Journal Article

An immune-humanized patient-derived xenograft model of estrogen-independent, hormone receptor positive metastatic breast cancer

Li, Zheqi, Welm, Alana L., Scherer, Sandra D., Riggio, Alessandra I., Fujita, Maihi, Zhao, Ling, Ekiz, H. Atakan, Toner, Jennifer, Haroun, Fadi, DeRose, Yoko S., Samatar, Ahmed A., Oesterreich, Steffi

2021

Overview

Background Metastatic breast cancer (MBC) is incurable, with a 5-year survival rate of 28%. In the USA, more than 42,000 patients die from MBC every year. The most common type of breast cancer is estrogen receptor-positive (ER+), and more patients die from ER+ breast cancer than from any other subtype. ER+ tumors can be successfully treated with hormone therapy, but many tumors acquire endocrine resistance, at which point treatment options are limited. There is an urgent need for model systems that better represent human ER+ MBC in vivo, where tumors can metastasize. Patient-derived xenografts (PDX) made from MBC spontaneously metastasize, but the immunodeficient host is a caveat, given the known role of the immune system in tumor progression and response to therapy. Thus, we attempted to develop an immune-humanized PDX model of ER+ MBC. Methods NSG-SGM3 mice were immune-humanized with CD34+ hematopoietic stem cells, followed by engraftment of human ER+ endocrine resistant MBC tumor fragments. Strategies for exogenous estrogen supplementation were compared, and immune-humanization in blood, bone marrow, spleen, and tumors was assessed by flow cytometry and tissue immunostaining. Characterization of the new model includes assessment of the human tumor microenvironment performed by immunostaining. Results We describe the development of an immune-humanized PDX model of estrogen-independent endocrine resistant ER+ MBC. Importantly, our model harbors a naturally occurring ESR1 mutation, and immune-humanization recapitulates the lymphocyte-excluded and myeloid-rich tumor microenvironment of human ER+ breast tumors. Conclusion This model sets the stage for development of other clinically relevant models of human breast cancer and should allow future studies on mechanisms of endocrine resistance and tumor-immune interactions in an immune-humanized in vivo setting.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Analysis / Animals / Antigens, CD34 - metabolism / Biomedical and Life Sciences / Biomedicine / Bone marrow / Bone tumors / Breast cancer / Breast Neoplasms - genetics / Breast Neoplasms - immunology / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Cancer Research / Cancer therapies / CD34 antigen / Disease Models, Animal / Drinking water / Drug Resistance, Neoplasm - genetics / Endocrine therapy / ER+ metastatic breast cancer / ER+ PDX / ESR1 mutation / Estrogen / Estrogen Receptor alpha - genetics / Estrogen receptors / Estrogens / Estrogens - administration & dosage / Estrogens - pharmacology / Experiments / Female / Flow cytometry / Gene expression / Hematopoietic Stem Cell Transplantation / Hematopoietic stem cells / Hematopoietic Stem Cells - metabolism / Heterografts - drug effects / Heterografts - metabolism / Heterografts - pathology / Hormone therapy / Hormones / Humanized PDX / Humans / Immune system / Immune-humanization / Immunodeficiency / Immunotherapy / Lymphocytes / Medical prognosis / Metastases / Metastasis / Mice / Mice, Inbred NOD / Mice, SCID / Mice, Transgenic / Mutation / Oncology / Patients / Phenols / Receptors, Estrogen - genetics / Receptors, Estrogen - metabolism / Research Article / Spleen / Stem cell transplantation / Stem cells / Supplements / Surgical Oncology / Tumor microenvironment / Tumor Microenvironment - immunology / Tumors / Xenograft Model Antitumor Assays - methods / Xenografts / Y537S