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Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors
Published on: December 16, 2022
A better immune reaction to Erbb-2 tumors is elicited in mice by DNA vaccines encoding rat/human chimeric proteins
Elena Quaglino1, Cristina Mastini, Augusto Amici
1Molecular Biotechnology Center, University of Torino, Torino, Italy.
Abstract:
The Erbb-2 (neu in rat and Her-2 in humans) tyrosine kinase receptor is an oncoantigen (i.e., a tumor-associated molecule directly involved in cancer progression). Because oncoantigens are self-tolerated molecules, to trigger a response circumventing tolerance, we generated two plasmids (RHuT and HuRT) coding for chimeric neu-Her-2 extracellular and transmembrane proteins that are expressed on the cell membrane of the transfected cells and recognized by monoclonal antibodies reacting against neu and Her-2. RHuT encodes a protein in which the 410 NH(2)-terminal residues are from the neu extracellular domain and the remaining residues from Her-2. Almost symmetrically, HuRT encodes for a protein in which the 390 NH(2)-terminal residues are from Her-2 and the remainder from neu. The ability of RHuT and HuRT to elicit a protective response to neu and Her-2 in wild-type mice and in transgenic mice tolerant to neu and Her-2 proteins was compared with that of plasmids coding for the fully rat or fully human extracellular and transmembrane domains of the Erbb-2 receptor. In most cases, RHuT and HuRT elicited a stronger response, although this chimeric benefit is markedly modulated by the location of the heterologous moiety in the protein coded by the plasmid, the immune tolerance of the responding mouse, and the kind of Erbb-2 orthologue on the targeted tumor.
Insights
Chimeric plasmids RHuT and HuRT enhance immune responses against the Erbb-2 (neu/Her-2) oncoantigen. These novel constructs offer a promising strategy for cancer immunotherapy by overcoming self-tolerance to tumor-associated molecules.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- The Erbb-2 (neu/Her-2) receptor is an oncoantigen crucial for cancer progression.
- Self-tolerance to oncoantigens poses a challenge for effective cancer immunotherapy.
- Developing strategies to circumvent immune tolerance is essential for therapeutic success.
Purpose of the Study:
- To generate and evaluate chimeric plasmids (RHuT and HuRT) for eliciting immune responses against Erbb-2.
- To compare the efficacy of chimeric constructs versus fully rat or human Erbb-2 plasmids.
- To investigate factors modulating the immune response to Erbb-2.
Main Methods:
- Construction of two chimeric plasmids, RHuT and HuRT, encoding novel neu-Her-2 fusion proteins.
- Transfection of cells with plasmids expressing chimeric or full-length Erbb-2 extracellular and transmembrane domains.
- Assessment of immune responses in wild-type and tolerant transgenic mice.
Main Results:
- RHuT and HuRT plasmids generally elicited stronger immune responses compared to fully rat or human Erbb-2 constructs.
- The location of chimeric protein domains significantly modulated the elicited immune response.
- Factors such as host immune tolerance and targeted tumor type influenced the chimeric benefit.
Conclusions:
- Chimeric Erbb-2 constructs (RHuT, HuRT) show potential for enhancing anti-tumor immunity.
- The design of chimeric proteins and host immune status are critical for therapeutic efficacy.
- These findings support the development of novel immunotherapies targeting oncoantigens like Erbb-2.
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