Anti-HER2 induced myeloid cell alterations correspond with increasing vascular maturation in a murine model of HER2+ breast cancer.
Animals
Antineoplastic Agents, Immunological
/ pharmacology
Apoptosis
Breast Neoplasms
/ drug therapy
Cell Proliferation
Disease Models, Animal
Female
Humans
Macrophages
/ drug effects
Mice
Mice, Nude
Microvessels
/ drug effects
Myeloid Cells
/ drug effects
Receptor, ErbB-2
/ antagonists & inhibitors
Trastuzumab
/ pharmacology
Tumor Cells, Cultured
Tumor Microenvironment
Xenograft Model Antitumor Assays
Angiogenesis
BT474
Herceptin
Trastuzumab
Tumor associated macrophages
Journal
BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800
Informations de publication
Date de publication:
28 Apr 2020
28 Apr 2020
Historique:
received:
19
12
2019
accepted:
14
04
2020
entrez:
30
4
2020
pubmed:
30
4
2020
medline:
3
2
2021
Statut:
epublish
Résumé
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. 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. HER2+ 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. Immunophenotyping 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). Preliminary 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.
Sections du résumé
BACKGROUND
BACKGROUND
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. 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.
METHODS
METHODS
HER2+ 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.
RESULTS
RESULTS
Immunophenotyping 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).
CONCLUSIONS
CONCLUSIONS
Preliminary 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.
Identifiants
pubmed: 32345237
doi: 10.1186/s12885-020-06868-4
pii: 10.1186/s12885-020-06868-4
pmc: PMC7189470
doi:
Substances chimiques
Antineoplastic Agents, Immunological
0
ERBB2 protein, human
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
Trastuzumab
P188ANX8CK
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
359Subventions
Organisme : NCI NIH HHS
ID : U01CA174706
Pays : United States
Organisme : Cancer Prevention and Research Institute of Texas
ID : RR160005
Organisme : NCI NIH HHS
ID : P30 CA013148
Pays : United States
Organisme : NCI NIH HHS
ID : R01CA186193
Pays : United States
Organisme : NIBIB NIH HHS
ID : T32 EB007507
Pays : United States
Organisme : American Cancer Society
ID : RSG-18-006-01-CCE
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