Tumor-targeted antibody therapy has had a major impact on reducing morbidity and mortality in a wide range of cancers. Antibodies mediate their anti-tumor activity in part by activating immune effector cells; however, the tumor microenvironment is enriched with cellular and soluble mediators that actively suppress generation of anti-tumor immunity. Here, we investigate the potential of prospectively identifying and neutralizing an immunomodulatory soluble mediator within the tumor microenvironment to enhance therapeutic efficacy of the HER2-directed antibody trastuzumab. Using the D5-HER2 cell line and an immunocompetent human HER2 transgenic animal (hmHER2Tg) in which human HER2 is seen as a self-antigen, we determined that IL-4 was present in the tumor microenvironment and produced by both tumor and stromal cells. A siRNA-based screening approach identified Stat5a as a novel negative regulator of IL-4 production by D5-HER2 tumor cells. Furthermore, IL-4 neutralization using the anti-IL-4 antibody 11B11 enhanced the efficacy of trastuzumab and modulated the tumor microenvironment. For example, IL-4 neutralization resulted in reduced levels of myeloid chemoattractants CCL2, CCL11, and CXCL5 in the tumor microenvironment. Combination therapy with 11B11 and trastuzumab resulted in a reduction of tumor-infiltrating CD11b+CD206+ myeloid cells compared to monotherapy. These data suggest that IL-4 neutralization enhances the efficacy of trastuzumab by influencing the phenotype of myeloid cells within the tumor microenvironment and provides further rationale for combining tumor-targeted antibody therapy with agents that neutralize factors in the tumor microenvironment that suppress generation of productive anti-tumor immune responses.
- Received May 28, 2014.
- Revision received July 28, 2014.
- Accepted August 26, 2014.
- Copyright © 2014, American Association for Cancer Research.