Anti-HER2/Neu Antibody Therapy Inhibits HER2+ Breast Cancer by Blocking Myeloid-Derived Suppressor Cell Activity

Background: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population playing a key role in tumor-related immune suppression. MDSCs are immature cells with myeloid markers CD11b and Gr1 in mice and accumulate in tumor-bearing mice, including HER2/neu+ breast cancers. We previously reported that tumor regression by anti-neu antibody requires both innate and adaptive immunity. MDSCs inhibit both immunity types and are immunosuppressive, particularly for T cells. However, the effect of anti-neu antibody on MDSCs remains unclear. Methods: HER2+ TUBO tumor-bearing mice were treated with anti-neu antibody or control. MDSC populations were analyzed via flow cytometry, and immunosuppressive function by suppression assay. Tumors were analyzed using RT2-PCR array and RT-PCR for gene expression related to MDSC activation, migration, and function. Additional mice received combination therapy with 5-FU or Zoledronic acid to assess enhanced MDSC inhibition and changes in MDSC and TAM (tumor-associated macrophage) populations. Results: MDSCs decreased within 3 days after anti-neu antibody treatment in tumor and spleen, with tumor MDSCs declining one day earlier. Monocytic MDSCs were significantly reduced in both tissues (p>0.05). Anti-neu antibody also reduced MDSC immunosuppressive activity. Gene expression analysis showed decreased IL-1β, VEGF, and CX3CL1, linked to MDSC activation and migration. The immunosuppressive factor IDO (Indoleamine 2,3-dioxygenase) was also reduced. Combination therapy with 5-FU further suppressed MDSCs and TAMs, resulting in better tumor suppression than antibody alone. Conclusions: Tumor suppression by anti-neu antibody is associated with MDSC reduction via inhibition of key MDSC-related factors. MDSCs may be a therapeutic target to enhance Herceptin efficacy in breast cancer.