Combination of thermally ablative focused ultrasound with gemcitabine controls breast cancer via adaptive immunity
- PMID: 32819975
- PMCID: PMC7443308
- DOI: 10.1136/jitc-2020-001008
Combination of thermally ablative focused ultrasound with gemcitabine controls breast cancer via adaptive immunity
Abstract
Background: Triple-negative breast cancer (TNBC) remains recalcitrant to most targeted therapy approaches. However, recent clinical studies suggest that inducing tumor damage can render TNBC responsive to immunotherapy. We therefore tested a strategy for immune sensitization of murine TNBC (4T1 tumors) through combination of focused ultrasound (FUS) thermal ablation and a chemotherapy, gemcitabine (GEM), known to attenuate myeloid-derived suppressor cells (MDSCs).
Methods: We applied a sparse-scan thermally ablative FUS regimen at the tumor site in combination with systemically administered GEM. We used flow cytometry analysis to investigate the roles of monotherapy and combinatorial therapy in mediating local and systemic immunity. We also tested this combination in Rag1-/- mice or T cell-depleted wild-type mice to determine the essentiality of adaptive immunity. Further, we layered Programmed cell death protein 1 (PD-1) blockade onto this combination to evaluate its impact on tumor outgrowth and survival.
Results: The immune-modulatory effect of FUS monotherapy was insufficient to promote a robust T cell response against 4T1, consistent with the dominant MDSC-driven immunosuppression evident in this model. The combination of FUS+GEM significantly constrained primary TNBC tumor outgrowth and extended overall survival of mice. Tumor control correlated with increased circulating antigen-experienced T cells and was entirely dependent on T cell-mediated immunity. The ability of FUS+GEM to control primary tumor outgrowth was moderately enhanced by either neoadjuvant or adjuvant treatment with anti-PD-1.
Conclusion: Thermally ablative FUS in combination with GEM restricts primary tumor outgrowth, improves survival and enhances immunogenicity in a murine metastatic TNBC model. This treatment strategy promises a novel option for potentiating the role of FUS in immunotherapy of metastatic TNBC and is worthy of future clinical evaluation.
Trial registration numbers: NCT03237572 and NCT04116320.
Keywords: adaptive immunity; breast neoplasms; combined modality therapy; immunotherapy.
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Conflict of interest statement
Competing interests: None declared.
Figures
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7443308/bin/jitc-2020-001008f01.gif)
![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7443308/bin/jitc-2020-001008f02.gif)
![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7443308/bin/jitc-2020-001008f03.gif)
![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7443308/bin/jitc-2020-001008f04.gif)
![Figure 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7443308/bin/jitc-2020-001008f05.gif)
![Figure 6](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7443308/bin/jitc-2020-001008f06.gif)
Similar articles
-
A triple combination gemcitabine + romidepsin + cisplatin to effectively control triple-negative breast cancer tumor development, recurrence, and metastasis.Cancer Chemother Pharmacol. 2021 Sep;88(3):415-425. doi: 10.1007/s00280-021-04298-y. Epub 2021 May 27. Cancer Chemother Pharmacol. 2021. PMID: 34043046 Free PMC article.
-
Ganoderic acid D attenuates gemcitabine resistance of triple-negative breast cancer cells by inhibiting glycolysis via HIF-1α destabilization.Phytomedicine. 2024 Jul;129:155675. doi: 10.1016/j.phymed.2024.155675. Epub 2024 Apr 23. Phytomedicine. 2024. PMID: 38678954
-
Multifunctional Theranostic Nanoparticles for Enhanced Tumor Targeted Imaging and Synergistic FUS/Chemotherapy on Murine 4T1 Breast Cancer Cell.Int J Nanomedicine. 2022 May 13;17:2165-2187. doi: 10.2147/IJN.S360161. eCollection 2022. Int J Nanomedicine. 2022. PMID: 35592098 Free PMC article.
-
Rational combination of immunotherapy for triple negative breast cancer treatment.Chin Clin Oncol. 2017 Oct;6(5):54. doi: 10.21037/cco.2017.08.04. Chin Clin Oncol. 2017. PMID: 29129094 Review.
-
Biomarkers of Immune Checkpoint Blockade Response in Triple-Negative Breast Cancer.Curr Treat Options Oncol. 2021 Mar 20;22(5):38. doi: 10.1007/s11864-021-00833-4. Curr Treat Options Oncol. 2021. PMID: 33743085 Review.
Cited by
-
Fundamentals and Applications of Focused Ultrasound-Assisted Cancer Immune Checkpoint Inhibition for Solid Tumors.Pharmaceutics. 2024 Mar 16;16(3):411. doi: 10.3390/pharmaceutics16030411. Pharmaceutics. 2024. PMID: 38543305 Free PMC article. Review.
-
Nanomaterials augmented bioeffects of ultrasound in cancer immunotherapy.Mater Today Bio. 2023 Dec 22;24:100926. doi: 10.1016/j.mtbio.2023.100926. eCollection 2024 Feb. Mater Today Bio. 2023. PMID: 38179429 Free PMC article. Review.
-
Guidelines for immunological analyses following focused ultrasound treatment.J Immunother Cancer. 2023 Nov 24;11(11):e007455. doi: 10.1136/jitc-2023-007455. J Immunother Cancer. 2023. PMID: 38007236 Free PMC article.
-
Therapeutic ultrasound-enhanced immune checkpoint inhibitor therapy.Front Phys. 2021 Mar;9:636985. doi: 10.3389/fphy.2021.636985. Epub 2021 Mar 24. Front Phys. 2021. PMID: 37994329 Free PMC article.
-
T-lymphocytes from focused ultrasound ablation subsequently mediate cellular antitumor immunity after adoptive cell transfer immunotherapy.Front Immunol. 2023 Jul 26;14:1155229. doi: 10.3389/fimmu.2023.1155229. eCollection 2023. Front Immunol. 2023. PMID: 37564660 Free PMC article.
References
-
- Miyashita M, Sasano H, Tamaki K, et al. . Prognostic significance of tumor-infiltrating CD8+ and Foxp3+ lymphocytes in residual tumors and alterations in these parameters after neoadjuvant chemotherapy in triple-negative breast cancer: a retrospective multicenter study. Breast Cancer Res 2015;17:124. 10.1186/s13058-015-0632-x - DOI - PMC - PubMed
Publication types
MeSH terms
Substances
Associated data
Grants and funding
LinkOut - more resources
Full Text Sources
Medical
Research Materials