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June 23, 2021 | OncoBone article

Osteoimmuno-oncology, a novel concept describing interactions in bone metastasis to guide development of novel therapies

OncoBone contributed to an invited review article to the special issue ‘Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities’ in the Journal ‘Cells’, published on June 17, 2021. The review article titled ‘Osteoimmuno-Oncology: Therapeutic Opportunities for Targeting Immune Cells in Bone Metastasis‘ describes the novel concept of osteoimmuno-oncology (OIO) for the first time. OIO highlights the important interactions between bone, immune and tumor cells in cancer bone metastasis. The concept can be utilized as a basis for guiding development of novel immunotherapies for the currently incurable bone metastases.

It is well established that immunotherapies provide a potential treatment option for currently incurable bone metastases. What is not commonly taken into consideration is that bone marrow is an important secondary lymphoid organ with a unique immune contexture. Even at non-disease state immune cells and bone cells interact with each other, bone cells supporting the development of immune cells and immune cells regulating bone turnover. This homeostatic process is disrupted in cancer when tumor cells enter the bone marrow and grow into secondary tumors.

In this review, the novel OIO concept is introduced. OIO refers to interactions between bone, immune and tumor cells in bone metastatic microenvironment. Understanding the interplay between these three separate, but tightly linked compartments is essential when developing novel therapies for bone metastases. Below is a summary of the key points addressed in the review.

Bone metastases are common and cause high mortality in many cancers including some of the most common cancers such as breast, prostate and lung cancer. One compelling approach for providing effective prevention and treatment options for bone metastasis are immunotherapies. It needs to be understood that the metastatic tumor microenvironment is more than tumor and immune cells, and the cells within the metastatic microenvironment greatly affect the growth of metastasis. OIO is based on two well established concepts: osteoimmunology and immuno-oncology that are now combined in OIO to understanding the interactions in cancer bone metastasis. Next, we briefly describe the three concepts separately in chronological order when we consider formation and growth of bone metastases.

Osteoimmunology: Homeostatic regulation of bone turnover

Bone marrow is an important secondary immune organ where immune cells have multiple interactions with bone marrow stromal cells, and they regulate each others function and activity. To highlight this further, at healthy stage about 25% of bone marrow immune cells are myeloid cells, about 10% are lymphocytes, and about 5% are dendritic cells, antigen-producing plasma cells and natural killer cells. Osteoimmunology is an interdisciplinary research field focusing to understand the interactions between the immune and skeletal system at healthy and disease stages.

Multipotent mesenchymal stem cells (MSCs) in the bone marrow can differentiate into bone-forming osteoblasts that later differentiate into osteocytes. The primary function of the osteoblast is to secrete mineralized extracellular matrix, but it has also an important function in regulating hematopoietic stem cell (HSC) niches. Osteoblast interactions with HSCs are important because HSCs differentiate into bone-resorbing osteoclasts. Osteoblasts and osteoclasts are responsible for the regulation of homeostatic balance between bone formation and resorption. Importantly, HSCs are also progenitors of all immune cells. Signals coming from mature osteoblasts are important for lymphoid progenitor cells and generation of mature T and B cells. Furthermore, osteocytes are important for the maintenance of myeloid cells in the bone marrow. As mentioned previously, immune cells regulate the function of bone cells. As examples of this, T cells regulate bone turnover by promoting osteoclastogenesis and bone loss, and B cells regulate development of osteoblasts and osteoclasts and contribute to homeostatic regulation of bone turnover.

This homeostatic regulation is disrupted in bone metastasis, which is shortly described in the next paragraph.

Cancer-induced bone disease: Vicious cycle of bone metastasis

The formation of metastases in a process called metastatic cascade is well established. However, it is often neglected what happens in the microenvironment where the metastases are formed. Cancer cells have a self-promoting effect in bone, which is called the vicious cycle of bone metastasis. In the vicious cycle, tumor cells promote function of bone cells, affecting primarily to either  osteoblasts (sclerotic bone metastases), osteoclasts (osteolytic bone metastases), or both (mixed bone metastases) to disturb the homeostatic regulation of bone and release growth factors that in turn promote tumor growth. These changes then lead to increased risk of fractures, bone pain and decreased quality of life.

When considering treatment options for patients with bone metastases, it is essential to understand that the tumor that was once growing in the primary organ changes during the metastatic process and typically becomes resistant to standard-of-care therapies due to influence of the metastatic tumor microenvironment. For this reason, the discovery of new therapies should take into account the metastatic microenvironment that you wish to treat, and this is highlighted in the context of immunotherapies in bone microenvironment in the next paragraph.

Immuno-oncology: Immune cells in bone metastasis

Tumor cells modulate the immunological contexture in the bone metastatic microenvironment, in most cases leading to immunosuppression and low response rate to different therapies. In fact, most bone metastases have typically low immunogenicity compared to the primary tumor, and therefore they may respond poorly to immunotherapies, which should be considered when targeting bone metastasis with immunotherapies. Currently, immune cells such as T cells (CD4+, CD8+ and Tregs), MDSCs, macrophages, neutrophils and NK cells are targeted for treating bone metastases. Some promising results have been gained in preclinical and clinical research, and effects of all these cell types are discussed in the review separately.

Based on the OIO concept, most interesting targets would be shared within these three compartments, and they could potentially eradicate tumor growth and restore the homeostatic regulation of bone turnover.

To conclude, in order to develop novel therapies for bone metastasis, it is important to understand how the local microenvironment contributes to the regulation of metastasis. OIO provides one means to understand this in the bone microenvironment, and it may reveal completely new therapeutic opportunities for the currently incurable bone metastases.

Full text of the review can be found from the following link.

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