Regression of Triple-Negative Breast Cancer in a Patient-Derived Xenograft Mouse Model by Monoclonal Antibodies against IL-12 p40 Monomer
Although some therapies are available for regular breast cancers, there are very few options for triple-negative breast cancer (TNBC). Here, we demonstrated that serum level of IL-12p40 monomer (p40) was much higher in breast cancer patients than healthy controls. On the other hand, levels of IL-12,...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-01-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/11/2/259 |
| _version_ | 1797495222306865152 |
|---|---|
| author | Madhuchhanda Kundu Sumita Raha Avik Roy Kalipada Pahan |
| author_facet | Madhuchhanda Kundu Sumita Raha Avik Roy Kalipada Pahan |
| author_sort | Madhuchhanda Kundu |
| collection | DOAJ |
| description | Although some therapies are available for regular breast cancers, there are very few options for triple-negative breast cancer (TNBC). Here, we demonstrated that serum level of IL-12p40 monomer (p40) was much higher in breast cancer patients than healthy controls. On the other hand, levels of IL-12, IL-23 and p40 homodimer (p40<sub>2</sub>) were lower in serum of breast cancer patients as compared to healthy controls. Similarly, human TNBC cells produced greater level of p40 than p40<sub>2</sub>. The level of p40 was also larger than p40<sub>2</sub> in serum of a patient-derived xenograft (PDX) mouse model. Accordingly, neutralization of p40 by p40 mAb induced death of human TNBC cells and tumor shrinkage in PDX mice. While investigating the mechanism, we found that neutralization of p40 led to upregulation of human CD4<sup>+</sup>IFNγ<sup>+</sup> and CD8<sup>+</sup>IFNγ<sup>+</sup> T cell populations, thereby increasing the level of human IFNγ and decreasing the level of human IL-10 in PDX mice. Finally, we demonstrated the infiltration of human cytotoxic T cells, switching of tumor-associated macrophage M2 (TAM2) to TAM1 and suppression of transforming growth factor β (TGFβ) in tumor tissues of p40 mAb-treated PDX mice. Our studies identify a possible new immunotherapy for TNBC in which p40 mAb inhibits tumor growth in PDX mice. |
| first_indexed | 2024-03-10T01:44:44Z |
| format | Article |
| id | doaj.art-eab0ff3641e043b29d68aae169c50993 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T01:44:44Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-eab0ff3641e043b29d68aae169c509932023-11-23T13:18:36ZengMDPI AGCells2073-44092022-01-0111225910.3390/cells11020259Regression of Triple-Negative Breast Cancer in a Patient-Derived Xenograft Mouse Model by Monoclonal Antibodies against IL-12 p40 MonomerMadhuchhanda Kundu0Sumita Raha1Avik Roy2Kalipada Pahan3Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USADepartment of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USADepartment of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USADepartment of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USAAlthough some therapies are available for regular breast cancers, there are very few options for triple-negative breast cancer (TNBC). Here, we demonstrated that serum level of IL-12p40 monomer (p40) was much higher in breast cancer patients than healthy controls. On the other hand, levels of IL-12, IL-23 and p40 homodimer (p40<sub>2</sub>) were lower in serum of breast cancer patients as compared to healthy controls. Similarly, human TNBC cells produced greater level of p40 than p40<sub>2</sub>. The level of p40 was also larger than p40<sub>2</sub> in serum of a patient-derived xenograft (PDX) mouse model. Accordingly, neutralization of p40 by p40 mAb induced death of human TNBC cells and tumor shrinkage in PDX mice. While investigating the mechanism, we found that neutralization of p40 led to upregulation of human CD4<sup>+</sup>IFNγ<sup>+</sup> and CD8<sup>+</sup>IFNγ<sup>+</sup> T cell populations, thereby increasing the level of human IFNγ and decreasing the level of human IL-10 in PDX mice. Finally, we demonstrated the infiltration of human cytotoxic T cells, switching of tumor-associated macrophage M2 (TAM2) to TAM1 and suppression of transforming growth factor β (TGFβ) in tumor tissues of p40 mAb-treated PDX mice. Our studies identify a possible new immunotherapy for TNBC in which p40 mAb inhibits tumor growth in PDX mice.https://www.mdpi.com/2073-4409/11/2/259triple-negative breast cancerpatient-derived xenograft mouse modelimmunotherapyIL-12p40 monomertumor-associated macrophage |
| spellingShingle | Madhuchhanda Kundu Sumita Raha Avik Roy Kalipada Pahan Regression of Triple-Negative Breast Cancer in a Patient-Derived Xenograft Mouse Model by Monoclonal Antibodies against IL-12 p40 Monomer Cells triple-negative breast cancer patient-derived xenograft mouse model immunotherapy IL-12p40 monomer tumor-associated macrophage |
| title | Regression of Triple-Negative Breast Cancer in a Patient-Derived Xenograft Mouse Model by Monoclonal Antibodies against IL-12 p40 Monomer |
| title_full | Regression of Triple-Negative Breast Cancer in a Patient-Derived Xenograft Mouse Model by Monoclonal Antibodies against IL-12 p40 Monomer |
| title_fullStr | Regression of Triple-Negative Breast Cancer in a Patient-Derived Xenograft Mouse Model by Monoclonal Antibodies against IL-12 p40 Monomer |
| title_full_unstemmed | Regression of Triple-Negative Breast Cancer in a Patient-Derived Xenograft Mouse Model by Monoclonal Antibodies against IL-12 p40 Monomer |
| title_short | Regression of Triple-Negative Breast Cancer in a Patient-Derived Xenograft Mouse Model by Monoclonal Antibodies against IL-12 p40 Monomer |
| title_sort | regression of triple negative breast cancer in a patient derived xenograft mouse model by monoclonal antibodies against il 12 p40 monomer |
| topic | triple-negative breast cancer patient-derived xenograft mouse model immunotherapy IL-12p40 monomer tumor-associated macrophage |
| url | https://www.mdpi.com/2073-4409/11/2/259 |
| work_keys_str_mv | AT madhuchhandakundu regressionoftriplenegativebreastcancerinapatientderivedxenograftmousemodelbymonoclonalantibodiesagainstil12p40monomer AT sumitaraha regressionoftriplenegativebreastcancerinapatientderivedxenograftmousemodelbymonoclonalantibodiesagainstil12p40monomer AT avikroy regressionoftriplenegativebreastcancerinapatientderivedxenograftmousemodelbymonoclonalantibodiesagainstil12p40monomer AT kalipadapahan regressionoftriplenegativebreastcancerinapatientderivedxenograftmousemodelbymonoclonalantibodiesagainstil12p40monomer |