Abstract
BackgroundTherapy targeted to the human epidermal growth factor receptor type 2 (HER2) is used in combination with cytotoxic therapy in treatment of HER2+ breast cancer. Trastuzumab, a monoclonal antibody that targets HER2, has been shown pre-clinically to induce vascular changes that can increase delivery of chemotherapy. To quantify the role of immune modulation in treatment-induced vascular changes, this study identifies temporal changes in myeloid cell infiltration with corresponding vascular alterations in a preclinical model of HER2+ breast cancer following trastuzumab treatment.MethodsHER2+ tumor-bearing mice (N = 46) were treated with trastuzumab or saline. After extraction, half of each tumor was analyzed by immunophenotyping using flow cytometry. The other half was quantified by immunohistochemistry to characterize macrophage infiltration (F4/80), vascularity (CD31 and α-SMA), proliferation (Ki67) and cellularity (H&E). Additional mice (N = 10) were used to quantify differences in tumor cytokines between control and treated groups.ResultsImmunophenotyping showed an increase in macrophage infiltration 24 h after trastuzumab treatment (P ≤ 0.05). With continued trastuzumab treatment, the M1 macrophage population increased (P = 0.02). Increases in vessel maturation index (i.e., the ratio of α-SMA to CD31) positively correlated with increases in tumor infiltrating M1 macrophages (R = 0.33, P = 0.04). Decreases in VEGF-A and increases in inflammatory cytokines (TNF-α, IL-1β, CCL21, CCL7, and CXCL10) were observed with continued trastuzumab treatment (P ≤ 0.05).ConclusionsPreliminary results from this study in a murine model of HER2+ breast cancer show correlations between immune modulation and vascular changes, and reveals the potential for anti-HER2 therapy to reprogram immunosuppressive components of the tumor microenvironment. The quantification of immune modulation in HER2+ breast cancer, as well as the mechanistic insight of vascular alterations after anti-HER2 treatment, represent novel contributions and warrant further assessment for potential clinical translation.
Highlights
Therapy targeted to the human epidermal growth factor receptor type 2 (HER2) is used in combination with cytotoxic therapy in treatment of HER2+ breast cancer
On Day 7, 24 h following a third doses of trastuzumab, the macrophage population increased from 26.54 ± 6.54% in control tumors to 50.05 ± 5.14% in treated tumors (P = 0.03)
M1 macrophage phenotype increases in tumors over the course of trastuzumab treatment Representative flow cytometry data plots of changes in M0 (CD38−/CD206-), M1 (CD38+/CD206-), M2 (CD38 −/CD206+) macrophage subtypes and co-expression (CD38+/CD206+) over the course of trastuzumab treatment are shown in Fig. 3a [39, 40]
Summary
Therapy targeted to the human epidermal growth factor receptor type 2 (HER2) is used in combination with cytotoxic therapy in treatment of HER2+ breast cancer. The current standard-of-care therapy for HER2+ breast cancer is cytotoxic chemotherapy in combination with trastuzumab, a targeted monoclonal antibody that binds to the HER2/neu receptor. Trastuzumab has been shown to alter the characteristics of tumor-associated vessels through increasing vascular maturation and stabilization in HER2+ tumors [7,8,9,10] Such changes can subsequently enhance the efficacy of combination therapies and improve treatment response in multiple types of cancer including breast, colon and lung [7, 11, 12]. With less than half of patients responsive to neoadjuvant therapy in HER2+ breast cancer, further understanding of vascular changes that have potential to enhance therapeutic response may provide a clinically translatable benefit [13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
