Human Immune System Increases Breast Cancer-Induced Osteoblastic Bone Growth in a Humanized Mouse Model without Affecting Normal Bone.

Tiina E Kähkönen,Michael Seiler,Jussi M Halleen,Jenni H E Mäki-Jouppila,Mari I Suominen,Jenni Bernoulli,Azusa Tanaka

doi:10.1155/2019/4260987

Tiina E Kähkönen, Michael Seiler + Show 5 more

Open Access

https://doi.org/10.1155/2019/4260987

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Abstract

Bone metastases are prevalent in many common cancers such as breast, prostate, and lung cancers, and novel therapies for treating bone metastases are needed. Human immune system-engrafted models are used in immuno-oncology (IO) studies for subcutaneous cancer cell or patient-derived xenograft implantations that mimic primary tumor growth. Novel efficacy models for IO compounds on bone metastases need to be established. The study was performed using CIEA NOG (NOG) mice engrafted with human CD34+ hematopoietic stem cells (huNOG) and age-matched immunodeficient NOG mice. Bone phenotyping was performed to evaluate baseline differences. BT-474 human breast cancer cells were inoculated into the tibia bone marrow, and cancer-induced bone changes were monitored by X-ray imaging. Bone content and volume were analyzed by dual X-ray absorptiometry and microcomputed tomography. Tumor-infiltrating lymphocytes (TILs) and the expression of immune checkpoint markers were analyzed by immunohistochemistry. Bone phenotyping showed no differences in bone architecture or volume of the healthy bones in huNOG and NOG mice, but the bone marrow fat was absent in huNOG mice. Fibrotic areas were observed in the bone marrow of some huNOG mice. BT-474 tumors induced osteoblastic bone growth. Bone lesions appeared earlier and were larger, and bone mineral density was higher in huNOG mice. huNOG mice had a high number of human CD3-, CD4-, and CD8-positive T cells and CD20-positive B cells in immune-related organs. A low number of TILs and PD-1-positive cells and low PD-L1 expression were observed in the BT-474 tumors at the endpoint. This study reports characterization of the first breast cancer bone growth model in huNOG mice. BT-474 tumors represent a “cold” tumor with a low number of TILs. This model can be used for evaluating the efficacy of combination treatments of IO therapies with immune-stimulatory compounds or therapeutic approaches on bone metastatic breast cancer.

Highlights

In many of the most common cancers including breast, prostate, and lung cancers, the majority of metastases are formed at the skeleton [1,2,3,4]
When cancer cells migrate to the bone, they can stay quiescent for decades before the clinically detectable bone metastasis is observed, and the immune system is hypothesized to have a role in this process [5, 8, 9]
Even though the humanized mouse models recapitulate the distribution of human immune cell populations, they still have proportional changes in the immune cell quantities compared to humans [20]

Summary

Introduction

In many of the most common cancers including breast, prostate, and lung cancers, the majority of metastases are formed at the skeleton [1,2,3,4]. These bone metastases are incurable and remarkably decrease the quality of life at end-stage disease [1,2,3,4,5,6]. To overcome the incurable bone metastases, many therapies are under investigation and the most promising approaches come from the field of immuno-oncology (IO) [6, 8].

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