Targeting the Tumor Microenvironment to Enhance the Efficacy of Tumor-Targeted Antibody Therapy
Year: 2014
Type: dissertation
Abstract: 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. 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.
Author: Rishi Surana
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W647405614