ADAM12 abrogation alters immune cell infiltration and improves response to checkpoint blockade therapy in the T11 murine model of triple-negative breast cancer
ABSTRACTImmunosuppressive tumor microenvironment (TME) impedes anti-tumor immune responses and contributes to immunotherapy resistance in triple-negative breast cancer (TNBC). ADAM12, a member of cell surface metalloproteases, is selectively upregulated in mesenchymal/claudin-low TNBCs, where its ex...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2023-12-01
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| Series: | OncoImmunology |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/2162402X.2022.2158006 |
| _version_ | 1797367114059743232 |
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| author | Guanpeng Wang Yeni Romero Indhujah Thevarajan Anna Zolkiewska |
| author_facet | Guanpeng Wang Yeni Romero Indhujah Thevarajan Anna Zolkiewska |
| author_sort | Guanpeng Wang |
| collection | DOAJ |
| description | ABSTRACTImmunosuppressive tumor microenvironment (TME) impedes anti-tumor immune responses and contributes to immunotherapy resistance in triple-negative breast cancer (TNBC). ADAM12, a member of cell surface metalloproteases, is selectively upregulated in mesenchymal/claudin-low TNBCs, where its expression is largely restricted to tumor cells. The role of cancer cell-expressed ADAM12 in modulating the immune TME is not known. We show that Adam12 knockout in the T11 mouse syngeneic transplantation model of claudin-low TNBC leads to decreased numbers of tumor-infiltrating neutrophils (TINs)/polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and increased numbers of tumor-infiltrating B cells and T cells. ADAM12 loss in cancer cells increases chemotaxis of B cells in vitro and this effect is eliminated by inhibition of CXCR4, a receptor for CXCL12, or anti-CXCL12 blocking antibody. Importantly, ADAM12 loss in T11 cancer cells sensitizes tumors to anti-PD1/anti-CTLA4 combination therapy, although the initial responsiveness is followed by acquired therapy resistance. Depletion of B cells in mice eliminates the improved response to immune checkpoint blockade of Adam12 knockout T11 tumors. Analysis of gene expression data for claudin-low TNBCs from the METABRIC patient cohort shows significant inverse correlations between ADAM12 and gene expression signatures of several anti-tumor immune cell populations, as well as a significant positive correlation between ADAM12 and gene expression signature of TINs/PMN-MDSCs. Collectively, these results implicate ADAM12 in immunosuppression within the TME in TNBC. |
| first_indexed | 2024-03-08T17:12:43Z |
| format | Article |
| id | doaj.art-4c09d7d8624c4835b3b7ae521096b86f |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-03-08T17:12:43Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-4c09d7d8624c4835b3b7ae521096b86f2024-01-03T19:25:36ZengTaylor & Francis GroupOncoImmunology2162-402X2023-12-0112110.1080/2162402X.2022.2158006ADAM12 abrogation alters immune cell infiltration and improves response to checkpoint blockade therapy in the T11 murine model of triple-negative breast cancerGuanpeng Wang0Yeni Romero1Indhujah Thevarajan2Anna Zolkiewska3Department of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, KS, USADepartment of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, KS, USADepartment of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, KS, USADepartment of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, KS, USAABSTRACTImmunosuppressive tumor microenvironment (TME) impedes anti-tumor immune responses and contributes to immunotherapy resistance in triple-negative breast cancer (TNBC). ADAM12, a member of cell surface metalloproteases, is selectively upregulated in mesenchymal/claudin-low TNBCs, where its expression is largely restricted to tumor cells. The role of cancer cell-expressed ADAM12 in modulating the immune TME is not known. We show that Adam12 knockout in the T11 mouse syngeneic transplantation model of claudin-low TNBC leads to decreased numbers of tumor-infiltrating neutrophils (TINs)/polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and increased numbers of tumor-infiltrating B cells and T cells. ADAM12 loss in cancer cells increases chemotaxis of B cells in vitro and this effect is eliminated by inhibition of CXCR4, a receptor for CXCL12, or anti-CXCL12 blocking antibody. Importantly, ADAM12 loss in T11 cancer cells sensitizes tumors to anti-PD1/anti-CTLA4 combination therapy, although the initial responsiveness is followed by acquired therapy resistance. Depletion of B cells in mice eliminates the improved response to immune checkpoint blockade of Adam12 knockout T11 tumors. Analysis of gene expression data for claudin-low TNBCs from the METABRIC patient cohort shows significant inverse correlations between ADAM12 and gene expression signatures of several anti-tumor immune cell populations, as well as a significant positive correlation between ADAM12 and gene expression signature of TINs/PMN-MDSCs. Collectively, these results implicate ADAM12 in immunosuppression within the TME in TNBC.https://www.tandfonline.com/doi/10.1080/2162402X.2022.2158006Triple negative breast cancermouse modelsADAMcheckpoint inhibitiontumor-infiltrating immune cellstumor microenvironment |
| spellingShingle | Guanpeng Wang Yeni Romero Indhujah Thevarajan Anna Zolkiewska ADAM12 abrogation alters immune cell infiltration and improves response to checkpoint blockade therapy in the T11 murine model of triple-negative breast cancer OncoImmunology Triple negative breast cancer mouse models ADAM checkpoint inhibition tumor-infiltrating immune cells tumor microenvironment |
| title | ADAM12 abrogation alters immune cell infiltration and improves response to checkpoint blockade therapy in the T11 murine model of triple-negative breast cancer |
| title_full | ADAM12 abrogation alters immune cell infiltration and improves response to checkpoint blockade therapy in the T11 murine model of triple-negative breast cancer |
| title_fullStr | ADAM12 abrogation alters immune cell infiltration and improves response to checkpoint blockade therapy in the T11 murine model of triple-negative breast cancer |
| title_full_unstemmed | ADAM12 abrogation alters immune cell infiltration and improves response to checkpoint blockade therapy in the T11 murine model of triple-negative breast cancer |
| title_short | ADAM12 abrogation alters immune cell infiltration and improves response to checkpoint blockade therapy in the T11 murine model of triple-negative breast cancer |
| title_sort | adam12 abrogation alters immune cell infiltration and improves response to checkpoint blockade therapy in the t11 murine model of triple negative breast cancer |
| topic | Triple negative breast cancer mouse models ADAM checkpoint inhibition tumor-infiltrating immune cells tumor microenvironment |
| url | https://www.tandfonline.com/doi/10.1080/2162402X.2022.2158006 |
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