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Targeting Tumor Acidosis and Regulatory T Cells Unmasks Anti-Metastatic Potential of Local Tumor Ablation in Triple-Negative Breast Cancer
Triple-negative breast cancer (TNBC) is an immunologically heterogenous disease that lacks clinically actionable targets and is more likely to progress to metastatic disease than other types of breast cancer. Tumor ablation has been used to increase response rates to checkpoint inhibitors, which rem...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9368760/ https://www.ncbi.nlm.nih.gov/pubmed/35955613 http://dx.doi.org/10.3390/ijms23158479 |
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author | Nief, Corrine A. Gonzales, Alana Chelales, Erika Agudogo, Júlia Sroda Crouch, Brian T. Nair, Smita K. Ramanujam, Nirmala |
author_facet | Nief, Corrine A. Gonzales, Alana Chelales, Erika Agudogo, Júlia Sroda Crouch, Brian T. Nair, Smita K. Ramanujam, Nirmala |
author_sort | Nief, Corrine A. |
collection | PubMed |
description | Triple-negative breast cancer (TNBC) is an immunologically heterogenous disease that lacks clinically actionable targets and is more likely to progress to metastatic disease than other types of breast cancer. Tumor ablation has been used to increase response rates to checkpoint inhibitors, which remain low for TNBC patients. We hypothesized that tumor ablation could produce an anti-tumor response without using checkpoint inhibitors if immunosuppression (i.e., Tregs, tumor acidosis) was subdued. Tumors were primed with sodium bicarbonate (200 mM p.o.) to reduce tumor acidosis and low-dose cyclophosphamide (100–200 mg/kg i.p.) to deplete regulatory T cells, as has been shown independently in previous studies. A novel injectable ablative was then used to necrose the tumor, release tumor antigens, and initiate an immune event that could create an abscopal effect. This combination of bicarbonate, cyclophosphamide, and ablation, called “BiCyclA”, was tested in three syngeneic models of TNBC: E0771 (C57BL/6), 67NR (BALB/c), and 4T1-Luc (BALB/c). In E0771 and 67NR, BiCyclA therapy significantly reduced tumor growth and cured 5/7 and 6/10 mice 50 days after treatment respectively. In the metastatic 4T1-Luc tumors, for which surgery and checkpoint inhibitors fail, BiCyclA cured 5/10 mice of primary tumors and lung metastases. Notably, CD4+ and CD8+ T cells were found to be crucial for the anti-metastatic response, and cured mice were able to resist tumor rechallenge, suggesting production of immune memory. Reduction of tumor acidity and regulatory T cells with ablation is a simple yet effective therapy for local and systemic tumor control with broad applicability as it is not limited by expensive supplies. |
format | Online Article Text |
id | pubmed-9368760 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-93687602022-08-12 Targeting Tumor Acidosis and Regulatory T Cells Unmasks Anti-Metastatic Potential of Local Tumor Ablation in Triple-Negative Breast Cancer Nief, Corrine A. Gonzales, Alana Chelales, Erika Agudogo, Júlia Sroda Crouch, Brian T. Nair, Smita K. Ramanujam, Nirmala Int J Mol Sci Article Triple-negative breast cancer (TNBC) is an immunologically heterogenous disease that lacks clinically actionable targets and is more likely to progress to metastatic disease than other types of breast cancer. Tumor ablation has been used to increase response rates to checkpoint inhibitors, which remain low for TNBC patients. We hypothesized that tumor ablation could produce an anti-tumor response without using checkpoint inhibitors if immunosuppression (i.e., Tregs, tumor acidosis) was subdued. Tumors were primed with sodium bicarbonate (200 mM p.o.) to reduce tumor acidosis and low-dose cyclophosphamide (100–200 mg/kg i.p.) to deplete regulatory T cells, as has been shown independently in previous studies. A novel injectable ablative was then used to necrose the tumor, release tumor antigens, and initiate an immune event that could create an abscopal effect. This combination of bicarbonate, cyclophosphamide, and ablation, called “BiCyclA”, was tested in three syngeneic models of TNBC: E0771 (C57BL/6), 67NR (BALB/c), and 4T1-Luc (BALB/c). In E0771 and 67NR, BiCyclA therapy significantly reduced tumor growth and cured 5/7 and 6/10 mice 50 days after treatment respectively. In the metastatic 4T1-Luc tumors, for which surgery and checkpoint inhibitors fail, BiCyclA cured 5/10 mice of primary tumors and lung metastases. Notably, CD4+ and CD8+ T cells were found to be crucial for the anti-metastatic response, and cured mice were able to resist tumor rechallenge, suggesting production of immune memory. Reduction of tumor acidity and regulatory T cells with ablation is a simple yet effective therapy for local and systemic tumor control with broad applicability as it is not limited by expensive supplies. MDPI 2022-07-30 /pmc/articles/PMC9368760/ /pubmed/35955613 http://dx.doi.org/10.3390/ijms23158479 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Nief, Corrine A. Gonzales, Alana Chelales, Erika Agudogo, Júlia Sroda Crouch, Brian T. Nair, Smita K. Ramanujam, Nirmala Targeting Tumor Acidosis and Regulatory T Cells Unmasks Anti-Metastatic Potential of Local Tumor Ablation in Triple-Negative Breast Cancer |
title | Targeting Tumor Acidosis and Regulatory T Cells Unmasks Anti-Metastatic Potential of Local Tumor Ablation in Triple-Negative Breast Cancer |
title_full | Targeting Tumor Acidosis and Regulatory T Cells Unmasks Anti-Metastatic Potential of Local Tumor Ablation in Triple-Negative Breast Cancer |
title_fullStr | Targeting Tumor Acidosis and Regulatory T Cells Unmasks Anti-Metastatic Potential of Local Tumor Ablation in Triple-Negative Breast Cancer |
title_full_unstemmed | Targeting Tumor Acidosis and Regulatory T Cells Unmasks Anti-Metastatic Potential of Local Tumor Ablation in Triple-Negative Breast Cancer |
title_short | Targeting Tumor Acidosis and Regulatory T Cells Unmasks Anti-Metastatic Potential of Local Tumor Ablation in Triple-Negative Breast Cancer |
title_sort | targeting tumor acidosis and regulatory t cells unmasks anti-metastatic potential of local tumor ablation in triple-negative breast cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9368760/ https://www.ncbi.nlm.nih.gov/pubmed/35955613 http://dx.doi.org/10.3390/ijms23158479 |
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