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Overcoming Drug Resistance by Paclitaxel Resistance in Triple-Negative Breast Cancer
Bo Chen1,2, Yangyi Wang1,2, Tingting Li3
1Department of General Surgery, Department of Medical Oncology, Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Abstract:
Drug resistance in solid tumors has emerged as a critical challenge, with limited effective therapeutic options available. In this study, we find that chemotherapy induces an increased tumor neoantigens burden (TNB) in breast cancer patients and both non-resistant and chemo-resistant triple-negative breast cancer 4T1 tumor-bearing mice. Consistently, proteomic analysis reveals that tumor antigens derived from in vitro chemotherapy-treated paclitaxel (PTX)-resistant 4T1 cells (chemo-rAg) are enriched in damage-associated molecular patterns and neoantigens, highlighting their potential to elicit antitumor immunity against chemo-resistant tumors. Based on these findings, we utilize the feature of PTX resistance and develop a nanovaccine incorporating chemo-rAg and a prodrug of a toll-like receptor 7 (TLR7) agonist. In preclinical mouse models, the nanovaccine effectively suppresses PTX-resistant 4T1 tumor growth, and it also reverses the innate resistance of immune checkpoint inhibitors. Notably, the therapeutic benefit of the nanovaccine is augmented by chemotherapy, which facilitates in situ release of tumor antigens. These results suggest that a chemo-rAg-based nanovaccine represents a promising strategy based on the 'like cures like' principle to overcome drug resistance by utilizing the characteristic of the drug resistance itself.
Insights
Chemotherapy increases tumor neoantigen burden, enhancing immune response. A novel nanovaccine using chemotherapy-resistant tumor antigens shows promise in overcoming drug resistance and boosting antitumor immunity.
Area of Science:
- Oncology
- Immunology
- Nanotechnology
Background:
- Drug resistance in solid tumors presents a significant therapeutic challenge.
- Limited effective treatment options exist for drug-resistant cancers.
Purpose of the Study:
- To investigate chemotherapy's effect on tumor neoantigen burden.
- To develop and evaluate a novel nanovaccine strategy to overcome chemotherapy resistance.
Main Methods:
- Analysis of tumor neoantigen burden in breast cancer patients and mouse models.
- Proteomic analysis of chemotherapy-resistant tumor antigens.
- Development of a nanovaccine incorporating chemotherapy-resistant antigens and a TLR7 agonist.
- Preclinical evaluation in mouse models of triple-negative breast cancer.
Main Results:
- Chemotherapy was found to increase tumor neoantigen burden.
- Chemotherapy-resistant tumor antigens were enriched in damage-associated molecular patterns and neoantigens.
- The developed nanovaccine suppressed paclitaxel-resistant tumor growth and reversed resistance to immune checkpoint inhibitors.
- Chemotherapy augmented the nanovaccine's therapeutic benefit by facilitating in situ antigen release.
Conclusions:
- Chemotherapy-induced neoantigens can be leveraged for therapeutic benefit.
- A nanovaccine based on chemotherapy-resistant antigens shows potential for overcoming drug resistance.
- This strategy offers a promising 'like cures like' approach to combat chemo-resistant tumors.
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