• Oncology
• Vaccine Development

Background:

• Cancer vaccine therapeutics offer advantages over chemotherapy but face challenges like antigen loss and immunoediting.
• Targeting tumor antigens directly can lead to tumor escape through mutations within T cell epitopes.
• An alternative strategy involves targeting normal cell types essential for tumor survival.

Purpose of the Study:

• To investigate an anti-angiogenesis Listeria monocytogenes (Lm)-based vaccine targeting vascular endothelial growth factor receptor-2 (VEGFR-2/Flk-1).
• To evaluate the vaccine's efficacy in an autochthonous Her-2/neu(+) breast cancer mouse model.
• To explore the mechanisms of epitope spreading and immunoediting in response to immunotherapy.

Main Methods:

• Utilized a Listeria monocytogenes (Lm)-based vector delivering VEGFR-2/Flk-1 fragments (Lm-LLO-Flk-E1 and Lm-LLO-Flk-11).
• Employed an autochthonous mouse model for Her-2/neu(+) breast cancer.
• Analyzed tumor mutations and T cell epitope regions to understand immunoediting.

Main Results:

• Vaccination induced epitope spreading to the endogenous Her-2/neu tumor antigen.
• Significant delay in tumor onset was observed following vaccination.
• Tumors that regrew exhibited mutations in Her-2/neu within or near cytotoxic T lymphocyte epitopes.

Conclusions:

• Anti-angiogenesis immunotherapy can delay spontaneous tumor onset through epitope spreading.
• Tumor escape can occur via immunoediting of endogenous tumor proteins, leading to outgrowth.
• Understanding these mechanisms is crucial for developing more effective cancer immunotherapies.