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...
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| Format: | Article |
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MDPI AG
2022-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/15/8479 |
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| author | Corrine A. Nief Alana Gonzales Erika Chelales Júlia Sroda Agudogo Brian T. Crouch Smita K. Nair Nirmala Ramanujam |
| author_facet | Corrine A. Nief Alana Gonzales Erika Chelales Júlia Sroda Agudogo Brian T. Crouch Smita K. Nair Nirmala Ramanujam |
| author_sort | Corrine A. Nief |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-09T10:08:17Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T10:08:17Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-1cee492a216641638ff1f1200ad3651a2023-12-01T22:57:43ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-07-012315847910.3390/ijms23158479Targeting Tumor Acidosis and Regulatory T Cells Unmasks Anti-Metastatic Potential of Local Tumor Ablation in Triple-Negative Breast CancerCorrine A. Nief0Alana Gonzales1Erika Chelales2Júlia Sroda Agudogo3Brian T. Crouch4Smita K. Nair5Nirmala Ramanujam6Department of Biomedical Engineering, Duke University, Durham, NC 27708, USADepartment of Biomedical Engineering, Duke University, Durham, NC 27708, USADepartment of Biomedical Engineering, Duke University, Durham, NC 27708, USADepartment of Biomedical Engineering, Duke University, Durham, NC 27708, USADepartment of Biomedical Engineering, Duke University, Durham, NC 27708, USADepartment of Surgery, Duke University School of Medicine, Durham, NC 27708, USADepartment of Biomedical Engineering, Duke University, Durham, NC 27708, USATriple-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.https://www.mdpi.com/1422-0067/23/15/8479ablationtumor microenvironmentimmunomodulationbreast cancerlow-resource |
| spellingShingle | Corrine A. Nief Alana Gonzales Erika Chelales Júlia Sroda Agudogo Brian T. Crouch Smita K. Nair Nirmala Ramanujam Targeting Tumor Acidosis and Regulatory T Cells Unmasks Anti-Metastatic Potential of Local Tumor Ablation in Triple-Negative Breast Cancer International Journal of Molecular Sciences ablation tumor microenvironment immunomodulation breast cancer low-resource |
| 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 | ablation tumor microenvironment immunomodulation breast cancer low-resource |
| url | https://www.mdpi.com/1422-0067/23/15/8479 |
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