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

INTRODUCTION

Myeloid-derived suppressor cells (MDSCs) constitute a heterogeneous population that plays a key role in tumor-related immune suppression. MDSCs are immature cells that express the myeloid markers CD11b and Gr1 in mice and accumulate in tumor-bearing mice, including those with HER2/neu+ breast cancer. We previously reported that tumor regression by anti-neu antibodies requires both innate and adaptive immunity. MDSCs inhibit both types of immunity and are immunosuppressive, particularly for T cells. However, the effect of anti-neu antibodies on MDSCs remains unclear.

METHODS

HER2+ TUBO tumor-bearing mice were treated with an anti-neu antibody or a control. MDSC populations were analyzed via flow cytometry, and immunosuppressive function was analyzed by a suppression assay. Tumors were analyzed using an 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 tumor-associated macrophage (TAM) populations.

RESULTS

The number of MDSCs decreased within 3 days after anti-neu antibody treatment in the tumor and spleen, with the number of tumor MDSCs declining 1 day earlier. The number of monocytic MDSCs was significantly reduced in both tissues (p > 0.05). Anti-neu antibodies also reduced MDSC immunosuppressive activity. Gene expression analysis revealed decreased levels of IL-1β, VEGF, and CX3CL1, which are linked to MDSC activation and migration. The level of the immunosuppressive factor indoleamine 2,3-dioxygenase was also reduced. Compared with treatment with the antibody alone, combination therapy with 5-FU further suppressed the number of MDSCs and TAMs, resulting in better tumor suppression.

CONCLUSIONS

Tumor suppression by anti-neu antibodies is associated with a reduction in MDSCs via the inhibition of key MDSC-related factors. MDSCs may be therapeutic targets for increasing Herceptin efficacy in patients with breast cancer.