ADAM12 abrogation alters immune cell infiltration and improves response to checkpoint blockade therapy in the T11 murine model of triple-negative breast cancer

• Published in: Oncoimmunology Vol. 12; no. 1; p. 2158006
• Main Authors: Wang, Guanpeng, Romero, Yeni, Thevarajan, Indhujah, Zolkiewska, Anna
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 31.12.2023; Taylor & Francis Group
• Subjects: ADAM; ADAM12 Protein - genetics; Animals; B cells; Cell Line, Tumor; checkpoint inhibition; Claudins - metabolism; CXCL12; Disease Models, Animal; mesenchymal tumors; Mice; mouse models; Original Research; T-Lymphocytes; Triple negative breast cancer; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Tumor Microenvironment; tumor-infiltrating immune cells; mouse models; ADAM; CXCL12; checkpoint inhibition; mesenchymal tumors; tumor-infiltrating immune cells; B cells; tumor microenvironment; Triple negative breast cancer
• ISSN: 2162-402X; 2162-4011; 2162-402X
• DOI: 10.1080/2162402X.2022.2158006

Immunosuppressive 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.